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Tanaka T, Takehara K, Usami T, Ishikawa M, Kondo E, Kagabu M, Hirabayashi K, Matsumura N, Sato S, Nishimura M, Arakawa A, Nakamura K, Konno Y, Fujiwara S, Sueoka K, Nakamura H, Koh I, Ito K, Hongo A. Evaluation of platinum-free interval and chemotherapeutic effect of subsequent platinum-containing chemotherapy in patients with recurrent ovarian cancer initially treated with bevacizumab: SGSG018/Intergroup study. Gynecol Oncol Rep 2025; 59:101740. [PMID: 40297564 PMCID: PMC12036064 DOI: 10.1016/j.gore.2025.101740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 03/30/2025] [Accepted: 04/06/2025] [Indexed: 04/30/2025] Open
Abstract
Objective The effect of bevacizumab on platinum sensitivity in recurrent ovarian cancer remains poorly understood. This study examined the association between platinum-free interval (PFI) and sensitivity to subsequent platinum-containing chemotherapy in patients with first relapsed ovarian cancer after bevacizumab chemotherapy. Methods We retrospectively analyzed patients who received platinum-based chemotherapy for platinum-sensitive recurrence between November 2013, and December 2019, and who were initially treated by platinum-based chemotherapy with concurrent and maintenance bevacizumab. The primary endpoint was response rate to subsequent chemotherapy after various periods of PFI. The relevance between response rate and PFI was assessed for each PFI of 6-12, 12-24 and ≧24 months using Cochran-Armitage test. The secondary endpoint was progression-free survival (PFS) defined as time from chemotherapy for first recurrence to subsequent progression and response rate to subsequent chemotherapy for each treatment-free interval since last administration of bevacizumab (Bev-TFI). Results A total of 77 patients were eligible. The median PFI until first recurrence was 12 months (range: 6-43). The response rates of subsequent chemotherapy for patients with PFI of 6-12, ≥12-24, and 24 months were 42 %, 65 %, and 80 %, showing a linear trend (p < 0.05). Median PFS among the three groups was 8 (95 %CI: 6.7-9.2), 11 (95 %CI: 8.4-13.5) and 13 months (95 % CI: 5.4-20.5) (p = 0.107, log-rank test), respectively. By contrast, no linear trend was observed between Bev-TFI and response rate (p = 0.225). Conclusion In patients with first relapse of primary ovarian cancer and bevacizumab beyond progression, the prolonged PFS effect of bevacizumab does not seem to affect sensitivity to subsequent platinum-based chemotherapy.
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Affiliation(s)
- Tamaki Tanaka
- Department of Perinatology and Gynecology, Kagawa University Graduate School of Medicine, Kagawa, Japan
| | - Kazuhiro Takehara
- Department of Gynecologic Oncology, NHO Shikoku Cancer Center, Ehime, Japan
| | - Tomoka Usami
- Department of Obstetrics and Gynecology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Masako Ishikawa
- Department of Obstetrics and Gynecology, Shimane University Faculty of Medicine, Shimane, Japan
| | - Eiji Kondo
- Department of Obstetrics and Gynecology, Mie University Graduate School of Medicine, Mie, Japan
| | - Masahiro Kagabu
- Department of Obstetrics and Gynecology, Iwate Medical University, Iwate, Japan
| | - Kei Hirabayashi
- Department of Obstetrics and Gynecology, JCHO Tokuyama Central Hospital, Yamaguchi, Japan
| | - Noriomi Matsumura
- Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Shinya Sato
- Department of Obstetrics and Gynecology, Faculty of Medicine Tottori University, Tottori, Japan
| | - Masato Nishimura
- Department of Obstetrics and Gynecology, Tokushima Prefectural Central Hospital, Tokushima, Japan
| | - Atsushi Arakawa
- Department of Obstetrics and Gynecology, Nagoya City University West Medical Center, Aichi, Japan
| | - Keiichiro Nakamura
- Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yosuke Konno
- Department of Obstetrics and Gynecology, Hokkaido University Hospital, Hokkaido, Japan
| | - Satoe Fujiwara
- Department of Obstetrics and Gynecology, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Kotaro Sueoka
- Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Hiroko Nakamura
- Department of Obstetrics and Gynecology, NHO Kure Medical Center and Chugoku Cancer Center, Hiroshima, Japan
| | - Iemasa Koh
- Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | - Kimihiko Ito
- Department of Obstetrics and Gynecology, Kansai Rosai Hospital, Hyogo, Japan
| | - Atsushi Hongo
- Department of Obstetrics and Gynecology, Kawasaki Medical School, Okayama, Japan
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Saeed A, Colby S, Oberstein PE, Duda DG, Park R, Agarwal R, Figueroa-Moseley C, Vaidya R, Unger JM, Guthrie KA, Rocha FG, Senthil M, Safyan RA, Wainberg ZA, Iqbal S, Chiorean EG, Philip PA. S2303: phase II/III trial of paclitaxel + ramucirumab ± nivolumab in gastric and esophageal adenocarcinoma (PARAMUNE). Future Oncol 2025; 21:1325-1331. [PMID: 40155326 PMCID: PMC12051544 DOI: 10.1080/14796694.2025.2485020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Accepted: 03/24/2025] [Indexed: 04/01/2025] Open
Abstract
TRIAL REGISTRATION NUMBER NCT06203600.
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Affiliation(s)
- Anwaar Saeed
- Department of Medicine, Division of Hematology & Oncology, UPMC Hillman Cancer Center, Pittsburgh, PL, USA
| | - Sarah Colby
- SWOG Statistical and Data Management Center, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Paul Eliezer Oberstein
- Department of Medicine, Division of Hematology & Oncology, NYU Langone Cancer Center, New York, NY, USA
| | - Dan G. Duda
- Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Boston, MA, USA
| | - Robin Park
- Department of Hematology/Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - Rajiv Agarwal
- Department of Medicine, Division of Hematology & Oncologyy, Vanderbilt Ingram Cancer Center, Nashville, TN, USA
| | | | - Riha Vaidya
- SWOG Statistical and Data Management Center, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Joseph M. Unger
- SWOG Statistical and Data Management Center, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Katherine A. Guthrie
- SWOG Statistical and Data Management Center, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Flavio G. Rocha
- Department of Surgery, Division of Surgical Oncology, Oregon Health & Science University, Portland, OR, USA
| | - Maheswari Senthil
- Department of Surgery, Division of Surgical Oncology, University of California Irvine Cancer Center, Irvine, CA, USA
| | - Rachael A. Safyan
- Department of Medicine, Fred Hutchinson Cancer Center, University of Washington, Seattle, WA, USA
| | - Zev A. Wainberg
- Department of Medicine, Division of Hematology & Oncology, UCLA Johnson Comprehensive Cancer Center, Santa Monica, CA, USA
| | - Syma Iqbal
- Department of Medicine, Division of Hematology & Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA
| | - E. Gabriela Chiorean
- Department of Medicine, Fred Hutchinson Cancer Center, University of Washington, Seattle, WA, USA
| | - Philip A. Philip
- Department of Medicine, Division of Hematology & Oncology, Wayne State University, Detroit, MI, USA
- Henry Ford Cancer Institute, Detroit, MI, USA
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Zhong T, Zhang L, Huang Z, Pang X, Jin C, Liu W, Du J, Yin W, Chen N, Min J, Xia M, Li B. Design of a fragment crystallizable-engineered tetravalent bispecific antibody targeting programmed cell death-1 and vascular endothelial growth factor with cooperative biological effects. iScience 2025; 28:111722. [PMID: 40034861 PMCID: PMC11872405 DOI: 10.1016/j.isci.2024.111722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 05/08/2024] [Accepted: 12/30/2024] [Indexed: 03/05/2025] Open
Abstract
Clinical studies have shown that combination therapy of PD-1 and VEGF antibodies significantly improves clinical benefit over PD-1 antibody alone in certain settings. Ivonescimab, an on-market tetravalent anti-PD-1/VEGF bispecific antibody, was designed to improve efficacy and safety over combo therapy. In this study, the mechanism of action is investigated. In the presence of VEGF, ivonescimab forms soluble complexes with VEGF dimers, leading to the enhanced binding avidity of ivonescimab to PD-1 therefore promoting its increased potency on PD-1/PD-L1-signaling blockade. Likewise, PD-1 binding enhanced ivonescimab binding to VEGF, therefore enhancing VEGF-signaling blockade. Furthermore, ivonescimab treatment demonstrated statistically significant anti-tumor response in vivo. Moreover, ivonescimab contains Fc-silencing mutations abrogating FcγRI/IIIa binding and showed significantly reduced effector function in vitro which is consistent with the better safety profile of ivonescimab in monkeys and humans. Briefly, ivonescimab displays unique cooperative binding and promotes the increased in vitro functional bioactivities with a favorable safety profile.
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Affiliation(s)
- Tingting Zhong
- Research and Development Department, Akeso Biopharma Inc., No.6 Shennong Road, Torch Development Zone, Zhongshan, Guangdong 528400, China
| | - Lingzhi Zhang
- Research and Development Department, Akeso Biopharma Inc., No.6 Shennong Road, Torch Development Zone, Zhongshan, Guangdong 528400, China
| | - Zhaoliang Huang
- Research and Development Department, Akeso Biopharma Inc., No.6 Shennong Road, Torch Development Zone, Zhongshan, Guangdong 528400, China
| | - Xinghua Pang
- Research and Development Department, Akeso Biopharma Inc., No.6 Shennong Road, Torch Development Zone, Zhongshan, Guangdong 528400, China
| | - Chunshan Jin
- Research and Development Department, Akeso Biopharma Inc., No.6 Shennong Road, Torch Development Zone, Zhongshan, Guangdong 528400, China
| | - Wenrong Liu
- Research and Development Department, Akeso Biopharma Inc., No.6 Shennong Road, Torch Development Zone, Zhongshan, Guangdong 528400, China
| | - Juan Du
- Research and Development Department, Akeso Biopharma Inc., No.6 Shennong Road, Torch Development Zone, Zhongshan, Guangdong 528400, China
| | - Wen Yin
- Research and Development Department, Akeso Biopharma Inc., No.6 Shennong Road, Torch Development Zone, Zhongshan, Guangdong 528400, China
| | - Na Chen
- Research and Development Department, Akeso Biopharma Inc., No.6 Shennong Road, Torch Development Zone, Zhongshan, Guangdong 528400, China
| | - Jing Min
- Research and Development Department, Akeso Biopharma Inc., No.6 Shennong Road, Torch Development Zone, Zhongshan, Guangdong 528400, China
| | - Michelle Xia
- President’s Office, Akeso Biopharma Inc., No.6 Shennong Road, Torch Development Zone, Zhongshan, Guangdong 528400, China
| | - Baiyong Li
- Research and Development Department, Akeso Biopharma Inc., No.6 Shennong Road, Torch Development Zone, Zhongshan, Guangdong 528400, China
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Lentz RW, Friedrich TJ, Blatchford PJ, Jordan KR, Pitts TM, Robinson HR, Davis SL, Kim SS, Leal AD, Lee MR, Waring MR, Martin AC, Dominguez AT, Bagby SM, Hartman SJ, Eckhardt SG, Messersmith WA, Lieu CH. A Phase II Study of Potentiation of Pembrolizumab with Binimetinib and Bevacizumab in Refractory Microsatellite-Stable Colorectal Cancer. Clin Cancer Res 2024; 30:3768-3778. [PMID: 38869830 PMCID: PMC11369619 DOI: 10.1158/1078-0432.ccr-24-0090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 04/17/2024] [Accepted: 06/11/2024] [Indexed: 06/14/2024]
Abstract
PURPOSE In this single-institution phase II investigator-initiated study, we assessed the ability of MAPK and VEGF pathway blockade to overcome resistance to immunotherapy in microsatellite-stable metastatic colorectal cancer (MSS mCRC). PATIENTS AND METHODS Patients with MSS, BRAF wild-type mCRC who progressed on ≥2 prior lines of therapy received pembrolizumab, binimetinib, and bevacizumab until disease progression or unacceptable toxicity. After a safety run-in, patients were randomized to a 7-day run-in of binimetinib or simultaneous initiation of all study drugs, to explore whether MEK inhibition may increase tumor immunogenicity. The primary endpoint was objective response rate (ORR) in all patients combined (by Response Evaluation Criteria in Solid Tumors v1.1). RESULTS Fifty patients received study drug treatment; 54% were male with a median age of 55 years (range, 31-79). The primary endpoint, ORR, was 12.0% [95% confidence interval (CI) 4.5%-24.3%], which was not statistically different than the historical control data of 5% (P = 0.038, exceeding prespecified threshold of 0.025). The disease control rate was 70.0% (95% CI, 55.4%-82.1%), the median progression-free survival 5.9 months (95% CI, 4.2-8.7 months), and the median overall survival 9.3 months (95% CI, 6.7-12.2 months). No difference in efficacy was observed between the randomized cohorts. Grade 3 and 4 adverse events were observed in 56% and 8% of patients, respectively; the most common were rash (12%) and increased aspartate aminotransferase (12%). CONCLUSIONS Pembrolizumab, binimetinib, and bevacizumab failed to meet its primary endpoint of higher ORR compared with historical control data, demonstrated a high disease control rate, and demonstrated acceptable tolerability in refractory MSS mCRC.
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Affiliation(s)
- Robert W. Lentz
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Tyler J. Friedrich
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Patrick J. Blatchford
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Kimberly R. Jordan
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado.
| | - Todd M. Pitts
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Hannah R. Robinson
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - S. Lindsey Davis
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Sunnie S. Kim
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Alexis D. Leal
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Mathew R. Lee
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Meredith R.N. Waring
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Anne C. Martin
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Adrian T.A. Dominguez
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Stacey M. Bagby
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Sarah J. Hartman
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - S. Gail Eckhardt
- Department of Oncology, The University of Texas at Austin Dell Medical School, Austin, Texas.
| | - Wells A. Messersmith
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Christopher H. Lieu
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Okano S. Immunotherapy for head and neck cancer: Fundamentals and therapeutic development. Auris Nasus Larynx 2024; 51:684-695. [PMID: 38729034 DOI: 10.1016/j.anl.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 04/03/2024] [Accepted: 05/01/2024] [Indexed: 05/12/2024]
Abstract
Squamous cell carcinoma of the head and neck (SCCHN) has been treated by multidisciplinary therapy consisting of surgery, radiotherapy, and cancer chemotherapy, but the recent advent of immunotherapy has produced significant changes in treatment systems and the results of these therapies. Immunotherapy has greatly improved the outcome of recurrent metastatic SCCHN, and the development of new treatment methods based on immunotherapy is now being applied not only to recurrent metastatic cases but also to locally advanced cases. To understand and practice cancer immunotherapy, it is important to understand the immune environment surrounding cancer, and the changes to which it is subject. Currently, the anti-PD-1 antibody drugs nivolumab and pembrolizumab are the only immunotherapies with proven efficacy in head and neck cancer. However, anti-PD-L1 and anti-CTLA-4 antibody drugs have also been shown to be useful in other types of cancer and are being incorporated into clinical practice. In head and neck cancer, numerous clinical trials have aimed to improve efficacy and safety by combining immunotherapy with other drug therapies and treatment modalities. Combinations of immunotherapy with cancer drugs with different mechanisms of action (cytotoxic agents, molecular-targeted agents, immune checkpoint inhibitors), as well as with radiation therapy and surgery are being investigated, and have the potential to significantly change medical care for these patients. The application of cancer immunotherapy not only to daily clinical practice but also to further therapeutic development requires a clear and complete understanding of the fundamentals of cancer immunotherapy, and knowledge of the numerous clinical studies conducted, both past and present. The results of these trials are numerous, both positive and negative, and a comprehensive understanding of this wide range of completed and ongoing clinical trials is critical to a systematic and comprehensive understanding of their scope and lessons learnt. In this article, after outlining the concepts of ``cancer immune cycle,'' ``cancer immune editing,'' and ``tumor microenvironment'' to provide an understanding of the basics of cancer immunity, we summarize the basics and clinical trial data on representative immune checkpoint inhibitors used in various cancer types, as well as recent therapeutic developments in cancer immunotherapy and the current status of these new treatments.
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Affiliation(s)
- Susumu Okano
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.
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Al-Ostoot FH, Salah S, Khanum SA. An Overview of Cancer Biology, Pathophysiological Development and It's Treatment Modalities: Current Challenges of Cancer anti-Angiogenic Therapy. Cancer Invest 2024; 42:559-604. [PMID: 38874308 DOI: 10.1080/07357907.2024.2361295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 11/22/2021] [Accepted: 05/25/2024] [Indexed: 06/15/2024]
Abstract
A number of conditions and factors can cause the transformation of normal cells in the body into malignant tissue by changing the normal functions of a wide range of regulatory, apoptotic, and signal transduction pathways. Despite the current deficiency in fully understanding the mechanism of cancer action accurately and clearly, numerous genes and proteins that are causally involved in the initiation, progression, and metastasis of cancer have been identified. But due to the lack of space and the abundance of details on this complex topic, we have emphasized here more recent advances in our understanding of the principles implied tumor cell transformation, development, invasion, angiogenesis, and metastasis. Inhibition of angiogenesis is a significant strategy for the treatment of various solid tumors, that essentially depend on cutting or at least limiting the supply of blood to micro-regions of tumors, leading to pan-hypoxia and pan-necrosis inside solid tumor tissues. Researchers have continued to enhance the efficiency of anti-angiogenic drugs over the past two decades, to identify their potential in the drug interaction, and to discover reasonable interpretations for possible resistance to treatment. In this review, we have discussed an overview of cancer history and recent methods use in cancer therapy, focusing on anti-angiogenic inhibitors targeting angiogenesis formation. Further, this review has explained the molecular mechanism of action of these anti-angiogenic inhibitors in various tumor types and their limitations use. In addition, we described the synergistic mechanisms of immunotherapy and anti-angiogenic therapy and summarizes current clinical trials of these combinations. Many phase III trials found that combining immunotherapy and anti-angiogenic therapy improved survival. Therefore, targeting the source supply of cancer cells to grow and spread with new anti-angiogenic agents in combination with different conventional therapy is a novel method to reduce cancer progression. The aim of this paper is to overview the varying concepts of cancer focusing on mechanisms involved in tumor angiogenesis and provide an overview of the recent trends in anti-angiogenic strategies for cancer therapy.
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Affiliation(s)
- Fares Hezam Al-Ostoot
- Department of Chemistry, Yuvaraja's College, University of Mysore, Mysuru, India
- Department of Biochemistry, Faculty of Education & Science, Albaydha University, Al-Baydha, Yemen
| | - Salma Salah
- Faculty of Medicine and Health Sciences, Thamar University, Dhamar, Yemen
| | - Shaukath Ara Khanum
- Department of Chemistry, Yuvaraja's College, University of Mysore, Mysuru, India
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Xu S, Ma K, Lu J, Wei T, Que R. A Patient With Hepatocellular Carcinoma and Lung Metastasis Successfully Underwent Curative Surgery Following the Downstaging Treatment: A Case Report. Cureus 2024; 16:e64621. [PMID: 39149649 PMCID: PMC11325086 DOI: 10.7759/cureus.64621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/14/2024] [Indexed: 08/17/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Hepatic resection constitutes the major curative treatment option, but a significant proportion of patients are not surgical candidates on initial evaluation. Along with the development of novel therapeutic strategies including targeted therapies and immunotherapies, a few HCCs can achieve tumor downstaging and be curatively resected. A 52-year-old man was diagnosed with HCC with portal vein invasion and extensive pulmonary and lymph node metastasis. Transarterial chemoembolization (TACE) in conjunction with donafenib and sintilimab was given. Primary tumors in the liver largely shrank with almost complete elimination of the lung metastases following treatment. The patient subsequently underwent curative surgery for HCC, and the pathological examination revealed complete necrosis of the tumor. Targeted immunotherapy was continued after surgery and no disease progression was found on the latest follow-up. Advanced HCC with distant metastasis might have an excellent response to combination therapy of TACE with tyrosine kinase-targeted inhibitors and PD-1 blocker, and achieve opportunity for curative surgery. This efficacy may be associated with the remodeling of immune microenvironment and angiogenesis. HCC is extremely heterogeneous, and the response to therapeutics varies among patients. There is a lack of useful biomarkers to predict therapeutic efficacy, which needs further studies.
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Affiliation(s)
- Shiguo Xu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, CHN
| | - Ke Ma
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, CHN
| | - Jianfeng Lu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, CHN
| | - Tao Wei
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, CHN
| | - Risheng Que
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, CHN
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Khafaga AF, Gaballa MMS, Karam R, Shoulah SA, Shamma RN, Khalifa NE, Farrag NE, Noreldin AE. Synergistic therapeutic strategies and engineered nanoparticles for anti-vascular endothelial growth factor therapy in cancer. Life Sci 2024; 341:122499. [PMID: 38342375 DOI: 10.1016/j.lfs.2024.122499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 01/29/2024] [Accepted: 02/07/2024] [Indexed: 02/13/2024]
Abstract
Angiogenesis is one of the defining characteristics of cancer. Vascular endothelial growth factor (VEGF) is crucial for the development of angiogenesis. A growing interest in cancer therapy is being caused by the widespread use of antiangiogenic drugs in treating several types of human cancer. However, this therapeutic approach can worsen resistance, invasion, and overall survival. As we proceed, refining combination strategies and addressing the constraint of targeted treatments are paramount. Therefore, major challenges in using novel combinations of antiangiogenic agents with cytotoxic treatments are currently focused on illustrating the potential of synergistic therapeutic strategies, alongside advancements in nanomedicine and gene therapy, present opportunities for more precise interference with angiogenesis pathways and tumor environments. Nanoparticles have the potential to regulate several crucial activities and improve several drug limitations such as lack of selectivity, non-targeted cytotoxicity, insufficient drug delivery at tumor sites, and multi-drug resistance based on their unique features. The goal of this updated review is to illustrate the enormous potential of novel synergistic therapeutic strategies and the targeted nanoparticles as an alternate strategy for t treating a variety of tumors employing antiangiogenic therapy.
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Affiliation(s)
- Asmaa F Khafaga
- Department of Pathology, Faculty of Veterinary Medicine, Alexandria University, Edfina 22758, Egypt.
| | - Mohamed M S Gaballa
- Department of Pathology, Faculty of Veterinary Medicine, Benha University, Toukh 13736, Egypt.
| | - Reham Karam
- Department of Virology, Faculty of Veterinary Medicine, Mansoura University, 35511, Egypt.
| | - Salma A Shoulah
- Department of Animal Medicine (Infectious Diseases), Faculty of Veterinary Medicine, Benha University, Toukh 13736, Egypt.
| | - Rehab N Shamma
- Department of Pharmaceutics & Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
| | - Norhan E Khalifa
- Department of Physiology, Faculty of Veterinary Medicine, Matrouh University, Matrouh 51511, Egypt.
| | - Nehal E Farrag
- Faculty of Veterinary Medicine, Alexandria University, Edfina 22758, Egypt.
| | - Ahmed E Noreldin
- Department of Histology and Cytology, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, Egypt.
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Deng W, Chen J, Deng XY. The occurrence of asthma in an extensive-stage small-cell lung cancer patient after combination therapy with atezolizumab and anlotinib: a case report. Front Immunol 2024; 15:1333850. [PMID: 38487532 PMCID: PMC10937454 DOI: 10.3389/fimmu.2024.1333850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 02/15/2024] [Indexed: 03/17/2024] Open
Abstract
Background Extensive-stage small-cell lung cancer (ES-SCLC) is highly malignant, with early metastasis and high recurrence. Since therapeutic options are limited, ES-SCLC has a characteristically short survival period and extremely poor prognosis. A combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic drugs can achieve promising efficacy and safety in patients with ES-SCLC as a second-line or subsequent treatment, extending survival to some extent. However, the clinical outcomes remain mostly unsatisfactory and are sometimes affected by treatment-related adverse events. Case presentation A 57-year-old woman with ES-SCLC was administered a combination therapy of atezolizumab (a PD-L1 inhibitor) and anlotinib [an oral multi-targeted tyrosine kinase inhibitor (TKI)]. She survived for 22 months, with no disease progression during the 28 courses of therapy. Unexpectedly, despite having no history of asthma, the patient developed asthma while receiving this regimen. This is possibly related to T-cell activation and the tumor immune microenvironment, which induce allergic inflammation after PD-L1 blockade. Conclusions This is the first report of an asthma-negative ES-SCLC patient who developed asthma after receiving atezolizumab plus anlotinib. Although this combination therapy may effectively extend survival in SCLC patients, asthmatic symptoms should be closely monitored.
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Affiliation(s)
- Wang Deng
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Pulmonary Medicine, Medical Research Center for Pulmonary and Critical Care Medicine, Chongqing, China
| | - Juan Chen
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Pulmonary Medicine, Medical Research Center for Pulmonary and Critical Care Medicine, Chongqing, China
| | - Xin-Yu Deng
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Khater I, Nassar A. Targeting EGFR and VEGFR-2 Kinases With Nanoparticles: A Computational Approach for Cancer Therapy Advancement. Cancer Invest 2024; 42:176-185. [PMID: 38486424 DOI: 10.1080/07357907.2024.2328529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 03/05/2024] [Indexed: 03/23/2024]
Abstract
The study investigates titanium and zinc nanoparticles as inhibitors for the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2), pivotal regulators of cell processes. VEGFR-2 activation fuels tumor angiogenesis in cancer cells, sustaining malignant tissue expansion. Molecular docking analysis illustrates the nanoparticles' binding to the active sites, inhibiting the phosphorylation of key proteins in downstream signaling. This inhibition offers a promising therapeutic approach to impede cancer-related signaling, potentially slowing down aberrant protein cascades controlled by EGFR and VEGFR-2. The findings propose a novel avenue for cancer treatment, targeting abnormal growth pathways using titanium and zinc nanoparticles.
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Affiliation(s)
- Ibrahim Khater
- Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Aaya Nassar
- Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt
- Department of Clinical Research and Leadership, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA
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11
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Moussion C, Delamarre L. Antigen cross-presentation by dendritic cells: A critical axis in cancer immunotherapy. Semin Immunol 2024; 71:101848. [PMID: 38035643 DOI: 10.1016/j.smim.2023.101848] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 10/30/2023] [Accepted: 10/30/2023] [Indexed: 12/02/2023]
Abstract
Dendritic cells (DCs) are professional antigen-presenting cells that play a key role in shaping adaptive immunity. DCs have a unique ability to sample their environment, capture and process exogenous antigens into peptides that are then loaded onto major histocompatibility complex class I molecules for presentation to CD8+ T cells. This process, called cross-presentation, is essential for initiating and regulating CD8+ T cell responses against tumors and intracellular pathogens. In this review, we will discuss the role of DCs in cancer immunity, the molecular mechanisms underlying antigen cross-presentation by DCs, the immunosuppressive factors that limit the efficiency of this process in cancer, and approaches to overcome DC dysfunction and therapeutically promote antitumoral immunity.
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Affiliation(s)
| | - Lélia Delamarre
- Cancer Immunology, Genentech, South San Francisco, CA 94080, USA.
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12
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Arnhold J. Inflammation-Associated Cytotoxic Agents in Tumorigenesis. Cancers (Basel) 2023; 16:81. [PMID: 38201509 PMCID: PMC10778456 DOI: 10.3390/cancers16010081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 12/16/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
Chronic inflammatory processes are related to all stages of tumorigenesis. As inflammation is closely associated with the activation and release of different cytotoxic agents, the interplay between cytotoxic agents and antagonizing principles is highlighted in this review to address the question of how tumor cells overcome the enhanced values of cytotoxic agents in tumors. In tumor cells, the enhanced formation of mitochondrial-derived reactive species and elevated values of iron ions and free heme are antagonized by an overexpression of enzymes and proteins, contributing to the antioxidative defense and maintenance of redox homeostasis. Through these mechanisms, tumor cells can even survive additional stress caused by radio- and chemotherapy. Through the secretion of active agents from tumor cells, immune cells are suppressed in the tumor microenvironment and an enhanced formation of extracellular matrix components is induced. Different oxidant- and protease-based cytotoxic agents are involved in tumor-mediated immunosuppression, tumor growth, tumor cell invasion, and metastasis. Considering the special metabolic conditions in tumors, the main focus here was directed on the disturbed balance between the cytotoxic agents and protective mechanisms in late-stage tumors. This knowledge is mandatory for the implementation of novel anti-cancerous therapeutic approaches.
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Affiliation(s)
- Jürgen Arnhold
- Institute of Medical Physics and Biophysics, Medical Faculty, Leipzig University, Härtelstr. 16-18, 04107 Leipzig, Germany
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13
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Olivera I, Luri-Rey C, Teijeira A, Eguren-Santamaria I, Gomis G, Palencia B, Berraondo P, Melero I. Facts and Hopes on Neutralization of Protumor Inflammatory Mediators in Cancer Immunotherapy. Clin Cancer Res 2023; 29:4711-4727. [PMID: 37522874 DOI: 10.1158/1078-0432.ccr-22-3653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/26/2023] [Accepted: 07/14/2023] [Indexed: 08/01/2023]
Abstract
In cancer pathogenesis, soluble mediators are responsible for a type of inflammation that favors the progression of tumors. The mechanisms chiefly involve changes in the cellular composition of the tumor tissue stroma and in the functional modulation of myeloid and lymphoid leukocytes. Active immunosuppression, proangiogenesis, changes in leukocyte traffic, extracellular matrix remodeling, and alterations in tumor-antigen presentation are the main mechanisms linked to the inflammation that fosters tumor growth and metastasis. Soluble inflammatory mediators and their receptors are amenable to various types of inhibitors that can be combined with other immunotherapy approaches. The main proinflammatory targets which can be interfered with at present and which are under preclinical and clinical development are IL1β, IL6, the CXCR1/2 chemokine axis, TNFα, VEGF, leukemia inhibitory factor, CCL2, IL35, and prostaglandins. In many instances, the corresponding neutralizing agents are already clinically available and can be repurposed as a result of their use in other areas of medicine such as autoimmune diseases and chronic inflammatory conditions.
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Affiliation(s)
- Irene Olivera
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Carlos Luri-Rey
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Alvaro Teijeira
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Iñaki Eguren-Santamaria
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Gabriel Gomis
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Belen Palencia
- Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, Pamplona, Spain
| | - Pedro Berraondo
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Ignacio Melero
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
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14
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Kim AE, Lou KW, Giobbie-Hurder A, Chang K, Gidwani M, Hoebel K, Patel JB, Cleveland MC, Singh P, Bridge CP, Ahmed SR, Bearce BA, Liu W, Fuster-Garcia E, Lee EQ, Lin NU, Overmoyer B, Wen PY, Nayak L, Cohen JV, Dietrich J, Eichler A, Heist R, Krop I, Lawrence D, Ligibel J, Tolaney S, Mayer E, Winer E, Perrino CM, Summers EJ, Mahar M, Oh K, Shih HA, Cahill DP, Rosen BR, Yen YF, Kalpathy-Cramer J, Martinez-Lage M, Sullivan RJ, Brastianos PK, Emblem KE, Gerstner ER. Structural and functional vascular dysfunction within brain metastases is linked to pembrolizumab inefficacy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.25.554868. [PMID: 37693537 PMCID: PMC10491098 DOI: 10.1101/2023.08.25.554868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
Structurally and functionally aberrant vasculature is a hallmark of tumor angiogenesis and treatment resistance. Given the synergistic link between aberrant tumor vasculature and immunosuppression, we analyzed perfusion MRI for 44 patients with brain metastases (BM) undergoing treatment with pembrolizumab. To date, vascular-immune communication, or the relationship between immune checkpoint inhibitor (ICI) efficacy and vascular architecture, has not been well-characterized in human imaging studies. We found that ICI-responsive BM possessed a structurally balanced vascular makeup, which was linked to improved vascular efficiency and an immune-stimulatory microenvironment. In contrast, ICI-resistant BM were characterized by a lack of immune cell infiltration and a highly aberrant vasculature dominated by large-caliber vessels. Peri-tumor region analysis revealed early functional changes predictive of ICI resistance before radiographic evidence on conventional MRI. This study was one of the largest functional imaging studies for BM and establishes a foundation for functional studies that illuminate the mechanisms linking patterns of vascular architecture with immunosuppression, as targeting these aspects of cancer biology may serve as the basis for future combination treatments.
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15
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Mooradian MJ, Sullivan RJ. Immunotherapy in Melanoma: Recent Advancements and Future Directions. Cancers (Basel) 2023; 15:4176. [PMID: 37627204 PMCID: PMC10452647 DOI: 10.3390/cancers15164176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/15/2023] [Accepted: 08/17/2023] [Indexed: 08/27/2023] Open
Abstract
Immune checkpoint inhibition has fundamentally altered the treatment paradigm of resectable and unresectable melanoma, resulting in dramatic improvements in patient outcomes. With these advances, the five-year overall survival in patients with newly diagnosed unresectable disease has eclipsed 50%. Ongoing research is focused on improving outcomes further, with a considerable emphasis on preventing de novo and acquired resistance and personalizing therapeutic options. Here, we review the ongoing advancements in the treatment of malignant melanoma, focusing on novel combination strategies that aim to build upon the successes of the last decade.
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16
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Tran TT, Caulfield J, Zhang L, Schoenfeld D, Djureinovic D, Chiang VL, Oria V, Weiss SA, Olino K, Jilaveanu LB, Kluger HM. Lenvatinib or anti-VEGF in combination with anti-PD-1 differentially augments antitumor activity in melanoma. JCI Insight 2023; 8:e157347. [PMID: 36821392 PMCID: PMC10132152 DOI: 10.1172/jci.insight.157347] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 02/22/2023] [Indexed: 02/24/2023] Open
Abstract
Targeting tumor-associated blood vessels to increase immune infiltration may enhance treatment effectiveness, yet limited data exist regarding anti-angiogenesis effects on the tumor microenvironment (TME). We hypothesized that dual targeting of angiogenesis with immune checkpoints would improve both intracranial and extracranial disease. We used subcutaneous and left ventricle melanoma models to evaluate anti-PD-1/anti-VEGF and anti-PD-1/lenvatinib (pan-VEGFR inhibitor) combinations. Cytokine/chemokine profiling and flow cytometry were performed to assess signaling and immune-infiltrating populations. An in vitro blood-brain barrier (BBB) model was utilized to study intracranial treatment effects on endothelial integrity and leukocyte transmigration. Anti-PD-1 with either anti-VEGF or lenvatinib improved survival and decreased tumor growth in systemic melanoma murine models; treatment increased Th1 cytokine/chemokine signaling. Lenvatinib decreased tumor-associated macrophages but increased plasmacytoid DCs early in treatment; this effect was not evident with anti-VEGF. Both lenvatinib and anti-VEGF resulted in decreased intratumoral blood vessels. Although anti-VEGF promoted endothelial stabilization in an in vitro BBB model, while lenvatinib did not, both regimens enabled leukocyte transmigration. The combined targeting of PD-1 and VEGF or its receptors promotes enhanced melanoma antitumor activity, yet their effects on the TME are quite different. These studies provide insights into dual anti-PD-1 and anti-angiogenesis combinations.
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Affiliation(s)
- Thuy T. Tran
- Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut, USA
| | - Jasmine Caulfield
- Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut, USA
| | - Lin Zhang
- Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut, USA
| | - David Schoenfeld
- Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut, USA
| | - Dijana Djureinovic
- Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut, USA
| | - Veronica L. Chiang
- Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut, USA
- Yale School of Medicine, Department of Neurosurgery, New Haven, Connecticut, USA
| | - Victor Oria
- Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut, USA
| | - Sarah A. Weiss
- Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut, USA
| | - Kelly Olino
- Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut, USA
- Yale School of Medicine, Department of Surgery, New Haven, Connecticut, USA
| | - Lucia B. Jilaveanu
- Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut, USA
| | - Harriet M. Kluger
- Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut, USA
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17
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Neth BJ, Webb MJ, Parney IF, Sener UT. The Current Status, Challenges, and Future Potential of Therapeutic Vaccination in Glioblastoma. Pharmaceutics 2023; 15:pharmaceutics15041134. [PMID: 37111620 PMCID: PMC10141140 DOI: 10.3390/pharmaceutics15041134] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/29/2023] [Accepted: 03/30/2023] [Indexed: 04/29/2023] Open
Abstract
Glioblastoma (GBM) is the most common malignant primary brain tumor and confers a dismal prognosis. With only two FDA-approved therapeutics showing modest survival gains since 2005, there is a great need for the development of other disease-targeted therapies. Due, in part, to the profound immunosuppressive microenvironment seen in GBMs, there has been a broad interest in immunotherapy. In both GBMs and other cancers, therapeutic vaccines have generally yielded limited efficacy, despite their theoretical basis. However, recent results from the DCVax-L trial provide some promise for vaccine therapy in GBMs. There is also the potential that future combination therapies with vaccines and adjuvant immunomodulating agents may greatly enhance antitumor immune responses. Clinicians must remain open to novel therapeutic strategies, such as vaccinations, and carefully await the results of ongoing and future trials. In this review of GBM management, the promise and challenges of immunotherapy with a focus on therapeutic vaccinations are discussed. Additionally, adjuvant therapies, logistical considerations, and future directions are discussed.
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Affiliation(s)
- Bryan J Neth
- Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
| | - Mason J Webb
- Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Ian F Parney
- Department of Neurosurgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Ugur T Sener
- Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
- Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA
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18
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Liu Z, Yu M, Zhao F, Zhu C. Anlotinib combined with Sintilimab is win-win cooperation for primary squamous cell carcinoma of the thyroid: A case report and literature review. Front Oncol 2023; 13:976415. [PMID: 37007162 PMCID: PMC10062477 DOI: 10.3389/fonc.2023.976415] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
BackgroundPrimary squamous cell carcinoma of the thyroid (PSCCT) is a rare malignant tumor. The incidence rate of PSCCT is less than 1%. However, the diagnosis and treatment of PSCCT are limited. Surgical resection is considered to be one of the few effective intervention methods. In this article, we reported a case of taking tyrosine kinase inhibitors (TKIs) combined with immune checkpoint inhibitors (ICIs) for PSCCT.Case summaryAn 80-year-old male was admitted to our hospital with dyspnea, cough, wheezing, and hoarseness for a giant thyroid mass. He underwent bronchoscopy and tracheal stent implantation to alleviate the respiratory obstruction. Then he accepted right partial thyroid and right lymph node biopsy. Postoperative pathology revealed squamous cell carcinoma. Subsequently, he underwent an endoscopy to exclude upper gastrointestinal squamous cell carcinoma. Finally, he was diagnosed with PSCCT. The patient was tentatively treated with a combination of Anlotinib and Sintilimab. After two courses, the tumor volume significantly reduced in MRI images and shrank further after five courses of combined treatment. Unfortunately, the patient died of fulminant liver failure and autoimmune liver disease after 5-month-treatment.ConclusionTKIs combined with ICIs may be an effective and novel way for PSCCT treatment, but immune-related complications, especially liver damage, should be cared.
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Affiliation(s)
| | | | - Feng Zhao
- *Correspondence: Chenfang Zhu, ; Feng Zhao,
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19
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Lahiri A, Maji A, Potdar PD, Singh N, Parikh P, Bisht B, Mukherjee A, Paul MK. Lung cancer immunotherapy: progress, pitfalls, and promises. Mol Cancer 2023; 22:40. [PMID: 36810079 PMCID: PMC9942077 DOI: 10.1186/s12943-023-01740-y] [Citation(s) in RCA: 459] [Impact Index Per Article: 229.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 08/22/2022] [Indexed: 02/23/2023] Open
Abstract
Lung cancer is the primary cause of mortality in the United States and around the globe. Therapeutic options for lung cancer treatment include surgery, radiation therapy, chemotherapy, and targeted drug therapy. Medical management is often associated with the development of treatment resistance leading to relapse. Immunotherapy is profoundly altering the approach to cancer treatment owing to its tolerable safety profile, sustained therapeutic response due to immunological memory generation, and effectiveness across a broad patient population. Different tumor-specific vaccination strategies are gaining ground in the treatment of lung cancer. Recent advances in adoptive cell therapy (CAR T, TCR, TIL), the associated clinical trials on lung cancer, and associated hurdles are discussed in this review. Recent trials on lung cancer patients (without a targetable oncogenic driver alteration) reveal significant and sustained responses when treated with programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint blockade immunotherapies. Accumulating evidence indicates that a loss of effective anti-tumor immunity is associated with lung tumor evolution. Therapeutic cancer vaccines combined with immune checkpoint inhibitors (ICI) can achieve better therapeutic effects. To this end, the present article encompasses a detailed overview of the recent developments in the immunotherapeutic landscape in targeting small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Additionally, the review also explores the implication of nanomedicine in lung cancer immunotherapy as well as the combinatorial application of traditional therapy along with immunotherapy regimens. Finally, ongoing clinical trials, significant obstacles, and the future outlook of this treatment strategy are also highlighted to boost further research in the field.
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Affiliation(s)
- Aritraa Lahiri
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, Nadia, West Bengal, 741246, India
| | - Avik Maji
- Department of Radiation Oncology, N. R. S. Medical College & Hospital, 138 A.J.C. Bose Road, Kolkata, 700014, India
| | - Pravin D Potdar
- Department of Molecular Medicine and Stem Cell Biology, Jaslok Hospital and Research Centre, Mumbai, 400026, India
| | - Navneet Singh
- Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Purvish Parikh
- Department of Clinical Hematology, Mahatma Gandhi Medical College and Hospital, Jaipur, Rajasthan, 302022, India
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, 400012, India
| | - Bharti Bisht
- Division of Thoracic Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Anubhab Mukherjee
- Esperer Onco Nutrition Pvt Ltd, 4BA, 4Th Floor, B Wing, Gundecha Onclave, Khairani Road, Sakinaka, Andheri East, Mumbai, Maharashtra, 400072, India.
| | - Manash K Paul
- Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
- Department of Microbiology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
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20
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Patel SA, Nilsson MB, Le X, Cascone T, Jain RK, Heymach JV. Molecular Mechanisms and Future Implications of VEGF/VEGFR in Cancer Therapy. Clin Cancer Res 2023; 29:30-39. [PMID: 35969170 DOI: 10.1158/1078-0432.ccr-22-1366] [Citation(s) in RCA: 176] [Impact Index Per Article: 88.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 06/28/2022] [Accepted: 08/03/2022] [Indexed: 02/06/2023]
Abstract
Angiogenesis, the sprouting of new blood vessels from existing vessels, is one of six known mechanisms employed by solid tumors to recruit blood vessels necessary for their initiation, growth, and metastatic spread. The vascular network within the tumor facilitates the transport of nutrients, oxygen, and immune cells and is regulated by pro- and anti-angiogenic factors. Nearly four decades ago, VEGF was identified as a critical factor promoting vascular permeability and angiogenesis, followed by identification of VEGF family ligands and their receptors (VEGFR). Since then, over a dozen drugs targeting the VEGF/VEGFR pathway have been approved for approximately 20 solid tumor types, usually in combination with other therapies. Initially designed to starve tumors, these agents transiently "normalize" tumor vessels in preclinical and clinical studies, and in the clinic, increased tumor blood perfusion or oxygenation in response to these agents is associated with improved outcomes. Nevertheless, the survival benefit has been modest in most tumor types, and there are currently no biomarkers in routine clinical use for identifying which patients are most likely to benefit from treatment. However, the ability of these agents to reprogram the immunosuppressive tumor microenvironment into an immunostimulatory milieu has rekindled interest and has led to the FDA approval of seven different combinations of VEGF/VEGFR pathway inhibitors with immune checkpoint blockers for many solid tumors in the past 3 years. In this review, we discuss our understanding of the mechanisms of response and resistance to blocking VEGF/VEGFR, and potential strategies to develop more effective therapeutic approaches.
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Affiliation(s)
- Sonia A Patel
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Monique B Nilsson
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xiuning Le
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Tina Cascone
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Rakesh K Jain
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - John V Heymach
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
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21
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Barnestein R, Galland L, Kalfeist L, Ghiringhelli F, Ladoire S, Limagne E. Immunosuppressive tumor microenvironment modulation by chemotherapies and targeted therapies to enhance immunotherapy effectiveness. Oncoimmunology 2022; 11:2120676. [PMID: 36117524 PMCID: PMC9481153 DOI: 10.1080/2162402x.2022.2120676] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
With the rapid clinical development of immune checkpoint inhibitors (ICIs), the standard of care in cancer management has evolved rapidly. However, immunotherapy is not currently beneficial for all patients. In addition to intrinsic tumor factors, other etiologies of resistance to ICIs arise from the complex interplay between cancer and its microenvironment. Recognition of the essential role of the tumor microenvironment (TME) in cancer progression has led to a shift from a tumor-cell-centered view of cancer development, to the concept of a complex tumor ecosystem that supports tumor growth and metastatic dissemination. The expansion of immunosuppressive cells represents a cardinal strategy deployed by tumor cells to escape detection and elimination by the immune system. Regulatory T lymphocytes (Treg), myeloid-derived suppressor cells (MDSCs), and type-2 tumor-associated macrophages (TAM2) are major components of these inhibitory cellular networks, with the ability to suppress innate and adaptive anticancer immunity. They therefore represent major impediments to anticancer therapies, particularly immune-based interventions. Recent work has provided evidence that, beyond their direct cytotoxic effects on cancer cells, several conventional chemotherapeutic (CT) drugs and agents used in targeted therapies (TT) can promote the elimination or inactivation of suppressive immune cells, resulting in enhanced antitumor immunity. In this review, we will analyze findings pertaining to this concept, discuss the possible molecular bases underlying the selective targeting of these immunosuppressive cells by antineoplastic agents (CT and/or TT), and consider current challenges and future prospects related to the integration of these molecules into more efficient anticancer strategies, in the era of immunotherapy.
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Affiliation(s)
- Robby Barnestein
- University of Burgundy, Dijon, France
- Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center, Dijon, France
| | - Loïck Galland
- University of Burgundy, Dijon, France
- Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center, Dijon, France
- Department of Medical Oncology, Georges François Leclerc Center, Dijon, France
| | - Laura Kalfeist
- University of Burgundy, Dijon, France
- Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center, Dijon, France
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France
- Genomic and Immunotherapy Medical Institute, Dijon University Hospital, Dijon, France
| | - François Ghiringhelli
- University of Burgundy, Dijon, France
- Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center, Dijon, France
- Department of Medical Oncology, Georges François Leclerc Center, Dijon, France
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France
- Genomic and Immunotherapy Medical Institute, Dijon University Hospital, Dijon, France
| | - Sylvain Ladoire
- University of Burgundy, Dijon, France
- Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center, Dijon, France
- Department of Medical Oncology, Georges François Leclerc Center, Dijon, France
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France
- Genomic and Immunotherapy Medical Institute, Dijon University Hospital, Dijon, France
| | - Emeric Limagne
- University of Burgundy, Dijon, France
- Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center, Dijon, France
- Department of Medical Oncology, Georges François Leclerc Center, Dijon, France
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France
- Genomic and Immunotherapy Medical Institute, Dijon University Hospital, Dijon, France
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22
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Ke CH, Chiu YH, Huang KC, Lin CS. Exposure of Immunogenic Tumor Antigens in Surrendered Immunity and the Significance of Autologous Tumor Cell-Based Vaccination in Precision Medicine. Int J Mol Sci 2022; 24:ijms24010147. [PMID: 36613591 PMCID: PMC9820296 DOI: 10.3390/ijms24010147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/05/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
The mechanisms by which immune systems identify and destroy tumors, known as immunosurveillance, have been discussed for decades. However, several factors that lead to tumor persistence and escape from the attack of immune cells in a normal immune system have been found. In the process known as immunoediting, tumors decrease their immunogenicity and evade immunosurveillance. Furthermore, tumors exploit factors such as regulatory T cells, myeloid-derived suppressive cells, and inhibitory cytokines that avoid cytotoxic T cell (CTL) recognition. Current immunotherapies targeting tumors and their surroundings have been proposed. One such immunotherapy is autologous cancer vaccines (ACVs), which are characterized by enriched tumor antigens that can escalate specific CTL responses. Unfortunately, ACVs usually fail to activate desirable therapeutic effects, and the low immunogenicity of ACVs still needs to be elucidated. This difficulty highlights the significance of immunogenic antigens in antitumor therapies. Previous studies have shown that defective host immunity triggers tumor development by reprogramming tumor antigenic expressions. This phenomenon sheds new light on ACVs and provides a potential cue to improve the effectiveness of ACVs. Furthermore, synergistically with the ACV treatment, combinational therapy, which can reverse the suppressive tumor microenvironments, has also been widely proposed. Thus, in this review, we focus on tumor immunogenicity sculpted by the immune systems and discuss the significance and application of restructuring tumor antigens in precision medicine.
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Affiliation(s)
- Chiao-Hsu Ke
- Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan
| | - Yi-Han Chiu
- Department of Microbiology, Soochow University, Taipei 111002, Taiwan
| | - Kuo-Chin Huang
- Holistic Education Center, Mackay Medical College, New Taipei City 25245, Taiwan
| | - Chen-Si Lin
- Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan
- Correspondence: ; Tel.: +886-233-661-286
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The Effect of Pleural Effusion on Prognosis in Patients with Non-Small Cell Lung Cancer Undergoing Immunochemotherapy: A Retrospective Observational Study. Cancers (Basel) 2022; 14:cancers14246184. [PMID: 36551668 PMCID: PMC9776517 DOI: 10.3390/cancers14246184] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/07/2022] [Accepted: 12/12/2022] [Indexed: 12/16/2022] Open
Abstract
Objectives: Combined immune checkpoint inhibitor (ICI) therapy and chemotherapy has become the standard treatment for advanced non-small-cell lung cancer (NSCLC). Pleural effusion (PE) is associated with poor outcomes among patients with NSCLC undergoing chemotherapy. However, minimal data exists on PE for patients undergoing combined ICI and chemotherapy. Therefore, we investigated how PE affects survival outcomes in patients with NSCLC undergoing this combined therapy. Methods: We identified patients with advanced NSCLC undergoing chemotherapy and ICI therapy from the Okayama Lung Cancer Study Group−Immune Chemotherapy Database (OLCSG−ICD) between December 2018 and December 2020; the OLCSG−ICD includes the clinical data of patients with advanced NSCLC from 13 institutions. Then, we analyzed the treatment outcomes based on the presence of PE. Results: We identified 478 patients who underwent combined ICI therapy and chemotherapy; 357 patients did not have PE, and 121 patients did have PE. Patients with PE had significantly shorter progression-free survival (PFS) and overall survival (OS) than those without PE (median PFS: 6.2 months versus 9.1 months; p < 0.001; median OS: 16.4 months versus 27.7 months; p < 0.001). The negative effect of PE differed based on the patient’s programmed cell death-ligand 1 (PD-L1) expression status; with the effect being more evident in patients with high PD-L1 expression. In addition, PFS and OS did not differ between patients who did and did not undergo bevacizumab treatment; thus, bevacizumab-containing regimens did not improve the survival outcomes for patients with PE. Conclusion: PE is associated with poor outcomes among patients with NSCLC undergoing combined ICI therapy and chemotherapy.
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Zhong FM, Yao FY, Liu J, Zhang HB, Zhang J, Zhang N, Lin J, Li SQ, Li MY, Jiang JY, Cheng Y, Xu S, Wen W, Yang YL, Zhang XR, Cheng XX, Huang B, Wang XZ. Ferroptosis-related molecular patterns reveal immune escape, inflammatory development and lipid metabolism characteristics of the tumor microenvironment in acute myeloid leukemia. Front Oncol 2022; 12:888570. [PMID: 36518303 PMCID: PMC9742468 DOI: 10.3389/fonc.2022.888570] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 11/08/2022] [Indexed: 08/16/2023] Open
Abstract
BACKGROUND An increasing number of studies have revealed the influencing factors of ferroptosis. The influence of immune cell infiltration, inflammation development and lipid metabolism in the tumor microenvironment (TME) on the ferroptosis of tumor cells requires further research and discussion. METHODS We explored the relationship between ferroptosis-related genes and acute myeloid leukemia (AML) from the perspective of large sample analysis and multiomics, used multiple groups to identify and verify ferroptosis-related molecular patterns, and analyzed the sensitivity to ferroptosis and the state of immune escape between different molecular pattern groups. The single-sample gene set enrichment analysis (ssGSEA) algorithm was used to quantify the phenotypes of ferroptosis-related molecular patterns in individual patients. HL-60 and THP-1 cells were treated with ferroptosis inducer RSL3 to verify the therapeutic value of targeted inhibition of GPX4. RESULTS Three ferroptosis-related molecular patterns and progressively worsening phenotypes including immune activation, immune exclusion and immunosuppression were found with the two different sequencing approaches. The FSscore we constructed can quantify the development of ferroptosis-related phenotypes in individual patients. The higher the FSscore is, the worse the patient's prognosis. The FSscore is also highly positively correlated with pathological conditions such as inflammation development, immune escape, lipid metabolism, immunotherapy resistance, and chemotherapy resistance and is negatively correlated with tumor mutation burden. Moreover, RSL3 can induce ferroptosis of AML cells by reducing the protein level of GPX4. CONCLUSIONS This study revealed the characteristics of immunity, inflammation, and lipid metabolism in the TME of different AML patients and differences in the sensitivity of tumor cells to ferroptosis. The FSscore can be used as a biomarker to provide a reference for the clinical evaluation of the pathological characteristics of AML patients and the design of personalized treatment plans. And GPX4 is a potential target for AML treatment.
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Affiliation(s)
- Fang-Min Zhong
- Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- School of Public Health, Nanchang University, Nanchang, Jiangxi, China
| | - Fang-Yi Yao
- Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jing Liu
- Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Hai-Bin Zhang
- Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jing Zhang
- Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Nan Zhang
- Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jin Lin
- Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Shu-Qi Li
- Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Mei-Yong Li
- Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jun-Yao Jiang
- Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Ying Cheng
- Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- School of Public Health, Nanchang University, Nanchang, Jiangxi, China
| | - Shuai Xu
- Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- School of Public Health, Nanchang University, Nanchang, Jiangxi, China
| | - Wen Wen
- Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- School of Public Health, Nanchang University, Nanchang, Jiangxi, China
| | - Yu-Lin Yang
- Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- School of Public Health, Nanchang University, Nanchang, Jiangxi, China
| | - Xue-Ru Zhang
- Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- School of Public Health, Nanchang University, Nanchang, Jiangxi, China
| | - Xue-Xin Cheng
- Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Bo Huang
- Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xiao-Zhong Wang
- Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- School of Public Health, Nanchang University, Nanchang, Jiangxi, China
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25
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Yang Y, Cao Y. The impact of VEGF on cancer metastasis and systemic disease. Semin Cancer Biol 2022; 86:251-261. [PMID: 35307547 DOI: 10.1016/j.semcancer.2022.03.011] [Citation(s) in RCA: 135] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 03/08/2022] [Accepted: 03/15/2022] [Indexed: 01/27/2023]
Abstract
Metastasis is the leading cause of cancer-associated mortality and the underlying mechanisms of cancer metastasis remain elusive. Both blood and lymphatic vasculatures are essential structures for mediating distal metastasis. The vasculature plays multiple functions, including accelerating tumor growth, sustaining the tumor microenvironment, supplying growth and invasive signals, promoting metastasis, and causing cancer-associated systemic disease. VEGF is one of the key angiogenic factors in tumors and participates in the initial stage of tumor development, progression and metastasis. Consequently, VEGF and its receptor-mediated signaling pathways have become one of the most important therapeutic targets for treating various cancers. Today, anti-VEGF-based antiangiogenic drugs (AADs) are widely used in the clinic for treating different types of cancer in human patients. Despite nearly 20-year clinical experience with AADs, the impact of these drugs on cancer metastasis and systemic disease remains largely unknown. In this review article, we focus our discussion on tumor VEGF in cancer metastasis and systemic disease and mechanisms underlying AADs in clinical benefits.
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Affiliation(s)
- Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - Yihai Cao
- Department of Microbiology, Tumor and Cell Biology, Biomedicum, Karolinska Institute, 171 77 Stockholm, Sweden.
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26
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Nagasaki J, Ishino T, Togashi Y. Mechanisms of resistance to immune checkpoint inhibitors. Cancer Sci 2022; 113:3303-3312. [PMID: 35848888 PMCID: PMC9530865 DOI: 10.1111/cas.15497] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/03/2022] [Accepted: 07/11/2022] [Indexed: 11/28/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) are effective for various types of cancer, and their application has led to paradigm shifts in cancer treatment. While many patients can obtain clinical benefits from ICI treatment, a large number of patients are primarily resistant to such treatment or acquire resistance after an initial response. Thus, elucidating the resistance mechanisms is warranted to improve the clinical outcomes of ICI treatment. ICIs exert their antitumor effects by activating T cells in the tumor microenvironment. There are various resistance mechanisms, such as insufficient antigen recognition by T cells, impaired T-cell migration and/or infiltration, and reduced T-cell cytotoxicity, most of which are related to the T-cell activation process. Thus, we classify them into three main mechanisms: resistance mechanisms related to antigen recognition, T-cell migration and/or infiltration, and effector functions of T cells. In this review, we summarize these mechanisms of resistance to ICIs related to the T-cell activation process and progress in the development of novel therapies that can overcome resistance.
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Affiliation(s)
- Joji Nagasaki
- Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical SciencesOkayama UniversityOkayamaJapan
- Department of Hematology, Graduate School of MedicineOsaka Metropolitan UniversityOsakaJapan
| | - Takamasa Ishino
- Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical SciencesOkayama UniversityOkayamaJapan
- Department of Gastroenterology, Graduate School of MedicineChiba UniversityChibaJapan
| | - Yosuke Togashi
- Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical SciencesOkayama UniversityOkayamaJapan
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27
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Guo Q, Liu L, Chen Z, Fan Y, Zhou Y, Yuan Z, Zhang W. Current treatments for non-small cell lung cancer. Front Oncol 2022; 12:945102. [PMID: 36033435 PMCID: PMC9403713 DOI: 10.3389/fonc.2022.945102] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/06/2022] [Indexed: 12/12/2022] Open
Abstract
Despite improved methods of diagnosis and the development of different treatments, mortality from lung cancer remains surprisingly high. Non-small cell lung cancer (NSCLC) accounts for the large majority of lung cancer cases. Therefore, it is important to review current methods of diagnosis and treatments of NSCLC in the clinic and preclinic. In this review, we describe, as a guide for clinicians, current diagnostic methods and therapies (such as chemotherapy, chemoradiotherapy, targeted therapy, antiangiogenic therapy, immunotherapy, and combination therapy) for NSCLC.
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Affiliation(s)
- Qianqian Guo
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou University, Zhengzhou, China
| | - Liwei Liu
- Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zelong Chen
- Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Artificial Intelligence and IoT Smart Medical Engineering Research Center of Henan Province, Zhengzhou, China
| | - Yannan Fan
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou University, Zhengzhou, China
| | - Yang Zhou
- Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, China
| | - Ziqiao Yuan
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, China
- *Correspondence: Wenzhou Zhang, ; Ziqiao Yuan,
| | - Wenzhou Zhang
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou University, Zhengzhou, China
- *Correspondence: Wenzhou Zhang, ; Ziqiao Yuan,
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28
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Li H, Deng C, Tan Y, Dong J, Zhao Y, Wang X, Yang X, Luo J, Gao H, Huang Y, Zhang ZR, Gong T. Chondroitin sulfate-based prodrug nanoparticles enhance photodynamic immunotherapy via Golgi apparatus targeting. Acta Biomater 2022; 146:357-369. [PMID: 35577045 DOI: 10.1016/j.actbio.2022.05.014] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 04/28/2022] [Accepted: 05/09/2022] [Indexed: 01/02/2023]
Abstract
Photodynamic therapy (PDT) is an emerging therapeutic approach that can inhibit tumor growth by destroying local tumors and activating systemic antitumor immune responses. However, PDT can be ineffective because of photosensitizer aggregation, tumor-induced dendritic cells (DCS) dysfunction and PDT-mediated immunosuppression. Therefore, we designed chondroitin sulfate-based prodrug nanoparticles for the co-delivery of the photosensitizer chlorin e6 (Ce6) and retinoic acid (RA), which can reduce PDT-mediated immunosuppression by disrupting the Golgi apparatus and blocking the production of immunosuppressive cytokines. Moreover, CpG oligodeoxynucleotide was combined as immunoadjuvant to promote the maturation of DCs. As expected, the strategy of Golgi apparatus targeting immunotherapy combined PDT was confirmed to relieve PDT-induced immunosuppression, showed excellent PDT antitumor efficacy in B16F10-subcutaneous bearing mice model. Thus, our finding offers a promising approach for photodynamic immunotherapy of advanced cancers. STATEMENT OF SIGNIFICANCE: Golgi apparatus has been shown to be a potential target of immunosuppression for producing several immunosuppressive cytokines. In this work, a Golgi apparatus-targeted prodrug nanoparticle was developed to enhance the immune response in photodynamic immunotherapy. The nanoparticle can target and disrupt the Golgi apparatus in tumor cells, which reduced PDT-mediated immunosuppression by blocking the production of immunosuppressive cytokines. This work provides an effective strategy of PDT in combination with the Golgi apparatus-targeted nanovesicle for enhanced cancer therapy.
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Affiliation(s)
- Haohuan Li
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, China; Department of Pharmacy, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Caifeng Deng
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, China; Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Yulu Tan
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, China
| | - Jianxia Dong
- Department of Clinical Pharmacy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Yuanhao Zhao
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, China
| | - Xiaorong Wang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, China
| | - Xingyue Yang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, China
| | - Jingwen Luo
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Key Laboratory of Industrial Biotechnology and Hubei Collaborative Innovation Center for Green Transformation of Bio-resources, School of Life Sciences, Hubei University, Wuhan 430062, China
| | - Huile Gao
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, China
| | - Yuan Huang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, China
| | - Zhi-Rong Zhang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, China
| | - Tao Gong
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, China.
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Dimitriou F, Hauschild A, Mehnert JM, Long GV. Double Trouble: Immunotherapy Doublets in Melanoma-Approved and Novel Combinations to Optimize Treatment in Advanced Melanoma. Am Soc Clin Oncol Educ Book 2022; 42:1-22. [PMID: 35658500 DOI: 10.1200/edbk_351123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Immune checkpoint inhibitors, particularly anti-PD-1-based immune checkpoint inhibitors, have dramatically improved outcomes for patients with advanced melanoma and are currently deemed a standard of care. Ipilimumab/nivolumab is the first combination of immune checkpoint inhibitors to improve progression-free survival and overall survival in the first-line setting, with durable responses and the longest median overall survival, 72.1 months, of any drug therapy approved for advanced melanoma. However, its use is limited by the high rate of severe (grade 3-4) treatment-related adverse events. More recently, the novel immune checkpoint inhibitor combination of nivolumab/relatlimab (anti-PD-1/anti-LAG3) showed improved progression-free survival compared with nivolumab alone in the first-line setting and was well tolerated; thus, it is likely this combination will be added to the armamentarium as a first-line treatment for advanced melanoma. These changes in the treatment landscape have several treatment implications for decision-making. The choice of first-line systemic drug therapy, and the decision between immune checkpoint inhibitor monotherapy or combination therapy, requires a comprehensive assessment of disease-related factors and patient characteristics. Despite this striking progress, many patients' disease still progresses. Several new agents and therapeutic approaches are under investigation in clinical trials. Intralesional treatments hold promise for accessible metastases, although their broad application in the clinic will be limited. Prognostic and predictive biomarkers, as well as strategies to reduce treatment-related toxicities and overcome resistance, are required and are now the focus of clinical and translational research.
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Affiliation(s)
- Florentia Dimitriou
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.,Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Axel Hauschild
- Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Germany
| | - Janice M Mehnert
- NYU Grossman School of Medicine and Perlmutter Cancer Center, New York, NY
| | - Georgina V Long
- Melanoma Institute Australia, The University of Sydney, Sydney, Australia.,Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.,Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, Australia
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30
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Zhang Z, Bu L, Luo J, Guo J. Targeting protein kinases benefits cancer immunotherapy. Biochim Biophys Acta Rev Cancer 2022; 1877:188738. [PMID: 35660645 DOI: 10.1016/j.bbcan.2022.188738] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 05/16/2022] [Accepted: 05/28/2022] [Indexed: 02/07/2023]
Abstract
Small-molecule kinase inhibitors have been well established and successfully developed in the last decades for cancer target therapies. However, intrinsic or acquired drug resistance is becoming the major barrier for their clinical application. With the development of immunotherapies, in particular the discovery of immune checkpoint inhibitors (ICIs), the combination of ICIs with other therapies have recently been extensively explored, among which combination of ICIs with kinase inhibitors achieves promising clinical outcome in a plethora of cancer types. Here we comprehensively summarize the potent roles of protein kinases in modulating immune checkpoints both in tumor and immune cells, and reshaping tumor immune microenvironments by evoking innate immune response and neoantigen generation or presentation. Moreover, the clinical trial and approval of combined administration of kinase inhibitors with ICIs are collected, highlighting the precise strategies to benefit cancer immune therapies.
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Affiliation(s)
- Zhengkun Zhang
- Department of Urology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Lang Bu
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Junhang Luo
- Department of Urology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
| | - Jianping Guo
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
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31
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Jiang Z, Zhu H, Wang P, Que W, Zhong L, Li X, Du F. Different subpopulations of regulatory T cells in human autoimmune disease, transplantation, and tumor immunity. MedComm (Beijing) 2022; 3:e137. [PMID: 35474948 PMCID: PMC9023873 DOI: 10.1002/mco2.137] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 04/06/2022] [Accepted: 04/07/2022] [Indexed: 12/11/2022] Open
Abstract
CD4+CD25+ regulatory T cells (Tregs), a subpopulation of naturally CD4+ T cells that characteristically express transcription factor Forkhead box P3 (FOXP3), play a pivotal role in the maintenance of immune homeostasis and the prevention of autoimmunity. With the development of biological technology, the understanding of plasticity and stability of Tregs has been further developed. Recent studies have suggested that human Tregs are functionally and phenotypically diverse. The functions and mechanisms of different phenotypes of Tregs in different disease settings, such as tumor microenvironment, autoimmune diseases, and transplantation, have gradually become hot spots of immunology research that arouse extensive attention. Among the complex functions, CD4+CD25+FOXP3+ Tregs possess a potent immunosuppressive capacity and can produce various cytokines, such as IL‐2, IL‐10, and TGF‐β, to regulate immune homeostasis. They can alleviate the progression of diseases by resisting inflammatory immune responses, whereas promoting the poor prognosis of diseases by helping cells evade immune surveillance or suppressing effector T cells activity. Therefore, methods for targeting Tregs to regulate their functions in the immune microenvironment, such as depleting them to strengthen tumor immunity or expanding them to treat immunological diseases, need to be developed. Here, we discuss that different subpopulations of Tregs are essential for the development of immunotherapeutic strategies involving Tregs in human diseases.
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Affiliation(s)
- Zhongyi Jiang
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Haitao Zhu
- Department of Hepatobiliary Surgery The Affiliated Hospital of Guizhou Medical University Guizhou P. R. China
| | - Pusen Wang
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Weitao Que
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Lin Zhong
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Xiao‐Kang Li
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
- Division of Transplantation Immunology National Research Institute for Child Health and Development Tokyo Japan
| | - Futian Du
- Department of Hepatobiliary Surgery Weifang People's Hospital Shandong P. R. China
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Yap TA, Bessudo A, Hamilton E, Sachdev J, Patel MR, Rodon J, Evilevitch L, Duncan M, Guo W, Kumar S, Lu S, Dezube BJ, Gabrail N. IOLite: phase 1b trial of doublet/triplet combinations of dostarlimab with niraparib, carboplatin-paclitaxel, with or without bevacizumab in patients with advanced cancer. J Immunother Cancer 2022; 10:jitc-2021-003924. [PMID: 35332062 PMCID: PMC8948406 DOI: 10.1136/jitc-2021-003924] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/03/2022] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Doublet combination therapies targeting immune checkpoints have shown promising efficacy in patients with advanced solid tumors, but it is unknown if rational triplet combinations will be well tolerated and associated with improved antitumor activity. The objective of this trial was to determine the recommended phase 2 doses (RP2Ds) and to assess the safety and efficacy of the programmed cell death protein 1 (PD-1) inhibitor dostarlimab in combination with (1) the poly(ADP-ribose) polymerase inhibitor niraparib with or without vascular endothelial growth factor inhibitor bevacizumab or (2) carboplatin-paclitaxel chemotherapy with or without bevacizumab, in patients with advanced cancer. METHODS IOLite is a multicenter, open-label, multi-arm clinical trial. Patients with advanced solid tumors were enrolled. Patients received dostarlimab in combination with niraparib with or without bevacizumab or in combination with carboplatin-paclitaxel with or without bevacizumab until disease progression, unacceptable toxicity, or withdrawal from the study. Prespecified endpoints in all parts were to evaluate the dose-limiting toxicities (DLTs), RP2Ds, pharmacokinetics (PKs), and preliminary efficacy for each combination. RESULTS A total of 55 patients were enrolled; patients received dostarlimab and: (1) niraparib in part A (n=22); (2) carboplatin-paclitaxel in part B (n=14); (3) niraparib plus bevacizumab in part C (n=13); (4) carboplatin-paclitaxel plus bevacizumab in part D (n=6). The RP2Ds of all combinations were determined. All combinations were safe and tolerable, with no new safety signals observed. DLTs were reported in 2, 1, 2, and 0 patients, in parts A-D, respectively. Preliminary antitumor activity was observed, with confirmed Response Evaluation Criteria in Solid Tumors v1.1 complete/partial responses reported in 4 of 22 patients (18.2%), 6 of 14 patients (42.9%), 4 of 13 patients (30.8%), and 3 of 6 (50.0%) patients, in parts A-D, respectively. Disease control rates were 40.9%, 57.1%, 84.6%, and 83.3%, in parts A-D, respectively. Dostarlimab PK was unaffected by any combinations tested. Coadministration of bevacizumab showed no impact on niraparib PKs. The overall mean PD-1 receptor occupancy was 99.0%. CONCLUSIONS Dostarlimab was well tolerated in both doublet and triplet regimens tested, with promising antitumor activity observed with all combinations. We observed higher disease control rates in the triplet regimens than in doublet regimens. TRIAL REGISTRATION NUMBER NCT03307785.
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Affiliation(s)
- Timothy A Yap
- Department of Investigational Cancer Therapeutics (Phase 1 Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Alberto Bessudo
- California Cancer Associates for Research and Excellence, San Diego, California, USA
| | - Erika Hamilton
- Sara Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee, USA
| | - Jasgit Sachdev
- HonorHealth Research Institute/TGen, Scottsdale, Arizona, USA
| | - Manish R Patel
- Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, Florida, USA
| | - Jordi Rodon
- Department of Investigational Cancer Therapeutics (Phase 1 Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | | | | | - Wei Guo
- GlaxoSmithKline, Waltham, Massachusetts, USA
| | | | - Sharon Lu
- GlaxoSmithKline, Waltham, Massachusetts, USA
| | | | - Nashat Gabrail
- Department of Oncology, Gabrail Cancer Center, Canton, Ohio, USA
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Hu H, Chen Y, Tan S, Wu S, Huang Y, Fu S, Luo F, He J. The Research Progress of Antiangiogenic Therapy, Immune Therapy and Tumor Microenvironment. Front Immunol 2022; 13:802846. [PMID: 35281003 PMCID: PMC8905241 DOI: 10.3389/fimmu.2022.802846] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 02/01/2022] [Indexed: 02/05/2023] Open
Abstract
Anti-angiogenesis therapy, a promising strategy against cancer progression, is limited by drug-resistance, which could be attributed to changes within the tumor microenvironment. Studies have increasingly shown that combining anti-angiogenesis drugs with immunotherapy synergistically inhibits tumor growth and progression. Combination of anti-angiogenesis therapy and immunotherapy are well-established therapeutic options among solid tumors, such as non-small cell lung cancer, hepatic cell carcinoma, and renal cell carcinoma. However, this combination has achieved an unsatisfactory effect among some tumors, such as breast cancer, glioblastoma, and pancreatic ductal adenocarcinoma. Therefore, resistance to anti-angiogenesis agents, as well as a lack of biomarkers, remains a challenge. In this review, the current anti-angiogenesis therapies and corresponding drug-resistance, the relationship between tumor microenvironment and immunotherapy, and the latest progress on the combination of both therapeutic modalities are discussed. The aim of this review is to discuss whether the combination of anti-angiogenesis therapy and immunotherapy can exert synergistic antitumor effects, which can provide a basis to exploring new targets and developing more advanced strategies.
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Affiliation(s)
- Haoyue Hu
- Lung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.,Department of Medical Oncology, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Medicine School of University of Electronic Science and Technology, Chengdu, China
| | - Yue Chen
- Department of Pathology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Songtao Tan
- Lung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| | - Silin Wu
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Yan Huang
- Lung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| | - Shengya Fu
- Lung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.,Second Department of Oncology, Sichuan Friendship Hospital, Chengdu, China
| | - Feng Luo
- Lung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| | - Jun He
- Department of Oncology, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, China
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Bagegni NA, Park H, Kraft K, O-Toole M, Gao F, Waqar SN, Ratner L, Morgensztern D, Devarakonda S, Amin M, Baggstrom MQ, Liang C, Selvaggi G, Wang-Gillam A. Phase 1b trial of anti-VEGF/PDGFR vorolanib combined with immune checkpoint inhibitors in patients with advanced solid tumors. Cancer Chemother Pharmacol 2022; 89:487-497. [PMID: 35247086 PMCID: PMC8956523 DOI: 10.1007/s00280-022-04406-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 01/31/2022] [Indexed: 12/30/2022]
Abstract
Purpose Vorolanib is a multi-target tyrosine kinase inhibitor with anti-angiogenic properties. This study aimed to evaluate the tolerability, safety and efficacy of vorolanib when added to checkpoint inhibitors (CPIs) in patients with advanced solid tumors. Methods We conducted a phase 1b study of vorolanib (300 or 400 mg orally once daily) plus pembrolizumab or nivolumab using a standard 3 + 3 design to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). The endpoints included safety, toxicity and objective response rate, according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). Results Sixteen patients (9 in pembrolizumab arm, 7 in nivolumab arm) with gastrointestinal or lung cancers were enrolled. All patients had at least 1 treatment-related adverse event (TRAE). The most common TRAEs across all cohorts were lymphopenia (n = 7), leukopenia (n = 5), fatigue (n = 5), and alanine aminotransferase elevation (n = 5); most toxicities were grade (G) 1–2. DLTs were reported in 3 patients at vorolanib 400 mg dose level, with G3 aspartate aminotransferase elevation, G3 rectal hemorrhage, and G3 rash. Of 13 total response-evaluable patients, 2 patients had confirmed partial responses (1 rectal squamous cell cancer and 1 small cell lung cancer). Two patients achieved prolonged stable disease. Vorolanib 300 mg daily was determined to be the RP2D for either pembrolizumab or nivolumab. Conclusion Combination vorolanib 300 mg orally once daily plus CPI appears to be a feasible regimen with manageable toxicity and promising efficacy in select tumor types. NCT03511222. Date of Registration: April 18, 2018.
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Affiliation(s)
- Nusayba A Bagegni
- Division of Oncology, Washington University in St. Louis School of Medicine, St Louis, MO, USA
| | - Haeseong Park
- Division of Oncology, Washington University in St. Louis School of Medicine, St Louis, MO, USA
| | - Katlyn Kraft
- Division of Oncology, Washington University in St. Louis School of Medicine, St Louis, MO, USA
| | - Maura O-Toole
- Division of Oncology, Washington University in St. Louis School of Medicine, St Louis, MO, USA
| | - Feng Gao
- Department of Surgery, Washington University in St. Louis School of Medicine, St Louis, MO, USA
| | - Saiama N Waqar
- Division of Oncology, Washington University in St. Louis School of Medicine, St Louis, MO, USA
| | - Lee Ratner
- Division of Oncology, Washington University in St. Louis School of Medicine, St Louis, MO, USA
| | - Daniel Morgensztern
- Division of Oncology, Washington University in St. Louis School of Medicine, St Louis, MO, USA
| | - Siddhartha Devarakonda
- Division of Oncology, Washington University in St. Louis School of Medicine, St Louis, MO, USA
| | - Manik Amin
- Division of Hematology/Oncology, Dartmouth Giesel School of Medicine, Hanover, NH, USA
| | - Maria Q Baggstrom
- Division of Oncology, Washington University in St. Louis School of Medicine, St Louis, MO, USA
| | - Chris Liang
- Xcovery Holdings, Inc., North Palm Beach, USA
| | | | - Andrea Wang-Gillam
- Division of Oncology, Washington University in St. Louis School of Medicine, St Louis, MO, USA.
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Jain S, Chalif EJ, Aghi MK. Interactions Between Anti-Angiogenic Therapy and Immunotherapy in Glioblastoma. Front Oncol 2022; 11:812916. [PMID: 35096619 PMCID: PMC8790087 DOI: 10.3389/fonc.2021.812916] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 12/17/2021] [Indexed: 12/21/2022] Open
Abstract
Glioblastoma is the most aggressive brain tumor with a median survival ranging from 6.2 to 16.7 months. The complex interactions between the tumor and the cells of tumor microenvironment leads to tumor evolution which ultimately results in treatment failure. Immunotherapy has shown great potential in the treatment of solid tumors but has been less effective in treating glioblastoma. Failure of immunotherapy in glioblastoma has been attributed to low T-cell infiltration in glioblastoma and dysfunction of the T-cells that are present in the glioblastoma microenvironment. Recent advances in single-cell sequencing have increased our understanding of the transcriptional changes in the tumor microenvironment pre and post-treatment. Another treatment modality targeting the tumor microenvironment that has failed in glioblastoma has been anti-angiogenic therapy such as the VEGF neutralizing antibody bevacizumab, which did not improve survival in randomized clinical trials. Interestingly, the immunosuppressed microenvironment and abnormal vasculature of glioblastoma interact in ways that suggest the potential for synergy between these two therapeutic modalities that have failed individually. Abnormal tumor vasculature has been associated with immune evasion and the creation of an immunosuppressive microenvironment, suggesting that inhibiting pro-angiogenic factors like VEGF can increase infiltration of effector immune cells into the tumor microenvironment. Remodeling of the tumor vasculature by inhibiting VEGFR2 has also been shown to improve the efficacy of PDL1 cancer immunotherapy in mouse models of different cancers. In this review, we discuss the recent developments in our understanding of the glioblastoma tumor microenvironment specially the tumor vasculature and its interactions with the immune cells, and opportunities to target these interactions therapeutically. Combining anti-angiogenic and immunotherapy in glioblastoma has the potential to unlock these therapeutic modalities and impact the survival of patients with this devastating cancer.
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Affiliation(s)
- Saket Jain
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Eric J Chalif
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Manish K Aghi
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States
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ZHU H, ZENG B, ZOU J, SU C. Efficacy of pembrolizumab combined with anlotinib in 3 patients with advanced non-small cell lung cancer. FOOD SCIENCE AND TECHNOLOGY 2022. [DOI: 10.1590/fst.33621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
| | - Bo ZENG
- Sun Yat-sen University, China
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Guo W, Sun X, Zhang R, Xu J, Xie L. First line anlotinib plus liposomal doxorubicin for locally advanced or metastatic soft tissue sarcoma: A prospective, single-arm trial. ASIAN PAC J TROP MED 2022. [DOI: 10.4103/1995-7645.348155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Javier-DesLoges J, Derweesh I, McKay RR. Targeted Therapy for Renal Cell Carcinoma. Urol Oncol 2022. [DOI: 10.1007/978-3-030-89891-5_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Barroso-Sousa R, Keenan TE, Li T, Tayob N, Trippa L, Pastorello RG, Richardson Iii ET, Dillon D, Amoozgar Z, Overmoyer B, Schnitt SJ, Winer EP, Mittendorf EA, Van Allen E, Duda DG, Tolaney SM. Nivolumab in combination with cabozantinib for metastatic triple-negative breast cancer: a phase II and biomarker study. NPJ Breast Cancer 2021; 7:110. [PMID: 34433812 PMCID: PMC8387440 DOI: 10.1038/s41523-021-00287-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 05/27/2021] [Indexed: 02/07/2023] Open
Abstract
This single-arm phase II study investigated the efficacy and safety of cabozantinib combined with nivolumab in metastatic triple-negative breast cancer (mTNBC). The primary endpoint was objective response rate (ORR) by RECIST 1.1. Biopsies at baseline and after cycle 1 were analyzed for tumor-infiltrating lymphocytes (TILs), PD-L1, and whole-exome and transcriptome sequencing. Only 1/18 patients achieved a partial response (ORR 6%), and the trial was stopped early. Toxicity led to cabozantinib dose reduction in 50% of patients. One patient had a PD-L1-positive tumor, and three patients had TILs > 10%. The responding patient had a PD-L1-negative tumor with low tumor mutational burden but high TILs and enriched immune gene expression. High pretreatment levels of plasma immunosuppressive cytokines, chemokines, and immune checkpoint molecules were associated with rapid progression. Although this study did not meet its primary endpoint, immunostaining, genomic, and proteomic studies indicated a high degree of tumor immunosuppression in this mTNBC cohort.
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Affiliation(s)
- Romualdo Barroso-Sousa
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA
- Oncology Center, Hospital Sírio-Libanês, Brasilia, Brazil
| | - Tanya E Keenan
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA
| | - Tianyu Li
- Biostatistics, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Nabihah Tayob
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Lorenzo Trippa
- Biostatistics, Dana-Farber Cancer Institute, Boston, MA, USA
| | | | | | - Deborah Dillon
- Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Zohreh Amoozgar
- Steele Laboratories for Tumor Biology, Massachusetts General Hospital, Boston, MA, USA
| | - Beth Overmoyer
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA
| | | | - Eric P Winer
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA
| | - Elizabeth A Mittendorf
- Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA
- Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA
| | - Eliezer Van Allen
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Dan G Duda
- Steele Laboratories for Tumor Biology, Massachusetts General Hospital, Boston, MA, USA
| | - Sara M Tolaney
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA.
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Ahluwalia P, Ahluwalia M, Mondal AK, Sahajpal NS, Kota V, Rojiani MV, Kolhe R. Natural Killer Cells and Dendritic Cells: Expanding Clinical Relevance in the Non-Small Cell Lung Cancer (NSCLC) Tumor Microenvironment. Cancers (Basel) 2021; 13:cancers13164037. [PMID: 34439191 PMCID: PMC8394984 DOI: 10.3390/cancers13164037] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/03/2021] [Accepted: 08/05/2021] [Indexed: 12/25/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer that accounts for almost 85% of lung cancer cases worldwide. Although recent advances in chemotherapy, radiotherapy, and immunotherapy have helped in the clinical management of these patients, the survival rate in advanced stages remains dismal. Furthermore, there is a critical lack of accurate prognostic and stratification markers for emerging immunotherapies. To harness immune response modalities for therapeutic benefits, a detailed understanding of the immune cells in the complex tumor microenvironment (TME) is required. Among the diverse immune cells, natural killer (NK cells) and dendritic cells (DCs) have generated tremendous interest in the scientific community. NK cells play a critical role in tumor immunosurveillance by directly killing malignant cells. DCs link innate and adaptive immune systems by cross-presenting the antigens to T cells. The presence of an immunosuppressive milieu in tumors can lead to inactivation and poor functioning of NK cells and DCs, which results in an adverse outcome for many cancer patients, including those with NSCLC. Recently, clinical intervention using modified NK cells and DCs have shown encouraging response in advanced NSCLC patients. Herein, we will discuss prognostic and predictive aspects of NK cells and DC cells with an emphasis on NSCLC. Additionally, the discussion will extend to potential strategies that seek to enhance the anti-tumor functionality of NK cells and DCs.
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Affiliation(s)
- Pankaj Ahluwalia
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (P.A.); (A.K.M.); (N.S.S.)
| | - Meenakshi Ahluwalia
- Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA;
| | - Ashis K. Mondal
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (P.A.); (A.K.M.); (N.S.S.)
| | - Nikhil S. Sahajpal
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (P.A.); (A.K.M.); (N.S.S.)
| | - Vamsi Kota
- Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA;
| | - Mumtaz V. Rojiani
- Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USA;
| | - Ravindra Kolhe
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (P.A.); (A.K.M.); (N.S.S.)
- Correspondence: ; Tel.: +1-706-721-2771; Fax: +1-706-434-6053
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Zhu C, Gu L, Liu Z, Li J, Yao M, Fang C. Correlation between vascular endothelial growth factor pathway and immune microenvironment in head and neck squamous cell carcinoma. BMC Cancer 2021; 21:836. [PMID: 34284746 PMCID: PMC8290614 DOI: 10.1186/s12885-021-08547-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 07/07/2021] [Indexed: 12/29/2022] Open
Abstract
Background Immunotherapy is a crucial therapeutic approach in oncology. However, most patients with head and neck squamous cell carcinoma (HNSCC) do not derive benefit from immunotherapy. Vascular endothelial growth factor (VEGF)/VEGF Receptor 2 (VEGFR2) signaling pathway is one of the most important pathways regulating angiogenesis in tumor. The combination of immunotherapy and anti-angiogenic therapy is considered to improve efficacy of immunotherapy. The correlation between VEGF signaling pathway and tumor immune microenvironment in HNSCC patients is unclear. Methods We utilized RNA sequencing and clinical data of HNSCC patients from the TCGA database to study the correlation between VEGF signaling pathway and tumor immune microenvironment, on aspect of immune cell infiltration, immune-related gene expression profiling and immune-related biological pathways. Results We observed that VEGF signaling pathway is positively correlated with immune cell infiltration, immune-related gene expression profiles, and the prognosis of HNSCC patients. The functional enrichment analysis of differentially expressed genes between different VEGF score subtypes detected multiple immune-related biological processes. Conclusion Our findings suggested that combining anti-VEGF signaling pathway agents with immunotherapy, such as immune checkpoint inhibitors (ICI) therapy, may exhibit encouraging benefits in HNSCC. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08547-4.
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Affiliation(s)
- Chao Zhu
- Department of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Liqun Gu
- Department of Pediatric Stomatology, Xiangya Stomatological Hospital, Central South University, Changsha, China
| | - Zelong Liu
- Division of Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jiang Li
- Department of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Mianfeng Yao
- Department of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Changyun Fang
- Department of Stomatology, Xiangya Hospital, Central South University, Changsha, China.
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Jhunjhunwala S, Hammer C, Delamarre L. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion. Nat Rev Cancer 2021; 21:298-312. [PMID: 33750922 DOI: 10.1038/s41568-021-00339-z] [Citation(s) in RCA: 800] [Impact Index Per Article: 200.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/01/2021] [Indexed: 01/31/2023]
Abstract
Immune checkpoint blockade, which blocks inhibitory signals of T cell activation, has shown tremendous success in treating cancer, although success still remains limited to a fraction of patients. To date, clinically effective CD8+ T cell responses appear to target predominantly antigens derived from tumour-specific mutations that accumulate in cancer, also called neoantigens. Tumour antigens are displayed on the surface of cells by class I human leukocyte antigens (HLA-I). To elicit an effective antitumour response, antigen presentation has to be successful at two distinct events: first, cancer antigens have to be taken up by dendritic cells (DCs) and cross-presented for CD8+ T cell priming. Second, the antigens have to be directly presented by the tumour for recognition by primed CD8+ T cells and killing. Tumours exploit multiple escape mechanisms to evade immune recognition at both of these steps. Here, we review the tumour-derived factors modulating DC function, and we summarize evidence of immune evasion by means of quantitative modulation or qualitative alteration of the antigen repertoire presented on tumours. These mechanisms include modulation of antigen expression, HLA-I surface levels, alterations in the antigen processing and presentation machinery in tumour cells. Lastly, as complete abrogation of antigen presentation can lead to natural killer (NK) cell-mediated tumour killing, we also discuss how tumours can harbour antigen presentation defects and still evade NK cell recognition.
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Mourad AAE, Farouk NA, El-Sayed ESH, Mahdy ARE. EGFR/VEGFR-2 dual inhibitor and apoptotic inducer: Design, synthesis, anticancer activity and docking study of new 2-thioxoimidazolidin-4one derivatives. Life Sci 2021; 277:119531. [PMID: 33887348 DOI: 10.1016/j.lfs.2021.119531] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 04/01/2021] [Accepted: 04/12/2021] [Indexed: 12/30/2022]
Abstract
AIMS EGFR and VEGFR-2 have emerged as promising targets for cancer management as they play a crucial role in tumor growth, angiogenesis and metastasis. A novel series of 2-thioxoimidazolidin-4-one derivatives were synthesized and evaluated as apoptotic inducers and EGFR/VEGFR-2 dual inhibitors. MAIN METHODS The cytotoxic activities of all synthesized compounds were tested against MCF-7, HepG2 and A549 cell lines. The molecular mechanism of the most promising cytotoxic compounds was investigated via a series of assays including in vitro EGFR and VEGFR-2 inhibitory activity in MCF-7 cell line. Additionally, levels of p53, Bax, Bcl-2, caspase 7, 9 as well as cell cycle analysis were assessed in MCF-7 cell line to gain better understanding of their apoptotic activity. Molecular docking study was carried out to predict binding pattern of these compounds with EGFR and VEGFR-2 active sites. Finally, in silico ADME and drug-likeness profiling were calculated. KEY FINDINGS Compounds 6 and 8a exhibited superior cytotoxic activity compared to sorafenib and erlotinib, against the three tested cell lines. In the same context, 6 and 8a showed better EGFR and VEGFR-2 inhibitory activity compared to the reference compounds. The later effect was further supported by the docking study. Furthermore, these compounds displayed potent apoptotic activity as evident by cell accumulation at pre-G1 phase and cell cycle arrest at G2/M phase together with increased p53, caspae-7 and caspase-9 levels and Bax/Bcl-2 ratio. Finally, synthesized compounds have acceptable drug likeness. SIGNIFICANCE Compounds 6 and 8a act as potent dual EGFR/VEGFR-2 inhibitors with evident apoptotic activity.
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Affiliation(s)
- Ahmed A E Mourad
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Port-Said University, Port-Said, Egypt.
| | - N A Farouk
- Chemistry Department, Faculty of Science, Port-Said University, Port-Said, Egypt
| | | | - Ahmed R E Mahdy
- Chemistry Department, Faculty of Science, Port-Said University, Port-Said, Egypt
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Chew SC, Choo SY, Chow PKH. A new perspective on the immune escape mechanism in HCC: onco-foetal reprogramming. Br J Cancer 2021; 124:1897-1899. [PMID: 33767421 DOI: 10.1038/s41416-021-01286-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/14/2021] [Accepted: 01/22/2021] [Indexed: 12/24/2022] Open
Abstract
We found a shared immunosuppressive microenvironment between foetal liver and hepatocellular carcinoma (HCC) which includes the re-emergence of foetal-associated endothelial cells (PLVAP/VEGFR2) and foetal-like (FOLR2) tumour-associated macrophages in HCC, mediated via VEGF-NOTCH signalling. The discoveries suggest possible novel targets for therapeutic interventions in HCC.
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Affiliation(s)
- Sin Chi Chew
- Programme in Translational and Clinical Liver Research, Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Si Ying Choo
- Programme in Translational and Clinical Liver Research, Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Pierce Kah-Hoe Chow
- Programme in Translational and Clinical Liver Research, Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore. .,Department of Hepato-pancreato-biliary and Transplant Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and National Cancer Centre Singapore, Singapore, Singapore. .,Academic Clinical Programme for Surgery, Duke-NUS Medical School, Singapore, Singapore.
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de Jong FC, Rutten VC, Zuiverloon TCM, Theodorescu D. Improving Anti-PD-1/PD-L1 Therapy for Localized Bladder Cancer. Int J Mol Sci 2021; 22:2800. [PMID: 33802033 PMCID: PMC7998260 DOI: 10.3390/ijms22062800] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 02/25/2021] [Accepted: 03/02/2021] [Indexed: 02/06/2023] Open
Abstract
In high-risk non-muscle invasive bladder cancer (HR-NMIBC), patient outcome is negatively affected by lack of response to Bacillus-Calmette Guérin (BCG) treatment. Lack of response to cisplatin-based neoadjuvant chemotherapy and cisplatin ineligibility reduces successful treatment outcomes in muscle-invasive bladder cancer (MIBC) patients. The effectiveness of PD-1/PD-L1 immune checkpoint inhibitors (ICI) in metastatic disease has stimulated its evaluation as a treatment option in HR-NMIBC and MIBC patients. However, the observed responses, immune-related adverse events and high costs associated with ICI have provided impetus for the development of methods to improve patient stratification, enhance anti-tumorigenic effects and reduce toxicity. Here, we review the challenges and opportunities offered by PD-1/PD-L1 inhibition in HR-NMIBC and MIBC. We highlight the gaps in the field that need to be addressed to improve patient outcome including biomarkers for response stratification and potentially synergistic combination therapy regimens with PD-1/PD-L1 blockade.
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Affiliation(s)
- Florus C. de Jong
- Department of Urology, Erasmus University Medical Center, Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands; (F.C.d.J.); (V.C.R.); (T.C.M.Z.)
| | - Vera C. Rutten
- Department of Urology, Erasmus University Medical Center, Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands; (F.C.d.J.); (V.C.R.); (T.C.M.Z.)
| | - Tahlita C. M. Zuiverloon
- Department of Urology, Erasmus University Medical Center, Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands; (F.C.d.J.); (V.C.R.); (T.C.M.Z.)
| | - Dan Theodorescu
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Departments of Surgery (Urology) and Pathology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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Lumish MA, Cercek A. Immunotherapy for the treatment of colorectal cancer. J Surg Oncol 2021; 123:760-774. [PMID: 33595891 DOI: 10.1002/jso.26357] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/18/2020] [Accepted: 11/23/2020] [Indexed: 12/12/2022]
Abstract
Immune checkpoint inhibition (ICI) has transformed the management of metastatic colorectal cancer (mCRC) with mismatch-repair deficiency (dMMR) and microsatellite instability (MSI-H), though this constitutes on average less than 5% of mCRC, and ICI is ineffective in preserved MMR/microsatellite stable disease (pMMR/MSS). Here we review the efficacy of ICI in dMMR/MSI-H mCRC, poor response to ICI in pMMR/MSS mCRC, role for ICI in locally advanced disease, biomarkers of response, novel immunotherapies, and future directions in targeting resistance mechanisms.
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Affiliation(s)
| | - Andrea Cercek
- Memorial Sloan Kettering Cancer Center, New York, New York
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Nagai N, Kudo Y, Aki D, Nakagawa H, Taniguchi K. Immunomodulation by Inflammation during Liver and Gastrointestinal Tumorigenesis and Aging. Int J Mol Sci 2021; 22:ijms22052238. [PMID: 33668122 PMCID: PMC7956754 DOI: 10.3390/ijms22052238] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 02/19/2021] [Indexed: 12/19/2022] Open
Abstract
Chronic inflammation is thought to promote tumorigenesis and metastasis by several mechanisms, such as affecting tumor cells directly, establishing a tumor-supporting microenvironment, enhancing tumor angiogenesis, and suppressing antitumor immunity. In this review, we discuss the recent advances in our understanding of how inflammation induces the immunosuppressive tumor microenvironment, such as increasing the level of pro-inflammatory cytokines, chemokines, and immunosuppressive molecules, inducing immune checkpoint molecules and cytotoxic T-cell exhaustion, and accumulating regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs). The suppression of antitumor immunity by inflammation is especially examined in the liver and colorectal cancer. In addition, chronic inflammation is induced during aging and causes age-related diseases, including cancer, by affecting immunity. Therefore, we also discuss the age-related diseases regulated by inflammation, especially in the liver and colon.
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Affiliation(s)
- Nao Nagai
- Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; (N.N.); (D.A.)
| | - Yotaro Kudo
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; (Y.K.); (H.N.)
| | - Daisuke Aki
- Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; (N.N.); (D.A.)
| | - Hayato Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; (Y.K.); (H.N.)
| | - Koji Taniguchi
- Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; (N.N.); (D.A.)
- Department of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan
- Correspondence: ; Tel.: +81-3-5363-3483
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Saeed A, Park R, Sun W. The integration of immune checkpoint inhibitors with VEGF targeted agents in advanced gastric and gastroesophageal adenocarcinoma: a review on the rationale and results of early phase trials. J Hematol Oncol 2021; 14:13. [PMID: 33436042 PMCID: PMC7802258 DOI: 10.1186/s13045-021-01034-0] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 01/04/2021] [Indexed: 12/11/2022] Open
Abstract
Several targeted therapies have shown efficacy in patients with advanced gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJC), including anti-angiogenic agents and immune checkpoint inhibitors. Ramucirumab, an anti-VEGFR2 antibody, has shown efficacy in GC, but the benefits are limited, in part due to MET-mediated resistance. Other VEGF targeted agents like VEGF tyrosine kinase inhibitors (TKIs) with broad multi-kinase inhibitory spectrum like regorafenib and cabozantinib have also shown modest single agent activity in early phase trials. For immune checkpoint inhibitors, pembrolizumab (anti-PD-1) monotherapy confers survival advantage as 3rd line therapy for the PD-L1 expressing GC and GEJC population and has been approved for use in this setting. Extensive tumor microenvironment immune modulatory effects from antiangiogenic agents have been demonstrated from preclinical data which support the clinical study rationale of dual blockade of VEGF and immune checkpoint. In addition, FDA has approved combinations of anti-VEGF/VEGFR with anti-PD-1/PD-L1 agents in hepatocellular carcinoma and renal cell carcinoma. Promising clinical activity has been demonstrated in patients with refractory GC/GEJC when treated with dual blockade combination with antiangiogenic agents and immune checkpoint inhibitors like PD-1/PD-L1 inhibitors in several phase I/II trials. This review highlights the trials investigating these novel combinations as well as their preclinical rationale.
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Affiliation(s)
- Anwaar Saeed
- Division of Medical Oncology, Department of Medicine, University of Kansas Medical Center, 2330 Shawnee Mission Pkwy, Suite 210, Westwood, Kansas City, KS, 66205, USA.
| | - Robin Park
- MetroWest Medical Center/Tufts University School of Medicine, Framingham, MA, USA
| | - Weijing Sun
- Division of Medical Oncology, Department of Medicine, University of Kansas Medical Center, 2330 Shawnee Mission Pkwy, Suite 210, Westwood, Kansas City, KS, 66205, USA
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Biphenylurea/thiourea derivatives tagged with heteroarylsulfonamide motifs as novel VEGFR2 inhibitors; Design, synthesis and anti-angiogenic activity. Bioorg Chem 2021; 107:104640. [PMID: 33485105 DOI: 10.1016/j.bioorg.2021.104640] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 01/01/2021] [Accepted: 01/04/2021] [Indexed: 12/19/2022]
Abstract
Anti-angiogenesis targeting vascular endothelial growth factor receptor 2 (VEGFR2) has emerged as a vital tool for cancer treatment. In this study, a new series of biphenylurea/thiourea derivatives tagged with heteroarylsulfonamide motifs (3a-l) was designed and synthesized as novel VEGFR2 inhibitors. The biochemical profiles of the target compounds were investigated using viability of human umbilical vascular endothelial cells (HUVECs), migration assay and Western blot using sorafenib as reference antiangiogenic drug. Most of the tested compounds exhibited significant antiproliferative activity against HUVECs, where compounds 3a, 3e, 3g, 3h and 3l exhibited better antiproliferative activity than sorafenib. All compounds significantly inhibited VEGF stimulated migration of HUVECs at 10 µM dose with (3a, 3e, 3g, 3h and 3l) showing better or comparable inhibitory activities to that of sorafenib. Moreover, Western blotting analysis confirmed antiangiogenic effect of those compounds with significant reduction in the level of VEGFR-2 compared to sorafenib. Finally, cytotoxicity screening of these derivatives against four cancer cells and RPE1 as normal cell line was performed. The mechanistic effectiveness in cell cycle progression and apoptotic induction were evaluated for the promising compound 3e due to its remarkable cytotoxic activity against tested cancer cell lines and significant VEGFR-2 inhibition. Flow cytometric analysis showed that compound 3e induced cell growth arrest at G2/M phase and stimulated the apoptotic death of HepG2 cells.
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Temozolomide treatment outcomes and immunotherapy efficacy in brain tumor. J Neurooncol 2021; 151:55-62. [PMID: 32813186 PMCID: PMC9833842 DOI: 10.1007/s11060-020-03598-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Accepted: 08/08/2020] [Indexed: 01/13/2023]
Abstract
INTRODUCTION Glioblastoma (GBM) has a survival rate of around 2 years with aggressive current standard of care. While other tumors have responded favorably to trials combining immunotherapy and chemotherapy, GBM remains uniformly deadly with minimal increases in overall survival. GBM differ from others due to being isolated behind the blood brain barrier, increased heterogeneity and mutational burden, and immunosuppression from the brain environment and tumor itself. METHODS We have reviewed clinical and preclinical studies investigating how different doses (dose intense (DI) and metronomic) and timing of immunotherapy following TMZ treatment can eradicate tumor cells, alter tumor mutational burden, and change immune cells. RESULTS Recent clinical trials with standard of care (SoC), DI and metronomic TMZ regimes are no able to completely eradicate GBM. Elevated TMZ levels in DI treatment can overcome MGMT resistance but may result in hypermutation of surviving tumor cells. Higher levels of TMZ will also generate a higher degree of lymphopenia compared to SoC and metronomic regimes in preclinical studies. CONCLUSION The different levels of lymphopenia and tumor eradication discussed in this review suggest possible beneficial pairings between immunotherapy and TMZ treatment. Treatments resulting in profound lymphopenia will allow for expansion of vaccine specific T cells or of CAT T cells. Clinical and preclinical studies are currently comparing different combinations of TMZ and immunotherapy timing to treat GBM through a balance between tumor killing and immune cell expansion. More frequent immune monitoring time points in ongoing clinical trials are crucial for further development of these combinations.
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