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Mantooth SM, Abdou Y, Saez-Ibañez AR, Upadhaya S, Zaharoff DA. Intratumoral delivery of immunotherapy to treat breast cancer: current development in clinical and preclinical studies. Front Immunol 2024; 15:1385484. [PMID: 38803496 PMCID: PMC11128577 DOI: 10.3389/fimmu.2024.1385484] [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: 02/12/2024] [Accepted: 04/22/2024] [Indexed: 05/29/2024] Open
Abstract
Breast cancer poses one of the largest threats to women's health. Treatment continues to improve for all the subtypes of breast cancer, but some subtypes, such as triple negative breast cancer, still present a significant treatment challenge. Additionally, metastasis and local recurrence are two prevalent problems in breast cancer treatment. A newer type of therapy, immunotherapy, may offer alternatives to traditional treatments for difficult-to-treat subtypes. Immunotherapy engages the host's immune system to eradicate disease, with the potential to induce long-lasting, durable responses. However, systemic immunotherapy is only approved in a limited number of indications, and it benefits only a minority of patients. Furthermore, immune related toxicities following systemic administration of potent immunomodulators limit dosing and, consequently, efficacy. To address these safety considerations and improve treatment efficacy, interest in local delivery at the site of the tumor has increased. Numerous intratumorally delivered immunotherapeutics have been and are being explored clinically and preclinically, including monoclonal antibodies, cellular therapies, viruses, nucleic acids, cytokines, innate immune agonists, and bacteria. This review summarizes the current and past intratumoral immunotherapy clinical landscape in breast cancer as well as current progress that has been made in preclinical studies, with a focus on delivery parameters and considerations.
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Affiliation(s)
- Siena M. Mantooth
- Joint Department of Biomedical Engineering, North Carolina State University and University of North Carolina at Chapel Hill, Raleigh, NC, United States
| | - Yara Abdou
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | | | | | - David A. Zaharoff
- Joint Department of Biomedical Engineering, North Carolina State University and University of North Carolina at Chapel Hill, Raleigh, NC, United States
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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Melero I, Sanmamed MF, Glez-Vaz J, Luri-Rey C, Wang J, Chen L. CD137 (4-1BB)-Based Cancer Immunotherapy on Its 25th Anniversary. Cancer Discov 2023; 13:552-569. [PMID: 36576322 DOI: 10.1158/2159-8290.cd-22-1029] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 10/28/2022] [Accepted: 11/21/2022] [Indexed: 12/29/2022]
Abstract
Twenty-five years ago, we reported that agonist anti-CD137 monoclonal antibodies eradicated transplanted mouse tumors because of enhanced CD8+ T-cell antitumor immunity. Mouse models indicated that anti-CD137 agonist antibodies synergized with various other therapies. In the clinic, the agonist antibody urelumab showed evidence for single-agent activity against melanoma and non-Hodgkin lymphoma but caused severe liver inflammation in a fraction of the patients. CD137's signaling domain is included in approved chimeric antigen receptors conferring persistence and efficacy. A new wave of CD137 agonists targeting tumors, mainly based on bispecific constructs, are in early-phase trials and are showing promising safety and clinical activity. SIGNIFICANCE CD137 (4-1BB) is a costimulatory receptor of T and natural killer lymphocytes whose activity can be exploited in cancer immunotherapy strategies as discovered 25 years ago. Following initial attempts that met unacceptable toxicity, new waves of constructs acting agonistically on CD137 are being developed in patients, offering signs of clinical and pharmacodynamic activity with tolerable safety profiles.
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Affiliation(s)
- Ignacio Melero
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
- Departments of Immunology-Immunotherapy and Oncology, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Miguel F Sanmamed
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
- Departments of Immunology-Immunotherapy and Oncology, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Javier Glez-Vaz
- 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
| | - Jun Wang
- Department of Pathology, New York University Grossman School of Medicine, New York, New York
| | - Lieping Chen
- Department of Immunobiology, Yale University, New Haven, Connecticut
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Prognostic Value of Pretreatment Neutrophil-to-Lymphocyte Ratio in HER2-Positive Metastatic Breast Cancer. Curr Oncol 2022; 29:6154-6166. [PMID: 36135052 PMCID: PMC9498194 DOI: 10.3390/curroncol29090483] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/19/2022] [Accepted: 08/22/2022] [Indexed: 11/25/2022] Open
Abstract
This study aimed to examine the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) and other clinicopathological features in HER2+ MBC patients who received first-line anti-HER2 therapy. A total of 129 patients were assigned to NLR-low and NLR-high groups based on a cutoff value of 3.0 at baseline. Peripheral blood lymphocyte subsets and gene mutations in circulating tumor DNA were analyzed by flow cytometry and Next-generation sequencing, respectively. Survival was evaluated by the Kaplan−Meier method and Cox regression analysis. Of the 129 patients, 77 and 52 were assigned to the NLR-low (≤3) and NLR-high (>3) groups, respectively. Compared with NLR-high patients, the NLR-low patients had significantly longer median progression-free survival (PFS) (11.7 vs. 7.7 months) (p = 0.001, HR = 2.703 95% CI 1.543−4.736 and overall survival (OS) (37.4 vs. 28.7 months) (p = 0.044, HR = 2.254 95% CI 1.024−4.924). Furthermore, this association was independent of metastatic sites or estrogen receptor status. Peripheral blood CD3+ (p = 0.034) and CD4+ (p = 0.010) T cell numbers were significantly higher in the NLR-low group than the NLR-high group. The mutational profile of MBC was generally similar between the two groups. Baseline NLR was a prognostic factor of PFS and OS for patients with HER2+ MBC in the first-line setting. These results may facilitate the selection of patients who will benefit most from anti-HER2 treatment.
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Quetglas JI, John LB, Kershaw MH, Alvarez-Vallina L, Melero I, Darcy PK, Smerdou C. Virotherapy, gene transfer and immunostimulatory monoclonal antibodies. Oncoimmunology 2021; 1:1344-1354. [PMID: 23243597 PMCID: PMC3518506 DOI: 10.4161/onci.21679] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Malignant cells are susceptible to viral infection and consequent cell death. Virus-induced cell death is endowed with features that are known to stimulate innate and adaptive immune responses. Thus danger signals emitted by cells succumbing to viral infection as well as viral nucleic acids are detected by specific receptors, and tumor cell antigens can be routed to professional antigen-presenting cells. The anticancer immune response triggered by viral infection is frequently insufficient to eradicate malignancy but may be further amplified. For this purpose, transgenes encoding cytokines as co-stimulatory molecules can be genetically engineered into viral vectors. Alternatively, or in addition, it is possible to use monoclonal antibodies that either block inhibitory receptors of immune effector cells, or act as agonists for co-stimulatory receptors. Combined strategies are based on the ignition of a local immune response at the malignant site plus systemic immune boosting. We have recently reported examples of this approach involving the Vaccinia virus or Semliki Forest virus, interleukin-12 and anti-CD137 monoclonal antibodies.
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Affiliation(s)
- José I Quetglas
- Division of Hepatology and Gene Therapy; Center for Applied Medical Research; University of Navarra; Pamplona, Spain
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5
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Oncolytic Virus Encoding a Master Pro-Inflammatory Cytokine Interleukin 12 in Cancer Immunotherapy. Cells 2020; 9:cells9020400. [PMID: 32050597 PMCID: PMC7072539 DOI: 10.3390/cells9020400] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 01/25/2020] [Accepted: 01/29/2020] [Indexed: 02/07/2023] Open
Abstract
Oncolytic viruses (OVs) are genetically modified or naturally occurring viruses, which preferentially replicate in and kill cancer cells while sparing healthy cells, and induce anti-tumor immunity. OV-induced tumor immunity can be enhanced through viral expression of anti-tumor cytokines such as interleukin 12 (IL-12). IL-12 is a potent anti-cancer agent that promotes T-helper 1 (Th1) differentiation, facilitates T-cell-mediated killing of cancer cells, and inhibits tumor angiogenesis. Despite success in preclinical models, systemic IL-12 therapy is associated with significant toxicity in humans. Therefore, to utilize the therapeutic potential of IL-12 in OV-based cancer therapy, 25 different IL-12 expressing OVs (OV-IL12s) have been genetically engineered for local IL-12 production and tested preclinically in various cancer models. Among OV-IL12s, oncolytic herpes simplex virus encoding IL-12 (OHSV-IL12) is the furthest along in the clinic. IL-12 expression locally in the tumors avoids systemic toxicity while inducing an efficient anti-tumor immunity and synergizes with anti-angiogenic drugs or immunomodulators without compromising safety. Despite the rapidly rising interest, there are no current reviews on OV-IL12s that exploit their potential efficacy and safety to translate into human subjects. In this article, we will discuss safety, tumor-specificity, and anti-tumor immune/anti-angiogenic effects of OHSV-IL12 as mono- and combination-therapies. In addition to OHSV-IL12 viruses, we will also review other IL-12-expressing OVs and their application in cancer therapy.
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Hinner MJ, Aiba RSB, Jaquin TJ, Berger S, Dürr MC, Schlosser C, Allersdorfer A, Wiedenmann A, Matschiner G, Schüler J, Moebius U, Rothe C, Matis L, Olwill SA. Tumor-Localized Costimulatory T-Cell Engagement by the 4-1BB/HER2 Bispecific Antibody-Anticalin Fusion PRS-343. Clin Cancer Res 2019; 25:5878-5889. [DOI: 10.1158/1078-0432.ccr-18-3654] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 03/14/2019] [Accepted: 05/22/2019] [Indexed: 11/16/2022]
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Jutzy JMS, Lemons JM, Luke JJ, Chmura SJ. The Evolution of Radiation Therapy in Metastatic Breast Cancer: From Local Therapy to Systemic Agent. Int J Breast Cancer 2018; 2018:4786819. [PMID: 29862083 PMCID: PMC5976948 DOI: 10.1155/2018/4786819] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Accepted: 04/12/2018] [Indexed: 12/20/2022] Open
Abstract
Radiation therapy is a mainstay of treatment in early and locally advanced breast cancer but is typically reserved for palliation of symptomatic lesions in patients with metastatic breast cancer. With new advances in the field of tumor biology and immunology, the role of radiation in the metastatic setting is evolving to harness its immune-enhancing properties. Through the release of tumor antigens, tumor DNA, and cytokines into the tumor microenvironment, radiation augments the antitumoral immune response to affect both the targeted lesion and distant sites of metastatic disease. The use of immunotherapeutics to promote antitumoral immunity has resulted in improved treatment responses in patients with metastatic disease and the combination of radiation therapy and immunotherapy has become an area of intense investigation. In this article, we will review the emerging role of radiation in the treatment of metastatic disease and discuss the current state of the science and clinical trials investigating the combination of radiation and immunotherapy.
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Affiliation(s)
| | - Jeffrey M. Lemons
- Department of Radiation Oncology, University of Chicago, Chicago, IL, USA
| | - Jason J. Luke
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Steven J. Chmura
- Department of Radiation Oncology, University of Chicago, Chicago, IL, USA
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8
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Fu G, Miao L, Wang M, Guo M, Wang C, Ji F, Cao M. The Postoperative Immunosuppressive Phenotypes of Peripheral T Helper Cells Are Associated with Poor Prognosis of Breast Cancer Patients. Immunol Invest 2017; 46:647-662. [PMID: 28872974 DOI: 10.1080/08820139.2017.1360337] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Ganglan Fu
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Liping Miao
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Meng Wang
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - MingYan Guo
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Chengli Wang
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Fengtao Ji
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Minghui Cao
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
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9
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Improving the detection of pathways in genome-wide association studies by combined effects of SNPs from Linkage Disequilibrium blocks. Sci Rep 2017; 7:3512. [PMID: 28615668 PMCID: PMC5471232 DOI: 10.1038/s41598-017-03826-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 05/05/2017] [Indexed: 01/31/2023] Open
Abstract
Genome-wide association studies (GWAS) have successfully identified single variants associated with diseases. To increase the power of GWAS, gene-based and pathway-based tests are commonly employed to detect more risk factors. However, the gene- and pathway-based association tests may be biased towards genes or pathways containing a large number of single-nucleotide polymorphisms (SNPs) with small P-values caused by high linkage disequilibrium (LD) correlations. To address such bias, numerous pathway-based methods have been developed. Here we propose a novel method, DGAT-path, to divide all SNPs assigned to genes in each pathway into LD blocks, and to sum the chi-square statistics of LD blocks for assessing the significance of the pathway by permutation tests. The method was proven robust with the type I error rate >1.6 times lower than other methods. Meanwhile, the method displays a higher power and is not biased by the pathway size. The applications to the GWAS summary statistics for schizophrenia and breast cancer indicate that the detected top pathways contain more genes close to associated SNPs than other methods. As a result, the method identified 17 and 12 significant pathways containing 20 and 21 novel associated genes, respectively for two diseases. The method is available online by http://sparks-lab.org/server/DGAT-path.
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10
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Immune Checkpoint Modulators: An Emerging Antiglioma Armamentarium. J Immunol Res 2016; 2016:4683607. [PMID: 26881264 PMCID: PMC4736366 DOI: 10.1155/2016/4683607] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 12/01/2015] [Accepted: 12/03/2015] [Indexed: 12/31/2022] Open
Abstract
Immune checkpoints have come to the forefront of cancer therapies as a powerful and promising strategy to stimulate antitumor T cell activity. Results from recent preclinical and clinical studies demonstrate how checkpoint inhibition can be utilized to prevent tumor immune evasion and both local and systemic immune suppression. This review encompasses the key immune checkpoints that have been found to play a role in tumorigenesis and, more specifically, gliomagenesis. The review will provide an overview of the existing preclinical and clinical data, antitumor efficacy, and clinical applications for each checkpoint with respect to GBM, as well as a summary of combination therapies with chemotherapy and radiation.
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11
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Bartkowiak T, Curran MA. 4-1BB Agonists: Multi-Potent Potentiators of Tumor Immunity. Front Oncol 2015; 5:117. [PMID: 26106583 PMCID: PMC4459101 DOI: 10.3389/fonc.2015.00117] [Citation(s) in RCA: 198] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 05/11/2015] [Indexed: 01/12/2023] Open
Abstract
Immunotherapy is a rapidly expanding field of oncology aimed at targeting, not the tumor itself, but the immune system combating the cancerous lesion. Of the many approaches currently under study to boost anti-tumor immune responses; modulation of immune co-receptors on lymphocytes in the tumor microenvironment has thus far proven to be the most effective. Antibody blockade of the T cell co-inhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) has become the first FDA approved immune checkpoint blockade; however, tumor infiltrating lymphocytes express a diverse array of additional stimulatory and inhibitory co-receptors, which can be targeted to boost tumor immunity. Among these, the co-stimulatory receptor 4-1BB (CD137/TNFSF9) possesses an unequaled capacity for both activation and pro-inflammatory polarization of anti-tumor lymphocytes. While functional studies of 4-1BB have focused on its prominent role in augmenting cytotoxic CD8 T cells, 4-1BB can also modulate the activity of CD4 T cells, B cells, natural killer cells, monocytes, macrophages, and dendritic cells. 4-1BB’s expression on both T cells and antigen presenting cells, coupled with its capacity to promote survival, expansion, and enhanced effector function of activated T cells, has made it an alluring target for tumor immunotherapy. In contrast to immune checkpoint blocking antibodies, 4-1BB agonists can both potentiate anti-tumor and anti-viral immunity, while at the same time ameliorating autoimmune disease. Despite this, 4-1BB agonists can trigger high grade liver inflammation which has slowed their clinical development. In this review, we discuss how the underlying immunobiology of 4-1BB activation suggests the potential for therapeutically synergistic combination strategies in which immune adverse events can be minimized.
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Affiliation(s)
- Todd Bartkowiak
- Department of Immunology, University of Texas MD Anderson Cancer Center , Houston, TX , USA ; The University of Texas Graduate School of Biomedical Sciences at Houston , Houston, TX , USA
| | - Michael A Curran
- Department of Immunology, University of Texas MD Anderson Cancer Center , Houston, TX , USA ; The University of Texas Graduate School of Biomedical Sciences at Houston , Houston, TX , USA
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12
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Kim JE, Lim M. The role of checkpoints in the treatment of GBM. J Neurooncol 2015; 123:413-23. [PMID: 25749875 DOI: 10.1007/s11060-015-1747-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Accepted: 02/16/2015] [Indexed: 12/18/2022]
Abstract
Targeted immunotherapy is founded on the principle that augmentation of effector T cell activity in the tumor microenvironment can translate to tumor regression. Targeted checkpoint inhibitors in the form of agonist or antagonist monoclonal antibodies have come to the fore as a promising strategy to activate systemic immunity and enhance T cell activity by blocking negative signals, enhancing positive signals, or altering the cytokine milieu. This review will examine several immune checkpoints and checkpoint modulators that play a role in cancer pathogenesis, with an emphasis on malignant gliomas.
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Affiliation(s)
- Jennifer E Kim
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Juhász K, Buzás K, Duda E. Importance of reverse signaling of the TNF superfamily in immune regulation. Expert Rev Clin Immunol 2014; 9:335-48. [DOI: 10.1586/eci.13.14] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Kermer V, Hornig N, Harder M, Bondarieva A, Kontermann RE, Müller D. Combining antibody-directed presentation of IL-15 and 4-1BBL in a trifunctional fusion protein for cancer immunotherapy. Mol Cancer Ther 2013; 13:112-21. [PMID: 24198185 DOI: 10.1158/1535-7163.mct-13-0282] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Influencing the cytokine receptor network that modulates the immune response holds great potential for cancer immunotherapy. Although encouraging results have been obtained by focusing on individual members of the common γ-chain (γc) receptor family and TNF receptor superfamily so far, combination strategies might be required to further improve the effectiveness of the antitumor response. Here, we propose the combination of interleukin (IL)-15 and 4-1BBL in a single, tumor-directed molecule. Therefore, a trifunctional antibody fusion protein was generated, composed of a tumor-specific recombinant antibody, IL-15 linked to a fragment of the IL-15Rα chain (RD) and the extracellular domain of 4-1BBL. In soluble and targeted forms, the trifunctional antibody fusion protein RD_IL-15_scFv_4-1BBL was shown to stimulate activated T-cell proliferation and induce T-cell cytotoxicity to a similar degree as the bifunctional scFv_RD_IL-15 fusion protein. On the other hand, in targeted form, the trifunctional fusion protein was much more effective in inducing T-cell proliferation and IFN-γ release of unstimulated peripheral blood mononuclear cells (PBMC). Here, the additional signal enhancement could be attributed to the costimulatory activity of 4-1BBL, indicating a clear benefit for the simultaneous presentation of IL-15 and 4-1BBL in one molecule. Furthermore, the trifunctional antibody fusion protein was more effective than the corresponding bifunctional fusion proteins in reducing metastases in a tumor mouse model in vivo. Hence, the targeted combination of IL-15 and 4-BBL in the form of a trifunctional antibody-fusion protein is a promising new approach for cancer immunotherapy.
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Affiliation(s)
- Vanessa Kermer
- Corresponding Author: Dafne Müller, Institut für Zellbiologie und Immunologie, Universität Stuttgart, Allmandring 31, Stuttgart 70569, Germany.
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15
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Abstract
4-1BB (CD137), a member of the TNF receptor superfamily, is an activation-induced T-cell costimulatory molecule. Signaling via 4-1BB upregulates survival genes, enhances cell division, induces cytokine production, and prevents activation-induced cell death in T cells. The importance of the 4-1BB pathway has been underscored in a number of diseases, including cancer. Growing evidence indicates that anti-4-1BB monoclonal antibodies possess strong antitumor properties, which in turn are the result of their powerful CD8+ T-cell activating, IFN-γ producing, and cytolytic marker-inducing capabilities. In addition, combination therapy of anti-4-1BB with other anticancer agents, such as radiation, has robust tumor-regressing abilities against nonimmunogenic or poorly immunogenic tumors. Furthermore, the adoptive transfer of ex vivo anti-4-1BB-activated CD8+ T cells from previously tumor-treated animals efficiently inhibits progression of tumors in recipient mice that have been inoculated with fresh tumors. In addition, targeting of tumors with variants of 4-1BBL directed against 4-1BB also have potent antitumor effects. Currently, a humanized anti-4-1BB is in clinical trials in patients with solid tumors, including melanoma, renal carcinoma, and ovarian cancer, and so far seems to have a favorable toxicity profile. In this review, we discuss the basis of the therapeutic potential of targeting the 4-1BB-4-1BBL pathway in cancer treatment.
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Affiliation(s)
- Dass S Vinay
- Section of Clinical Immunology, Allergy, and Rheumatology, Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
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16
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Snell LM, Lin GHY, McPherson AJ, Moraes TJ, Watts TH. T-cell intrinsic effects of GITR and 4-1BB during viral infection and cancer immunotherapy. Immunol Rev 2012; 244:197-217. [PMID: 22017440 DOI: 10.1111/j.1600-065x.2011.01063.x] [Citation(s) in RCA: 97] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
GITR [glucocorticoid inducible tumor necrosis factor receptor (TNFR)-related protein] and 4-1BB are costimulatory TNFR family members that are expressed on regulatory and effector T cells as well as on other cells of the immune system. Here we discuss the role of GITR and 4-1BB on T cells during viral infections and in cancer immunotherapy. Systemic treatment with agonistic anti-4-1BB antibody leads to a number of immune system abnormalities, and clinical trials of anti-4-1BB have been terminated. However, other modes of 4-1BB ligation may be less toxic. To date, similar toxicities have not been reported for anti-GITR treatment of mice, although anti-GITR antibodies can exacerbate mouse autoimmune models. Intrinsic effects of GITR and 4-1BB on effector T cells appear to predominate over their effects on other cell types in some models. Despite their similarities in enhancing T-cell survival, 4-1BB and GITR are clearly not redundant, and both pathways are required for maximal CD8(+) T-cell responses and mouse survival following severe respiratory influenza infection. GITR uses TNFR-associated factor (TRAF) 2 and TRAF5, whereas 4-1BB recruits TRAF1 and TRAF2 to mediate survival signaling in T cells. The differential use of signaling adapters combined with their differential expression may explain the non-redundant roles of GITR and 4-1BB in the immune system.
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Affiliation(s)
- Laura M Snell
- Department of Immunology, University of Toronto, Toronto, ON, Canada
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17
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CD137 ligand mediates opposite effects in human and mouse NK cells and impairs NK-cell reactivity against human acute myeloid leukemia cells. Blood 2009; 115:3058-69. [PMID: 20008791 DOI: 10.1182/blood-2009-06-227934] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Natural killer (NK) cells play an important role in the immunosurveillance of leukemia. Their reactivity is governed by a balance of activating and inhibitory receptors including various members of the tumor necrosis factor receptor (TNFR) family. Here we report that human NK cells acquire expression of the TNFR family member CD137 upon activation, and NK cells of acute myeloid leukemia (AML) patients display an activated phenotype with substantial CD137 expression. CD137 ligand (CD137L) was detectable on leukemic cells in 35% of 65 investigated AML patients, but not on healthy CD34(+) cells, and expression was associated with monocytic differentiation. Bidirectional signaling following CD137-CD137L interaction induced the release of the immunomodulatory cytokines interleukin-10 and TNF by AML cells and directly diminished granule mobilization, cytotoxicity, and interferon-gamma production of human NK cells, which was restored by blocking CD137. Cocultures of NK cells with CD137L transfectants confirmed that human CD137 inhibits NK-cell reactivity, while activating signals were transduced by its counterpart on NK cells in mice. Our data underline the necessity to study the function of seemingly analog immunoregulatory molecules in mice compared with men and demonstrate that CD137-CD137L interaction enables immune evasion of AML cells by impairing NK-cell tumor surveillance in humans.
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Cheuk ATC, Wells JW, Chan L, Westwood NB, Berger SA, Yagita H, Okumura K, Farzaneh F, Mufti GJ, Guinn BA. Anti-tumor immunity in a model of acute myeloid leukemia. Leuk Lymphoma 2009; 50:447-54. [PMID: 19197726 DOI: 10.1080/10428190802653776] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Whole-cell vaccines allow the induction of anti-tumor immune responses without the need to define tumor antigens. We wished to directly compare, for the first time, the capacity of B7-1, B7-2 and 4-1BB ligand (4-1BBL) costimulatory molecules to convert murine and human acute myeloid leukemia (AML) cells into whole vaccines. 32Dc-kit is a murine myeloid cell line, which develops an AML-like disease over a protracted period, emulating human AML disease development. 32Dc-kit cells were modified to express elevated levels of B7-1, B7-2 or 4-1BBL, and each led to tumor rejection, although only mice injected with 32Dc-kit/B7-2 cells were able to reject subsequent parental tumor cell challenge. T-cell deficient nude mice were able to reject the 32Dc-kit variants, but they could not reject parental cell challenge; however, we found no evidence of cytotoxic T lymphocyte or natural killer (NK) activity ex vivo suggesting that tumor cell killing was mediated by an immune response that could not be recapitulated using purified NK or T cells as lone effectors. In human allogeneic mixed lymphocyte reactions (MLRs), we found no single costimulatory molecule was more effective, suggesting that the induction of a universal anti-tumor response will require a combination of costimulatory molecules.
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Affiliation(s)
- Adam T C Cheuk
- Department of Haematological Medicine, Allergy & Respiratory Science, MRC/Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London School of Medicine, London, UK
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19
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Abstract
Costimulation is an essential step in T-cell activation and hence, represents an important aspect in cancer immunotherapy. 4-1BB, a member of the tumor necrosis factor receptor family, has gained particular interest as a costimulatory molecule. Here, we investigated the potential of a targeted activation of 4-1BB-mediated costimulation at the tumor site by generating a recombinant antibody-cytokine fusion protein composed of a single-chain antibody fragment (scFv36) specific for the tumor stromal antigen fibroblast activation protein (FAP) and the extracellular domain of the 4-1BB ligand (4-1BBL). The scFv36-4-1BBL fusion protein is a homotrimeric molecule that binds specifically to FAP and the receptor 4-1BB. T-cell costimulation was demonstrated by interferon-gamma release of peripheral blood mononuclear cells cocultured with FAP-expressing HT1080 cells upon T-cell receptor triggering by monoclonal anti-CD3 antibody. Costimulatory activity of the scFv36-4-1BBL fusion protein was concentration dependent, ligand-specific, and substantially constrained to FAP-expressing target cell binding. Furthermore, scFv36-4-1BBL enhanced T-cell activation when the bispecific antibody scDb33CD3 (specific for FAP and CD3) was used as primary stimulus. Thus, target cell-dependent costimulation with scFv36-4-1BBL constitutes a new option to enhance T-cell activation by bispecific antibodies or antigen-dependent T-cell receptor triggering and should be useful to improve T cell-mediated antitumor responses.
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20
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Cloning, expression and characterization of monkey (Macaca fascicularis) CD137. Vet Immunol Immunopathol 2008; 126:377-81. [PMID: 18771806 DOI: 10.1016/j.vetimm.2008.07.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2008] [Revised: 07/17/2008] [Accepted: 07/21/2008] [Indexed: 11/22/2022]
Abstract
CD137 plays an important role as a co-stimulatory molecule in activated T cells. Agonistic CD137 specific antibodies have been investigated as therapeutic agents to promote tumor-specific immune responses by direct activation of T cells. As part of the pre-clinical pharmacological evaluation of cynomolgus monkeys, monkey CD137 was cloned and characterized. The deduced amino acid sequence encoded a full-length gene of 254 amino acids 95% identical to human CD137. Sequence variants identified in monkey CD137 include four splice variants lacking the transmembrane domain. These variants were detectable in human including two previously unreported variants. Two missense single nucleotide polymorphisms were detected present in 42 and 50% of 36 monkeys tested. In both monkey and human, mRNA expression of full-length CD137 and splice variants were significantly increased in peripheral blood mononuclear cells (PBMCs) upon stimulation by anti-CD3 antibodies. Recombinant monkey CD137 protein was bound with high affinity by an agonistic anti-human CD137 antibody but not by an anti-mouse CD137 antibody. In summary, compared to human, monkey CD137 showed distinct extracellular domain amino acid sequence and sequence polymorphisms. Thus, antibodies directed against epitopes in this extracellular domain could have differences in pharmacologic activity between cynomolgus monkeys and human or across individual cynomolgus monkeys.
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21
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McNamara JO, Kolonias D, Pastor F, Mittler RS, Chen L, Giangrande PH, Sullenger B, Gilboa E. Multivalent 4-1BB binding aptamers costimulate CD8+ T cells and inhibit tumor growth in mice. J Clin Invest 2008; 118:376-86. [PMID: 18060045 DOI: 10.1172/jci33365] [Citation(s) in RCA: 250] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2007] [Accepted: 10/29/2007] [Indexed: 12/14/2022] Open
Abstract
4-1BB is a major costimulatory receptor that promotes the survival and expansion of activated T cells. Administration of agonistic anti-4-1BB Abs has been previously shown to enhance tumor immunity in mice. Abs are cell-based products posing significant cost, manufacturing, and regulatory challenges. Aptamers are oligonucleotide-based ligands that exhibit specificity and avidity comparable to, or exceeding, that of Abs. To date, various aptamers have been shown to inhibit the function of their cognate target. Here, we have described the development of an aptamer that binds 4-1BB expressed on the surface of activated mouse T cells and shown that multivalent configurations of the aptamer costimulated T cell activation in vitro and mediated tumor rejection in mice. Because aptamers can be chemically synthesized, manufacturing and the regulatory approval process should be substantially simpler and less costly than for Abs. Agonistic aptamers could therefore represent a superior alternative to Abs for the therapeutic manipulation of the immune system.
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Affiliation(s)
- James O McNamara
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
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22
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Augmentation of SIV DNA vaccine-induced cellular immunity by targeting the 4-1BB costimulatory molecule. Vaccine 2008; 26:3121-34. [PMID: 18336959 DOI: 10.1016/j.vaccine.2008.02.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
DNA vaccines are effective at inducing antigen-specific cellular immune responses. Approaches to improve these responses, however, are needed. We examined the effect of stimulating 4-1BB, an activation-inducible T-cell costimulatory receptor, by intravenously co-administering anti-human 4-1BB monoclonal antibody (mAb) in DNA-immunized cynomolgus macaques. Three groups of six cynomolgus macaques were immunized intramuscularly with a DNA vaccine encoding SIV Gag antigen (pSIVgag) at weeks 0, 4 and 8. At days 12, 15, and 19, six macaques received anti-4-1BB 4E9 mAb and six macaques received anti-4-1BB 10C7 mAb. Treatment with 10C7 mAb led to a significant augmentation of SIV Gag-specific IFN-gamma, granzyme B and perforin responses. Treatment with humanized 4E9 mAb also resulted in an enhancement of SIV Gag-specific cellular responses but the magnitude was lower compared to animals receiving 10C7 mAb. These responses persisted up to week 40 and were mostly mediated by CD8(+) T cells. Treatment with anti-4-1BB mAb was more effective in driving the CD8(+) T cells toward a more differentiated CCR7(-)/CD45RA(+) effector state. This study demonstrates that targeting the 4-1BB molecule in vivo results in an enhanced and long-lasting cellular immune response. 4-1BB stimulation may be a promising approach to enhance the effectiveness of DNA vaccines.
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23
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Lu ZY, Condomines M, Tarte K, Nadal L, Delteil MC, Rossi JF, Ferrand C, Klein B. B7-1 and 4-1BB ligand expression on a myeloma cell line makes it possible to expand autologous tumor-specific cytotoxic T cells in vitro. Exp Hematol 2007; 35:443-53. [PMID: 17309825 PMCID: PMC1934405 DOI: 10.1016/j.exphem.2006.11.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2006] [Revised: 11/01/2006] [Accepted: 11/03/2006] [Indexed: 12/18/2022]
Abstract
OBJECTIVE The aim of this study was to confer an antigen-presenting cell (APC) ability on multiple myeloma cell lines (HMCLs) using B7-1 and/or 4-1BBL gene transfer. MATERIALS AND METHODS HMCLs were retrovirally transduced with B7-1 and/or 4-1BBL cDNAs. Allogeneic or autologous T cells were stimulated by coculture with B7-1- and/or 4-1BBL-transduced HMCLs in the presence of interleukin-2. T cell clones were obtained by limiting dilution. T-cell activation was assessed by interferon-gamma Elispot assays and cytotoxicity by (51)Cr release assays. RESULTS Neither primary multiple myeloma cells (MMCs) nor HMCLs expressed B7-1 or 4-1BBL, and these molecules could not be induced by CD40 triggering. HMCLs failed to stimulate allogeneic or autologous T cells. Transduction of HMCLs with B7-1 and/or 4-1BBL retroviruses induced a high expression of B7-1 and 4-1BBL molecules and a strong T-cell activation ability. Long-term cultured CD8(+) T-cell lines could be obtained by stimulation with the autologous B7-1/4-1BBL XG-19 HMCL. These cytotoxic T lymphocytes (CTL) efficiently killed the autologous parental XG-19 HMCL as well as autologous primary MMCs and allogeneic HMCLs. They did not kill autologous CD34 cells and autologous EBV cell line or natural killer target K562 cells. Cloned CTL could recognize allogeneic HMCLs, demonstrating that a shared anti-MMC repertoire was expanded. CONCLUSION Transduction with B7-1 and 4-1BBL retroviruses turned HMCLs into efficient APCs. It permitted the long-term expansion of autologous anti-tumor CTL with a shared anti-MMC repertoire, for one HMCL. These data suggest developing an immunotherapy using modified tumor cells in patients with multiple myeloma.
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Affiliation(s)
| | - Maud Condomines
- Institut de Recherche en Biothérapie
CHU MontpellierHôpital Saint-Eloi
Montpellier,FR
- UFR de médecine
Université Montpellier IMontpellier,FR
- Immunopathologie des maladies tumorales et autoimmunes
INSERM : U475 IFR76 Institut de recherche en biothérapieUniversité Montpellier ICentre de Recherche Inserm
99, Rue Puech Villa
34197 MONTPELLIER CEDEX 5,FR
| | - Karin Tarte
- Immunopathologie des maladies tumorales et autoimmunes
INSERM : U475 IFR76 Institut de recherche en biothérapieUniversité Montpellier ICentre de Recherche Inserm
99, Rue Puech Villa
34197 MONTPELLIER CEDEX 5,FR
| | - Laure Nadal
- Institut de Recherche en Biothérapie
CHU MontpellierHôpital Saint-Eloi
Montpellier,FR
| | | | - Jean-François Rossi
- Service d'hématologie et oncologie médicale
CHU Montpellier Hôpital LapeyronieUniversité Montpellier I34000 Montpellier,FR
| | | | - Bernard Klein
- Unité de thérapie cellulaire
CHU MontpellierFR
- Institut de Recherche en Biothérapie
CHU MontpellierHôpital Saint-Eloi
Montpellier,FR
- UFR de médecine
Université Montpellier IMontpellier,FR
- Immunopathologie des maladies tumorales et autoimmunes
INSERM : U475 IFR76 Institut de recherche en biothérapieUniversité Montpellier ICentre de Recherche Inserm
99, Rue Puech Villa
34197 MONTPELLIER CEDEX 5,FR
- * Correspondence should be adressed to: Bernard Klein
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24
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Mazzolini G, Murillo O, Atorrasagasti C, Dubrot J, Tirapu I, Rizzo M, Arina A, Alfaro C, Azpilicueta A, Berasain C, Perez-Gracia JL, Gonzalez A, Melero I. Immunotherapy and immunoescape in colorectal cancer. World J Gastroenterol 2007; 13:5822-31. [PMID: 17990348 PMCID: PMC4205429 DOI: 10.3748/wjg.v13.i44.5822] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Immunotherapy encompasses a variety of interventions and techniques with the common goal of eliciting tumor cell destructive immune responses. Colorectal carcinoma often presents as metastatic disease that impedes curative surgery. Novel strategies such as active immunization with dendritic cells (DCs), gene transfer of cytokines into tumor cells or administration of immunostimulatory monoclonal antibodies (such as anti-CD137 or anti-CTLA-4) have been assessed in preclinical studies and are at an early clinical development stage. Importantly, there is accumulating evidence that chemotherapy and immunotherapy can be combined in the treatment of some cases with colorectal cancer, with synergistic potentiation as a result of antigens cross-presented by dendritic cells and/or elimination of competitor or suppressive T lymphocyte populations (regulatory T-cells). However, genetic and epigenetic unstable carcinoma cells frequently evolve mechanisms of immunoevasion that are the result of either loss of antigen presentation, or an active expression of immunosuppressive substances. Some of these actively immunosuppressive mechanisms are inducible by cytokines that signify the arrival of an effector immune response. For example, induction of 2, 3 indoleamine dioxygenase (IDO) by IFNγ in colorectal carcinoma cells. Combinational and balanced strategies fostering antigen presentation, T-cell costimulation and interference with immune regulatory mechanisms will probably take the stage in translational research in the treatment of colorectal carcinoma.
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25
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Elpek KG, Yolcu ES, Franke DDH, Lacelle C, Schabowsky RH, Shirwan H. Ex Vivo Expansion of CD4+CD25+FoxP3+ T Regulatory Cells Based on Synergy between IL-2 and 4-1BB Signaling. THE JOURNAL OF IMMUNOLOGY 2007; 179:7295-304. [DOI: 10.4049/jimmunol.179.11.7295] [Citation(s) in RCA: 108] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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26
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Chen L, Huang TG, Meseck M, Mandeli J, Fallon J, Woo SLC. Rejection of metastatic 4T1 breast cancer by attenuation of Treg cells in combination with immune stimulation. Mol Ther 2007; 15:2194-202. [PMID: 17968355 DOI: 10.1038/sj.mt.6300310] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
4T1 breast carcinoma is a highly malignant and poorly immunogenic murine tumor model that resembles advanced breast cancer in humans, and is refractory to most immune stimulation-based treatments. We hypothesize that the ineffectiveness of immune stimulatory treatment is mediated by the suppressive effects of CD4(+)CD25(+) regulatory T (Treg) cells, which can be attenuated by engaging the glucocorticoid-induced tumor necrosis factor receptor family-related protein with its natural ligand (GITRL); further, combination treatment with existing immune stimulation regimens will augment anti-tumor immunity and eradicate metastatic 4T1 tumors in mice.A soluble homodimeric form of mouse GITRL (mIg-mGITRLs) was molecularly constructed and used to treat orthotopic 4T1 tumors established in immune-competent, syngeneic Balb/c mice. When applied in combination with adenovirus-mediated intratumoral murine granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin-12 (IL-12) gene delivery plus systemic 4-1BB activation, mIg-mGITRLs attenuated the immune-suppressive function of splenic Treg cells, which led to elevated interferon-gamma (IFN-gamma) production, tumor-specific cytolytic T-cell activities, tumor rejection and long-term survival in 65% of the animals without apparent toxicities. The results demonstrate that addition of mIg-mGITRLs to an immune-stimulatory treatment regimen significantly improved long-term survival without apparent toxicity, and could potentially be clinically translated into an effective and safe treatment modality for metastatic breast cancer in patients.
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Affiliation(s)
- Li Chen
- Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York 10029-6574, USA
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27
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Serghides L, Vidric M, Watts TH. Approaches to studying costimulation of human antiviral T cell responses: prospects for immunotherapeutic vaccines. Immunol Res 2006; 35:137-50. [PMID: 17003516 DOI: 10.1385/ir:35:1:137] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/1999] [Revised: 11/30/1999] [Accepted: 11/30/1999] [Indexed: 12/19/2022]
Abstract
The generation of strong and specific CD8 T cell responses is important in the control of viral infections. Costimulatory molecules provide signals necessary for the development or maintenance of these responses. A major focus of our laboratory is to investigate the role of costimulatory molecules of the TNFR and CD28 families in antiviral responses. Our aim is to translate information obtained using murine models to the study of these molecules using human cells. We have devised an in vitro system using recombinant replication- deficient adenovirus to deliver costimulatory molecules to antigen-presenting cells that are then used to stimulate autologous T cells from both healthy and HIV-infected individuals. Here we describe our findings and discuss the implications of incorporating costimulatory molecules into viral vector vaccine strategies.
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Affiliation(s)
- Lena Serghides
- Department of Immunology, University of Toronto, Toronto, Canada
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28
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Xu DP, Sauter BV, Huang TG, Meseck M, Woo SLC, Chen SH. The systemic administration of Ig-4-1BB ligand in combination with IL-12 gene transfer eradicates hepatic colon carcinoma. Gene Ther 2006; 12:1526-33. [PMID: 15973445 DOI: 10.1038/sj.gt.3302556] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
We have previously shown that the local-membrane bound 4-1BB ligand and IL-12 gene transfer induced a significant antitumor response in a mouse colon carcinoma model. However, a high viral dose was required in order to achieve the best efficacy. In this study, we hypothesize that the systemic administration of soluble Ig-4-1BB ligand can give rise to better T-cell immune activation than local gene delivery. With potential clinical applications in mind, we further compare whether the natural 4-1BB ligand fused to mouse IgG2a (Ig-4-1BBL) would be as effective as the agonistic anti-4-1BB antibody. The dimeric form of Ig-4-1BBL was purified from HeLa cells transduced with a recombinant adenovirus (ADV/Ig-4-1BBL) expressing Ig-4-1BBL. Functional activity was confirmed by the ligand's ability to bind to activated splenic T cells or bone marrow (BM)-derived dendritic cells (DCs) that express 4-1BB receptor. The soluble Ig-4-1BBL efficiently costimulated CD3-activated T-cell proliferation in vitro. More importantly, it induced tumor-specific CTLs as effectively as the agonistic anti-4-1BB antibody. When combined with IL-12 gene transfer, systemic administration of the Ig-4-1BBL proved to be more potent than local gene delivery. In addition, the Ig-4-1BBL is as potent as the agonistic anti-4-1BB antibody for the treatment of hepatic MCA26 colon carcinoma, resulting in 50% complete tumor regression and long-term survival. In long-term surviving mice, both treatment modalities induced persistent tumor-specific CTL activity. In summary, these results suggest that the systemic delivery of Ig-4-1BBL can generate a better antitumor response than local gene delivery. Ig-4-1BBL had equivalent biological functions when compared to the agonistic anti-4-1BB antibody. Thus, soluble 4-1BBL dimmer can be developed as a promising agent for cancer therapy in humans.
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Affiliation(s)
- D-P Xu
- Department of Gene and Cell Medicine, Mount Sinai School of Medicine, NY 10029, USA
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29
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Waehler R, Ittrich H, Mueller L, Krupski G, Ameis D, Schnieders F. Low-dose adenoviral immunotherapy of rat hepatocellular carcinoma using single-chain interleukin-12. Hum Gene Ther 2005; 16:307-17. [PMID: 15812226 DOI: 10.1089/hum.2005.16.307] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Generation of antitumor immunity by adenoviral gene transfer of interleukin-12 (IL-12) is a very promising concept in cancer gene therapy. Systemically, IL-12 has provoked toxic side effects at therapeutically relevant doses. Native IL-12 lacks effectiveness in clinical trials even when expressed intratumorally from adenoviral vectors. Our strategy was to increase the therapeutic efficacy of IL-12 by expressing a fusion protein of its two subunits (scIL-12) in an adenoviral vector and to evaluate the effects after intratumoral administration. In a rat model of hepatocellular carcinoma, this vector revealed antitumor effects even at a low dosage of 4.6 x 10(5) i.u. in a dose-dependent manner. Long-term antitumor effects were determined at 2.3 x 10(6) and 2.3 x 10(7) i.u. per animal, resulting in 82% and 90% surviving animals, respectively. Magnetic resonance imaging (MRI) enabled individual tumor size follow-up and revealed the scIL-12 effects on large tumors. Treating one hepatic lesion also led to tumor elimination in a second non-treated hepatic lesion. Animals rechallenged with tumor cells remained tumor-free. Compared to studies applying native IL-12, our data show that the fusion of IL-12 subunits provides approximately 1000-fold higher biological activity. As a consequence of the observed gain in activity, scIL12 promises a substantially improved antitumor efficacy and safety profile of intratumoral adenoviral IL-12 immunotherapy, supporting its clinical use.
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Affiliation(s)
- Reinhard Waehler
- Center of Experimental Medicine, Institute of Biochemistry and Molecular Biology II: Molecular Cell Biology, University Hospital Hamburg-Eppendorf, D-20246 Hamburg, Germany
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30
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Abstract
The activation of T cells plays a central role in antitumor immunity. In order to activate naïve T cells, two key signals are required. Signal one is provided through the T-cell receptor (TCR) while signal two is that of costimulation. The CD28:B7 molecules are one of the best-studied costimulatory pathways, thought to be the main mechanism through which primary T-cell stimulation occurs. However, a number of molecules have been identified which serve to amplify and diversify the T-cell response, following initial T-cell activation. These include the more recently described 4-1BB:4-1BB ligand (4-1BBL) molecules. 4-1BB:4-1BBL are a member of the TNFR:TNF ligand family, which are expressed on T cells and antigen-presenting cells (APCs), respectively. Therapies utilizing the 4-1BB:4-1BBL signaling pathway have been shown to have antitumor effects in a number of model systems. In this paper, we focus on the 4-1BB:4-1BBL costimulatory molecules. In particular, we will describe the structure and function of the 4-1BB molecule, its receptor and how 4-1BB:4-1BBL costimulation has and may be used for the immunotherapy of cancer.
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Affiliation(s)
- Adam T C Cheuk
- Leukaemia Science Laboratories, Department of Haematological Medicine, Guy's, King's & St Thomas' School of Medicine, King's College London, Rayne Institute, 123 Coldharbour Lane, London SE5 9NU, UK
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31
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You TG, Wang HS, Yang JH, Qian QJ, Fan RF, Wu MC. Transfection of IL-2 and/or IL-12 genes into spleen in treatment of rat liver cancer. World J Gastroenterol 2004; 10:2190-4. [PMID: 15259063 PMCID: PMC4724966 DOI: 10.3748/wjg.v10.i15.2190] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To test the efficacy of gene therapy in rat liver tumor.
METHODS: A retroviral vector GCIL12EIL2PN encoding human IL-2 (hIL-2) and mouse IL-12 (mIL-12) fused gene and its packaging cell were constructed. The packaging cell lines contained of IL-2 and/or IL-12 genes were injected intrasplenically to transfect splenocyte at different time. The therapeutic effect, immune function and toxic effect were evaluated.
RESULTS: The average survival times of the 4 groups using IL genes at days 1, 3, 5 and 7 after tumor implantation were 53.3 ± 3.7, 49.3 ± 4.2, 31.0 ± 2.1 and 24.3 ± 1.4 d respectively in IL-2/IL-12 fused gene group, 25.0 ± 2.5, 23.5 ± 2.0, 18.3 ± 2.4 and 12.0 ± 1.8 d respectively in IL-2 gene treatment group, and 39.0 ± 4.8, 32.0 ± 3.9, 23.0 ± 2.5 and 19.4 ± 2.1 d respectively in IL-12 gene treatment group (P < 0.01, n = 10). In the IL-12/IL-2 fused gene treatment group, 30% of rats treated at days 1 and 3 survived more than 60 d and serum mIL-12 and hIL-2 levels were still high at day 3 after treatment. Compared with IL alone, NK cell activity was strongly stimulated by IL-2/IL-12 gene. Microscopy showed that livers were infiltrated by a number of lymphocytes.
CONCLUSION: IL-2 and/or IL-12 genes injected directly into spleen increase serum IL-2 and IL-12 levels and enhance the NK cell activity, which may inhibit the liver tumor growth. The therapy of fused gene IL-2/IL-12 is of low toxicity and relatively high NK cell activity. Our data suggest that IL-2/IL-12 fused gene may be a safe and efficient gene therapy for liver tumor. The gene therapy should be administrated as early as possible.
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Affiliation(s)
- Tian-Geng You
- Department of Comprehensive Treatment III, Eastern Hepatobiliary Hospital, Second Military Medical University, Changhai Road 225, Shanghai 200433, China
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32
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Tirapu I, Arina A, Mazzolini G, Duarte M, Alfaro C, Feijoo E, Qian C, Chen L, Prieto J, Melero I. Improving efficacy of interleukin-12-transfected dendritic cells injected into murine colon cancer with anti-CD137 monoclonal antibodies and alloantigens. Int J Cancer 2004; 110:51-60. [PMID: 15054868 DOI: 10.1002/ijc.20093] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Intralesional administration of cultured dendritic cells (DCs) engineered to produce IL-12 by in vitro infection with recombinant adenovirus frequently displays eradicating efficacy against established subcutaneous tumors derived from the CT26 murine colon carcinoma cell line. The elicited response is mainly mediated by cytolytic T lymphocytes. In order to search for strategies that would enhance the efficacy of the therapeutic procedure against less immunogenic tumors, we moved onto malignancies derived from the inoculation of MC38 colon cancer cells that are less prone to undergo complete regression upon a single intratumoral injection of IL-12-secreting DCs. In this model, we found that repeated injections of such DCs, as opposed to a single injection, achieved better efficacy against both the injected and a distantly implanted tumor; that the use of semiallogeneic DCs that are mismatched in one MHC haplotype with the tumor host showed slightly better efficacy; and that the combination of this treatment with systemic injections of immunostimulatory anti-CD137 (4-1BB) monoclonal antibody achieved potent combined effects that correlated with the antitumor immune response measured in IFN-gamma ELISPOT assays. The elicited systemic immune response eradicates concomitant untreated lesions in most cases. Curative efficacy was also found against some tumors established for 2 weeks when these strategies were used in combination. These are preclinical pieces of evidence to be considered in order to enhance the therapeutic benefit of a strategy that is currently being tested in clinical trials. Supplementary Material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html.
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Affiliation(s)
- Iñigo Tirapu
- Gene Therapy Division, Fundación para la Investigación Médica Aplicada, University of Navarre, Irunlarrea s/n 31008 Pamplona, Navarre, Spain
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Imai C, Mihara K, Andreansky M, Nicholson IC, Pui CH, Geiger TL, Campana D. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 2004; 18:676-84. [PMID: 14961035 DOI: 10.1038/sj.leu.2403302] [Citation(s) in RCA: 617] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
To develop a therapy for drug-resistant B-lineage acute lymphoblastic leukemia (ALL), we transduced T lymphocytes with anti-CD19 chimeric receptors, consisting of an anti-CD19 single-chain variable domain (reactive with most ALL cases), the hinge and transmembrane domains of CD8alpha, and the signaling domain of CD3zeta. We compared the antileukemic activity mediated by a novel receptor ('anti-CD19-BB-zeta') containing the signaling domain of 4-1BB (CD137; a crucial molecule for T-cell antitumor activity) to that of a receptor lacking costimulatory molecules. Retroviral transduction produced efficient and durable receptor expression in human T cells. Lymphocytes expressing anti-CD19-BB-zeta receptors exerted powerful and specific cytotoxicity against ALL cells, which was superior to that of lymphocytes with receptors lacking 4-1BB. Anti-CD19-BB-zeta lymphocytes were remarkably effective in cocultures with bone marrow mesenchymal cells, and against leukemic cells from patients with drug-resistant ALL: as few as 1% anti-CD19-BB-zeta-transduced T cells eliminated most ALL cells within 5 days. These cells also expanded and produced interleukin-2 in response to ALL cells at much higher rates than those of lymphocytes expressing equivalent receptors lacking 4-1BB. We conclude that anti-CD19 chimeric receptors containing 4-1BB are a powerful new tool for T-cell therapy of B-lineage ALL and other CD19+ B-lymphoid malignancies.
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MESH Headings
- Antigens, CD
- Antigens, CD19/immunology
- Burkitt Lymphoma/pathology
- Burkitt Lymphoma/therapy
- CD3 Complex/chemistry
- CD3 Complex/genetics
- CD3 Complex/pharmacology
- CD8 Antigens/chemistry
- CD8 Antigens/genetics
- CD8 Antigens/pharmacology
- Cell Line, Tumor
- Coculture Techniques
- Cytotoxicity Tests, Immunologic
- Humans
- Immunoconjugates/genetics
- Immunoconjugates/pharmacology
- Immunoglobulin Variable Region/genetics
- Immunoglobulin Variable Region/pharmacology
- Immunotherapy
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy
- Protein Structure, Tertiary
- Receptors, Nerve Growth Factor/genetics
- Receptors, Nerve Growth Factor/therapeutic use
- Receptors, Tumor Necrosis Factor/genetics
- Receptors, Tumor Necrosis Factor/therapeutic use
- Recombinant Fusion Proteins/genetics
- Recombinant Fusion Proteins/pharmacology
- T-Lymphocytes/cytology
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- Transduction, Genetic
- Tumor Necrosis Factor Receptor Superfamily, Member 9
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Affiliation(s)
- C Imai
- Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN 38105-2794, USA
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Wan YL, Zheng SS, Zhao ZC, Li MW, Jia CK, Zhang H. Expression of co-stimulator 4-1BB molecule in hepatocellular carcinoma and adjacent non-tumor liver tissue, and its possible role in tumor immunity. World J Gastroenterol 2004; 10:195-9. [PMID: 14716821 PMCID: PMC4717002 DOI: 10.3748/wjg.v10.i2.195] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To investigate the expression of 4-1BB molecule in hepatocellular carcinoma (HCC) and its adjacent tissues.
METHODS: Reverse transcription–polymerase chain reaction (RT-PCR) was used to determine the gene expression of 4-1BB in hepatocarcinoma and its adjacent tissues, and peripheral blood mononuclear cells (PBMCs) from both HCC and health control groups. Flow cytometry was used to analyse the phenotypes of T cell subsets from the blood of HCC patients and healthy volunteers, and further to determine whether 4-1BB molecules were also expressed on the surface of CD4+ and CD8+ T cells. The localization of 4-1BB proteins on tumor infiltrating T cells was determined by direct immunofluorescence cytochemical staining and detected by confocal microscopy.
RESULTS: 4-1BB mRNA, which was not detectable in normal liver, was found in 19 liver tissues adjacent to tumor edge (< 1.0 cm). Low expression of 4-1BB mRNA was shown in 8 tumor tissues and 6 liver tissues located within 1 to 5 cm away from tumor edge. In PBMCs, 4-1BB mRNA was almost not detected. Percentage of CD4+, CD8+ and CD3+/CD25+ T cells, as well as ratio of CD4 to CD8 revealed no difference between groups (P > 0.05, respectively), while a significant lower percentage of CD3+ T cell was found in HCC group as compared to healthy control group (P < 0.05). However, 4-1BB molecules were almost not found on the surface of CD4+ and CD8+ T cells in HCC and healthy control group. Double-staining of 4-1BB+/CD4+ and 4-1BB+/CD8+ immunofluorescence on tumor infiltrating T cells was detected in 13 liver tissues adjacent to tumor edge (< 1.0 cm) by confocal microscopy.
CONCLUSION: Although HCC may escape from immune attack by weak immunogenicity or downregulated expression of MHC-1 molecules on the tumor cell surface, tumor infiltrating T cells can be activated via other costimulatory signal pathways to exert a limited antitumor effect on local microenvironment. The present study also implicates that modulating 4-1BB/4-1BBL costimulatory pathway may be an effective immunotherapy strateg to augment the host response.
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MESH Headings
- Adult
- Aged
- Antigens, CD
- CD4-Positive T-Lymphocytes/physiology
- CD8-Positive T-Lymphocytes/physiology
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/physiopathology
- Female
- Gene Expression Regulation, Neoplastic/immunology
- Humans
- Liver Neoplasms/immunology
- Liver Neoplasms/physiopathology
- Male
- Middle Aged
- Phenotype
- RNA, Messenger/analysis
- Receptors, Nerve Growth Factor/genetics
- Receptors, Nerve Growth Factor/immunology
- Receptors, Tumor Necrosis Factor/genetics
- Receptors, Tumor Necrosis Factor/immunology
- Tumor Necrosis Factor Receptor Superfamily, Member 9
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Affiliation(s)
- Yun-Le Wan
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China.
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Xu D, Gu P, Pan PY, Li Q, Sato AI, Chen SH. NK and CD8+ T cell-mediated eradication of poorly immunogenic B16-F10 melanoma by the combined action of IL-12 gene therapy and 4-1BB costimulation. Int J Cancer 2004; 109:499-506. [PMID: 14991570 DOI: 10.1002/ijc.11696] [Citation(s) in RCA: 79] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
In previous reports, systemic administration of a stimulatory monoclonal antibody directed against the 4-1BB receptor had no effect on survival or tumor burden in mice inoculated with the poorly immunogenic B16-F10 melanoma. We combined IL-12 gene transfer with 4-1BB costimulation to explore a previously noted cooperative anti-tumor effect against this model tumor. We hypothesize that the innate immune response mediated by IL-12-activated natural killer (NK) cells initiates the activation of the immune system, leading to the priming of T cells, whereas 4-1BB costimulation enhances the function of primed tumor-specific T cells. The effect of the combination therapy on the growth of subcutaneous (s.c.) tumors and pulmonary metastasis was examined. The combination therapy significantly retarded the growth of subcutaneously-inoculated tumors, and 50% of tumor-bearing mice survived with complete tumor regression. In contrast, neither IL-12 gene transfer nor anti-4-1BB antibody administration alone was as effective. Enhanced CTL activity against both B16-F10 tumor cells and TRP-2-pulsed EL4 syngeneic tumor cells was observed in tumor-bearing animals treated with the combination therapy 2 weeks after treatment and, in long-term survivors from this combination therapy, at >120 days. In a pulmonary metastatic model, only the combination therapy generated significant protection against metastasis. In vivo depletion of NK or CD8(+) but not CD4(+) subsets eliminated the protective immunity. Furthermore, NK cell depletion significantly reduced both tumor-specific CTL activity and the number of tumor-specific IFN-gamma-producing cells, suggesting that this synergistic effect requires the participation of both NK and CD8(+) T cells.
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MESH Headings
- Adenoviridae/genetics
- Animals
- Antibodies, Monoclonal/therapeutic use
- Antigens, CD
- CD8-Positive T-Lymphocytes/immunology
- Combined Modality Therapy
- Drug Synergism
- Female
- Genetic Therapy
- Genetic Vectors/administration & dosage
- Genetic Vectors/genetics
- Immunity, Cellular
- Immunotherapy
- Interleukin-12/administration & dosage
- Killer Cells, Natural/immunology
- Lung Neoplasms/immunology
- Lung Neoplasms/secondary
- Lung Neoplasms/therapy
- Lymphocyte Depletion
- Melanoma, Experimental/immunology
- Melanoma, Experimental/pathology
- Melanoma, Experimental/therapy
- Mice
- Mice, Inbred C57BL
- Receptors, Nerve Growth Factor/immunology
- Receptors, Tumor Necrosis Factor/immunology
- Skin Neoplasms/immunology
- Skin Neoplasms/therapy
- T-Lymphocytes, Cytotoxic
- Tumor Necrosis Factor Receptor Superfamily, Member 9
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Affiliation(s)
- Dongping Xu
- Carl C. Icahn Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
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Kim YJ, Li G, Broxmeyer HE. 4-1BB ligand stimulation enhances myeloid dendritic cell maturation from human umbilical cord blood CD34+ progenitor cells. JOURNAL OF HEMATOTHERAPY & STEM CELL RESEARCH 2002; 11:895-903. [PMID: 12590704 DOI: 10.1089/152581602321080556] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
In humans, at least two subsets of dendritic cells (DCs) are identified on the basis of differential surface expression of CD11c antigens. CD11c(+) and CD11c(-) cells are respectively of myeloid and lympholoid origin and functionally distinct, eliciting inflammatory and tolerant T cell responses. We investigated whether 4-1BB ligand (4-1BBL), a member of the tumor necrosis factor (TNF) family, is involved in the maturation process to mature myeloid DCs during in vitro DC differentiation from immature DCs derived from human umbilical cord blood (CB) CD34(+) progenitor cells. Enhanced levels of CD11c as well as immunostimulatory molecules such as CD86, MHC class II, and 4-1BBL were induced in response to 4-1BBL stimulation. These changes were accompanied by noticeable morphological transition from nonadherent to adherent myeloid-like DCs. Stimulation of 4-1BBL on DCs with 4-1BB-Fc or with 4-1BB-transfected Jurkat cells resulted in acquisition of capacity for the immature DCs to produce interleukin-12 (IL-12). This suggests that 4-1BBL may be an important mediator for maturation of CD11c(+) myeloid DCs, information of possible relevance for the design of DC-based vaccines with enhanced activity.
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Affiliation(s)
- Young-June Kim
- Department of Microbiology and Immunology, Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202-5254, USA
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