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Rimailho L, Faria C, Domagala M, Laurent C, Bezombes C, Poupot M. γδ T cells in immunotherapies for B-cell malignancies. Front Immunol 2023; 14:1200003. [PMID: 37426670 PMCID: PMC10325712 DOI: 10.3389/fimmu.2023.1200003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 05/11/2023] [Indexed: 07/11/2023] Open
Abstract
Despite the advancements in therapy for B cell malignancies and the increase in long-term survival of patients, almost half of them lead to relapse. Combinations of chemotherapy and monoclonal antibodies such as anti-CD20 leads to mixed outcomes. Recent developments in immune cell-based therapies are showing many encouraging results. γδ T cells, with their potential of functional plasticity and their anti-tumoral properties, emerged as good candidates for cancer immunotherapies. The representation and the diversity of γδ T cells in tissues and in the blood, in physiological conditions or in B-cell malignancies such as B cell lymphoma, chronic lymphoblastic leukemia or multiple myeloma, provides the possibility to manipulate them with immunotherapeutic approaches for these patients. In this review, we summarized several strategies based on the activation and tumor-targeting of γδ T cells, optimization of expansion protocols, and development of gene-modified γδ T cells, using combinations of antibodies and therapeutic drugs and adoptive cell therapy with autologous or allogenic γδ T cells following potential genetic modifications.
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Affiliation(s)
- Léa Rimailho
- Cancer Research Center of Toulouse (CRCT), UMR1037 Inserm-Univ. Toulouse III Paul Sabatier-ERL5294 CNRS, Toulouse, France
| | - Carla Faria
- Cancer Research Center of Toulouse (CRCT), UMR1037 Inserm-Univ. Toulouse III Paul Sabatier-ERL5294 CNRS, Toulouse, France
| | - Marcin Domagala
- Cancer Research Center of Toulouse (CRCT), UMR1037 Inserm-Univ. Toulouse III Paul Sabatier-ERL5294 CNRS, Toulouse, France
| | - Camille Laurent
- Cancer Research Center of Toulouse (CRCT), UMR1037 Inserm-Univ. Toulouse III Paul Sabatier-ERL5294 CNRS, Toulouse, France
- Department of Pathology, Institut Universitaire du Cancer de Toulouse - Oncopôle, Toulouse, France
| | - Christine Bezombes
- Cancer Research Center of Toulouse (CRCT), UMR1037 Inserm-Univ. Toulouse III Paul Sabatier-ERL5294 CNRS, Toulouse, France
| | - Mary Poupot
- Cancer Research Center of Toulouse (CRCT), UMR1037 Inserm-Univ. Toulouse III Paul Sabatier-ERL5294 CNRS, Toulouse, France
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Chan KF, Duarte JDG, Ostrouska S, Behren A. γδ T Cells in the Tumor Microenvironment-Interactions With Other Immune Cells. Front Immunol 2022; 13:894315. [PMID: 35880177 PMCID: PMC9307934 DOI: 10.3389/fimmu.2022.894315] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 06/15/2022] [Indexed: 01/02/2023] Open
Abstract
A growing number of studies have shown that γδ T cells play a pivotal role in mediating the clearance of tumors and pathogen-infected cells with their potent cytotoxic, cytolytic, and unique immune-modulating functions. Unlike the more abundant αβ T cells, γδ T cells can recognize a broad range of tumors and infected cells without the requirement of antigen presentation via major histocompatibility complex (MHC) molecules. Our group has recently demonstrated parts of the mechanisms of T-cell receptor (TCR)-dependent activation of Vγ9Vδ2+ T cells by tumors following the presentation of phosphoantigens, intermediates of the mevalonate pathway. This process is mediated through the B7 immunoglobulin family-like butyrophilin 2A1 (BTN2A1) and BTN3A1 complexes. Such recognition results in activation, a robust immunosurveillance process, and elicits rapid γδ T-cell immune responses. These include targeted cell killing, and the ability to produce copious quantities of cytokines and chemokines to exert immune-modulating properties and to interact with other immune cells. This immune cell network includes αβ T cells, B cells, dendritic cells, macrophages, monocytes, natural killer cells, and neutrophils, hence heavily influencing the outcome of immune responses. This key role in orchestrating immune cells and their natural tropism for tumor microenvironment makes γδ T cells an attractive target for cancer immunotherapy. Here, we review the current understanding of these important interactions and highlight the implications of the crosstalk between γδ T cells and other immune cells in the context of anti-tumor immunity.
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Affiliation(s)
- Kok Fei Chan
- Olivia Newton-John Cancer Research Institute, and School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia
| | - Jessica Da Gama Duarte
- Olivia Newton-John Cancer Research Institute, and School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia
| | - Simone Ostrouska
- Olivia Newton-John Cancer Research Institute, and School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia
| | - Andreas Behren
- Olivia Newton-John Cancer Research Institute, and School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia
- Department of Medicine, University of Melbourne, Parkville, VIC, Australia
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Human γδ T Cell Subsets and Their Clinical Applications for Cancer Immunotherapy. Cancers (Basel) 2022; 14:cancers14123005. [PMID: 35740670 PMCID: PMC9221220 DOI: 10.3390/cancers14123005] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 06/15/2022] [Accepted: 06/16/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Research into the immunotherapeutic potential of T cells has predominantly focused on conventional alpha beta (αβ) T cells, which recognize peptide antigens presented by polymorphic major histocompatibility complex (MHC) class I and class II molecules. However, innate-like T cells, such as gamma delta (γδ) T cells, also play important roles in antitumor immunity. Here, we review the current understanding of γδ T cells in antitumor immunity and discuss strategies that could potentially maximize their potential in cancer immunotherapy. Abstract Gamma delta (γδ) T cells are a minor population of T cells that share adaptive and innate immune properties. In contrast to MHC-restricted alpha beta (αβ) T cells, γδ T cells are activated in an MHC-independent manner, making them ideal candidates for developing allogeneic, off-the-shelf cell-based immunotherapies. As the field of cancer immunotherapy progresses rapidly, different subsets of γδ T cells have been explored. In addition, γδ T cells can be engineered using different gene editing technologies that augment their tumor recognition abilities and antitumor functions. In this review, we outline the unique features of different subsets of human γδ T cells and their antitumor properties. We also summarize the past and the ongoing pre-clinical studies and clinical trials utilizing γδ T cell-based cancer immunotherapy.
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Galati D, Zanotta S, Bocchino M, De Filippi R, Pinto A. The subtle interplay between gamma delta T lymphocytes and dendritic cells: is there a role for a therapeutic cancer vaccine in the era of combinatorial strategies? Cancer Immunol Immunother 2021; 70:1797-1809. [PMID: 33386466 PMCID: PMC10991494 DOI: 10.1007/s00262-020-02805-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 11/21/2020] [Indexed: 12/12/2022]
Abstract
Human gamma delta (γδ) T cells represent heterogeneous subsets of unconventional lymphocytes with an HLA-unrestricted target cell recognition. γδ T cells display adaptive clonally restricted specificities coupled to a powerful cytotoxic function against transformed/injured cells. Dendritic cells (DCs) are documented to be the most potent professional antigen-presenting cells (APCs) able to induce adaptive immunity and support the innate immune response independently from T cells. Several data show that the cross-talk of γδ T lymphocytes with DCs can play a crucial role in the orchestration of immune response by bridging innate to adaptive immunity. In the last decade, DCs, as well as γδ T cells, have been of increasing clinical interest, especially as monotherapy for cancer immunotherapy, even though with unpredictable results mainly due to immune suppression and/or tumor-immune escape. For these reasons, new vaccine strategies have to be explored to reach cancer immunotherapy's full potential. The effect of DC-based vaccines on γδ T cell is less extensively investigated, and a combinatorial approach using DC-based vaccines with γδ T cells might promote a strong synergy for long-term tumor control and protection against escaping tumor clones. Here, we discuss the therapeutic potential of the interaction between DCs and γδ T cells to improve cancer vaccination. In particular, we describe the most relevant and updated evidence of such combinatorial approaches, including the use of Zoledronate, Interleukin-15, and protamine RNA, also looking towards future strategies such as CAR therapies.
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Affiliation(s)
- Domenico Galati
- Hematology-Oncology and Stem Cell Transplantation Unit, Department of Hematology and Developmental Therapeutics, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy.
| | - Serena Zanotta
- Hematology-Oncology and Stem Cell Transplantation Unit, Department of Hematology and Developmental Therapeutics, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy
| | - Marialuisa Bocchino
- Department of Clinical Medicine and Surgery, Università degli Studi di Napoli Federico II, Naples, Italy
| | - Rosaria De Filippi
- Department of Clinical Medicine and Surgery, Università degli Studi di Napoli Federico II, Naples, Italy
| | - Antonio Pinto
- Hematology-Oncology and Stem Cell Transplantation Unit, Department of Hematology and Developmental Therapeutics, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy
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Zou B, Xia S, Du X, Xu Y, Ning N, Li S, Teng D, Li H, Hu Z, Hu S, Wang Y. Treatment Effect of Tuftsin and Antigen Peptide Combined with Immune Cells on Colorectal Cancer. Med Sci Monit 2019; 25:5465-5472. [PMID: 31333222 PMCID: PMC6668490 DOI: 10.12659/msm.915037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background The aim of this study was to investigate the effect of antigenic peptides on dendritic cell maturation and activation as well as the role of dendritic cell induced cell function. The tumor-specific cytotoxic T lymphocytes induced by activation of the dendritic cells were also evaluated. Material/Methods SW-480 cell lysate and peptide antigens were selected as adjuvants in dendritic cell sensitization, and tuftsin was used to induce the phagocytosis of dendritic cells. Immature dendritic cells were stimulated with the antigen and adjuvant as follows: group A was negative control; group B was SW-480 (20 μg/mL); group C was SW-480 (20 μg/mL)+tumor necrosis factor (TNF)-α (10 μg/mL); group D was SW-480 (20 μg/mL)+tuftsin (20 μg/mL); group E was antigen peptide (2 μg/mL); group F was antigen peptide (2 μg/mL)+TNF-α (10 μg/mL); group G was antigen peptide (2 μg/mL)+tuftsin (20 μg/mL). Cytotoxic T lymphocytes activation and in vitro anti-tumor effects were examined by detecting the maturation marks of dendritic cells as well as interleukin (IL)-10 and IL-12 levels secreted by dendritic cells. Cells with the strongest immunizing effects were injected into nude mice and tumor suppression status was evaluated. Results Group D (SW-480+tuftsin), group E (antigen peptides), group F (antigen peptide+TNF-α), and group G (antigen peptides+tuftsin) displayed significant differences compared to the control group (P<0.05). Group G (antigen peptides+tuftsin) could also promote the secretion of cytokines IL-12, as well as inhibit cytokine IL-10 secretion, compared to the other experimental groups (P<0.05). In the in vivo experiments of tumor inhibitions, antigenic polypeptide+tuftsin was the most effective (P<0.05). Conclusions Combination of cytotoxic T lymphocytes and T peptide therapy in treating human colorectal cancer might be used as a new treatment strategy based on adoptive cellular immunotherapy.
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Affiliation(s)
- Boyuan Zou
- Department of Retroperitoneal Tumor Surgery, Peking University International Hospital, Beijing, China (mainland).,Department of General Surgery, The General Hospital of People's Liberation Army, Beijing, China (mainland)
| | - Shaoyou Xia
- Department of General Surgery, The General Hospital of People's Liberation Army, Beijing, China (mainland)
| | - Xiaohui Du
- Department of General Surgery, The General Hospital of People's Liberation Army, Beijing, China (mainland)
| | - Yingxin Xu
- Department of General Surgery, The General Hospital of People's Liberation Army, Beijing, China (mainland)
| | - Ning Ning
- Department of General Surgery, The General Hospital of People's Liberation Army, Beijing, China (mainland).,Department of Gastrointestinal Surgery, Peking University International Hospital, Beijing, China (mainland)
| | - Songyan Li
- Department of General Surgery, The General Hospital of People's Liberation Army, Beijing, China (mainland)
| | - Da Teng
- Department of General Surgery, The General Hospital of People's Liberation Army, Beijing, China (mainland)
| | - Hao Li
- Department of General Surgery, The General Hospital of People's Liberation Army, Beijing, China (mainland)
| | - Zilong Hu
- Department of General Surgery, The General Hospital of People's Liberation Army, Beijing, China (mainland)
| | - Shidong Hu
- Department of General Surgery, The General Hospital of People's Liberation Army, Beijing, China (mainland)
| | - Yufeng Wang
- Department of General Surgery, The General Hospital of People's Liberation Army, Beijing, China (mainland)
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Xie Y, Huang L, Chen L, Lin X, Chen L, Zheng Q. Effect of dendritic cell-cytokine-induced killer cells in patients with advanced colorectal cancer combined with first-line treatment. World J Surg Oncol 2017; 15:209. [PMID: 29179719 PMCID: PMC5704402 DOI: 10.1186/s12957-017-1278-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 11/15/2017] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Surgical resection combined with adjuvant chemotherapy is considered as the gold-standard treatment for advanced colorectal cancer patients. These patients have a poor 5-year survival rate of 5% or less. Furthermore, a large dose of chemotherapy can produce adverse side effects and severe toxicity. Therefore, this retrospective study aimed to evaluate the efficacy of dendritic cell-cytokine-induced killer (DC-CIK) cell infusion as an adjuvant therapy in patients with advanced colorectal cancer combined with first-line treatment. METHODS A total of 142 patients with stage III/IV colorectal carcinoma who had been treated with first-line therapy were included in this study. Among these patients, 71 patients received first-line treatment only (non-DC-CIK group), while the other 71 patients who had similar demographic and clinical characteristics received a DC-CIK cell infusion combined with first-line treatment (DC-CIK group). These patients were followed up until August 2014. Data were analyzed by Kaplan-Meier and Cox regression. RESULTS Our results showed that the 5-year overall survival (OS) rate for the DC-CIK group versus the non-DC-CIK group was 41.3 versus 19.4% (p = 0.001) and the 5-year progression-free survival (PFS) rate for the DC-CIK group versus the non-DC-CIK group was 57.4 versus 33.6% (p = 0.022). CONCLUSIONS Our results showed that patients with advanced colorectal cancer might benefit from DC-CIK immunotherapy combined with first-line therapy by significantly prolonging 5-year OS and PFS.
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Affiliation(s)
- Yunqing Xie
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fujian Medical University Cancer Hospital, Fuzhou, 350014, China
| | - Lijie Huang
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fujian Medical University Cancer Hospital, Fuzhou, 350014, China
| | - Luchuan Chen
- Department of Abdominal Surgery, Fujian Medical University Cancer Hospital, Fuzhou, 350014, China
| | - Xiaowei Lin
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fujian Medical University Cancer Hospital, Fuzhou, 350014, China
| | - Li Chen
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fujian Medical University Cancer Hospital, Fuzhou, 350014, China
| | - Qiuhong Zheng
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fujian Medical University Cancer Hospital, Fuzhou, 350014, China.
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2003-2013, a valuable study: Autologous tumor lysate-pulsed dendritic cell immunotherapy with cytokine-induced killer cells improves survival in stage IV breast cancer. Immunol Lett 2017; 183:37-43. [PMID: 28143792 DOI: 10.1016/j.imlet.2017.01.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 01/24/2017] [Accepted: 01/24/2017] [Indexed: 12/21/2022]
Abstract
Dendritic cells (DCs) and cytokine-induced killer (CIK) cells have both shown activity as immunotherapy in some malignancies. Our aim was to prospective assess the effect of this immunotherapy in patients with stage IV breast cancer. Between Aug 2003 and Dec 2013, we collected 368 patients who met inclusion criteria and divided into immunotherapy group (treatment group: 188 patients) and chemotherapy group (control group: 180 patients). DCs were prepared from the mononuclear cells isolated from patients in the treatment group using IL-2/GM-CSF and were loaded with tumour antigens; CIK cells were prepared by incubating peripheral blood lymphocytes with IL-2, IFN-γ, and CD3 antibodies. After the patients had received low-dose chemotherapy, those in the treatment group also received the DC-CIK therapy, which was repeated four times in a fortnight to form one cycle. At least three cycles of DC-CIK therapy were given. Immune function was measured in treatment group patients' sera. Disease-free survival (DFS) and Overall survival (OS) after the diagnosis of stage IV breast cancer was assessed after a 10-year follow-up. The result demonstrated that immune function is obviously enhanced after DC-CIK therapy. By Cox regression analysis, DC-CIK therapy reduced the risk of disease progression (p<0.01) with an increased OS (p<0.01). After low-dose chemotherapy, active immunization with DC-CIK immunotherapy is a potentially effective approach for the control of tumour growth in stage IV breast cancer patients.
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Luo XM, Niu LZ, Chen JB, Xu KC. Advances in cryoablation for pancreatic cancer. World J Gastroenterol 2016; 22:790-800. [PMID: 26811625 PMCID: PMC4716077 DOI: 10.3748/wjg.v22.i2.790] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2015] [Revised: 07/07/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
Pancreatic carcinoma is a common cancer of the digestive system with a poor prognosis. It is characterized by insidious onset, rapid progression, a high degree of malignancy and early metastasis. At present, radical surgery is considered the only curative option for treatment, however, the majority of patients with pancreatic cancer are diagnosed too late to undergo surgery. The sensitivity of pancreatic cancer to chemotherapy or radiotherapy is also poor. As a result, there is no standard treatment for patients with advanced pancreatic cancer. Cryoablation is generally considered to be an effective palliative treatment for pancreatic cancer. It has the advantages of minimal invasion and improved targeting, and is potentially safe with less pain to the patients. It is especially suitable in patients with unresectable pancreatic cancer. However, our initial findings suggest that cryotherapy combined with 125-iodine seed implantation, immunotherapy or various other treatments for advanced pancreatic cancer can improve survival in patients with unresectable or metastatic pancreatic cancer. Although these findings require further in-depth study, the initial results are encouraging. This paper reviews the safety and efficacy of cryoablation, including combined approaches, in the treatment of pancreatic cancer.
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Bai Y, Zheng JE, Wang N, Cai HH, Zhai LN, Wu YH, Wang F, Jin RM, Zhou DF. Effects of dendritic cell-activated and cytokine-induced killer cell therapy on 22 children with acute myeloid leukemia after chemotherapy. ACTA ACUST UNITED AC 2015; 35:689-693. [PMID: 26489623 DOI: 10.1007/s11596-015-1491-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Revised: 05/12/2015] [Indexed: 10/22/2022]
Abstract
The efficiency of dendritic cell-activated and cytokine-induced killer cell (DC-CIK) therapy on children with acute myeloid leukemia (AML) after chemotherapy was investigated. Mononuclear cells were collected from children achieving complete remission after chemotherapy, cultured in vitro and transfused back into the same patient. Interleukin-2 (IL-2) was injected subcutaneously every other day 10 times at the dose of 1 × 10(6) units. Peripheral blood lymphocyte subsets and minimal residual disease (MRD) were detected by flow cytometry. Function of bone marrow was monitored by methods of morphology, immunology, cytogenetics and molecular biology. The side effects were also observed during the treatment. The average follow-up period for all the 22 patients was 71 months and relapse occurred in two AML patients (9.1%). The percentage of CD3(+)/CD8(+) cells in peripheral blood of 15 patients at the 3rd month after DC-CIK treatment (36.73% ± 12.51%) was dramatically higher than that before treatment (29.20% ± 8.34%, P < 0.05). The MRD rate was >0.1% in 5 patients before the treatment, and became lower than 0.1% 3 months after the treatment. During the transfusion of DC-CIK, side effects including fever, chills and hives appeared in 7 out of 22 (31.82%) cases but disappeared quickly after symptomatic treatments. There were no changes in electrocardiography and liver-renal functions after the treatment. MRD in children with AML can be eliminated by DC-CIK therapy which is safe and has fewer side effects.
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Affiliation(s)
- Yan Bai
- Pediatric Department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jin-E Zheng
- Stem Cell Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Nan Wang
- Pediatric Department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - He-Hua Cai
- Pediatric Department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Li-Na Zhai
- Pediatric Department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yao-Hui Wu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Fang Wang
- Pediatric Department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Run-Ming Jin
- Pediatric Department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Dong-Feng Zhou
- Pediatric Department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Gao D, Li C, Xie X, Zhao P, Wei X, Sun W, Liu HC, Alexandrou AT, Jones J, Zhao R, Li JJ. Autologous tumor lysate-pulsed dendritic cell immunotherapy with cytokine-induced killer cells improves survival in gastric and colorectal cancer patients. PLoS One 2014; 9:e93886. [PMID: 24699863 PMCID: PMC3974849 DOI: 10.1371/journal.pone.0093886] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Accepted: 03/10/2014] [Indexed: 12/22/2022] Open
Abstract
Gastric and colorectal cancers (GC and CRC) have poor prognosis and are resistant to chemo- and/or radiotherapy. In the present study, the prophylactic effects of dendritic cell (DC) vaccination are evaluated on disease progression and clinical benefits in a group of 54 GC and CRC patients treated with DC immunotherapy combined with cytokine-induced killer (CIK) cells after surgery with or without chemo-radiotherapy. DCs were prepared from the mononuclear cells isolated from patients using IL-2/GM-CSF and loaded with tumor antigens; CIK cells were prepared by incubating peripheral blood lymphocytes with IL-2, IFN-γ, and CD3 antibodies. The DC/CIK therapy started 3 days after low-dose chemotherapy and was repeated 3–5 times in 2 weeks as one cycle with a total of 188.3±79.8×106 DCs and 58.8±22.3×108 CIK cells. Cytokine levels in patients' sera before and after treatments were measured and the follow-up was conducted for 98 months to determine disease-free survival (DFS) and overall survival (OS). The results demonstrate that all cytokines tested were elevated with significantly higher levels of IFN-γ and IL-12 in both GC and CRC cohorts of DC/CIK treated patients. By Cox regression analysis, DC/CIK therapy reduced the risk of post-operative disease progression (p<0.01) with an increased OS (<0.01). These results demonstrate that in addition to chemo- and/or radiotherapy, DC/CIK immunotherapy is a potential effective approach in the control of tumor growth for post-operative GC and CRC patients.
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Affiliation(s)
- Daiqing Gao
- Biotherapy Center, Qingdao Center Hospital, The Second Affiliated Hospital, Qingdao University Medical College, Qingdao, China
- * E-mail: (DG); (JJL)
| | - Changyou Li
- Biotherapy Center, Qingdao Center Hospital, The Second Affiliated Hospital, Qingdao University Medical College, Qingdao, China
| | - Xihe Xie
- Biotherapy Center, Qingdao Center Hospital, The Second Affiliated Hospital, Qingdao University Medical College, Qingdao, China
| | - Peng Zhao
- Biotherapy Center, Qingdao Center Hospital, The Second Affiliated Hospital, Qingdao University Medical College, Qingdao, China
| | - Xiaofang Wei
- Biotherapy Center, Qingdao Center Hospital, The Second Affiliated Hospital, Qingdao University Medical College, Qingdao, China
| | - Weihong Sun
- Biotherapy Center, Qingdao Center Hospital, The Second Affiliated Hospital, Qingdao University Medical College, Qingdao, China
| | - Hsin-Chen Liu
- Department of Radiation Oncology, NCI-Designated Comprehensive Cancer Center, University of California at Davis Sacramento, Sacramento, California, United States of America
| | - Aris T. Alexandrou
- Department of Radiation Oncology, NCI-Designated Comprehensive Cancer Center, University of California at Davis Sacramento, Sacramento, California, United States of America
| | - Jennifer Jones
- Department of Medicine, University of Saskatchewan, Saskatoon, Canada
| | - Ronghua Zhao
- Department of Medicine, University of Saskatchewan, Saskatoon, Canada
| | - Jian Jian Li
- Department of Radiation Oncology, NCI-Designated Comprehensive Cancer Center, University of California at Davis Sacramento, Sacramento, California, United States of America
- * E-mail: (DG); (JJL)
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Abstract
OBJECTIVE The aim of this study was to retrospectively assess the effect of comprehensive cryosurgery (ablation of intrapancreatic and extrapancreatic tumors) plus immunotherapy in metastatic pancreatic cancer. METHODS We divided 106 patients (57 men, 49 women; median age, 65 years) into the cryoimmunotherapy (31 patients), cryotherapy (36 patients), immunotherapy (17 patients), and chemotherapy groups (22 patients). Pretreatment immune function was tested in patients who underwent immunotherapy. Overall survival (OS) after diagnosis of metastatic pancreatic cancer was assessed after a 4-year follow-up. RESULTS Median OS was higher in the cryoimmunotherapy (13 months) and cryotherapy groups (7 months) than in the chemotherapy group (3.5 months; both P < 0.001) and was higher in the cryoimmunotherapy group than in the cryotherapy (P < 0.05) and immunotherapy groups (5 months; P < 0.001). In both the cryoimmunotherapy and cryotherapy groups, median OS was higher after multiple cryoablations than after a single cryoablation (P = 0.0048 and 0.041, respectively). In both groups, the median OS was higher in patients with normal immunologic function than in those with immune dysfunction (P < 0.0001 and P = 0.0004, respectively). CONCLUSIONS Cryoimmunotherapy significantly increased OS in metastatic pancreatic cancer. Multiple cryoablations and normal pretreatment immunologic function were associated with better prognosis.
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Liu C, Suksanpaisan L, Chen YW, Russell SJ, Peng KW. Enhancing cytokine-induced killer cell therapy of multiple myeloma. Exp Hematol 2013; 41:508-17. [PMID: 23403007 DOI: 10.1016/j.exphem.2013.01.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2012] [Revised: 01/16/2013] [Accepted: 01/25/2013] [Indexed: 12/22/2022]
Abstract
Cytokine-induced killer (CIK) cells are in clinical testing against various tumor types, including multiple myeloma. In this study, we show that CIK cells have activity against subcutaneous and disseminated models of human myeloma (KAS-6/1), which can be enhanced by infecting the CIK cells with an oncolytic measles virus (MV) or by pretreating the myeloma cells with ionizing radiation (XRT). KAS-6/1 cells were killed by coculture with CIK or MV-infected CIK (CIK/MV) cells, and the addition of an anti-NKG2D antibody inhibited cytolysis by 50%. However, human bone marrow stromal cells can reduce CIK and CIK/MV mediated killing of myeloma cells (RPMI 8226, JJN-3 and MM1). In vivo, CIK and CIK/MV prolonged the survival of mice with systemic myeloma, although CIK/MV showed enhanced antitumor activity compared with CIK. Irradiation of the KAS-6/1 cells induced mRNA and protein expression of NKG2D ligands, MICA, and MICB in a dose-dependent manner and enhanced delivery of CIK/MV to the irradiated tumors. In both subcutaneous and disseminated myeloma models, XRT at 2 Gy resulted in superior prolongation of the survival of mice given CIK/MV therapy compared with CIK/MV with no XRT. This study demonstrates the potential of CIK against myeloma and that the combination of virotherapy with radiation could be used to further enhance therapeutic outcome using CIK cells.
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MESH Headings
- Animals
- Antibodies, Monoclonal/immunology
- Antibodies, Monoclonal/pharmacology
- Antigens, Neoplasm/biosynthesis
- Antigens, Neoplasm/genetics
- Cells, Cultured/immunology
- Cells, Cultured/transplantation
- Cells, Cultured/virology
- Coculture Techniques
- Combined Modality Therapy
- Cytokine-Induced Killer Cells/immunology
- Cytokine-Induced Killer Cells/transplantation
- Cytokine-Induced Killer Cells/virology
- Cytotoxicity, Immunologic
- Female
- Histocompatibility Antigens Class I/biosynthesis
- Histocompatibility Antigens Class I/genetics
- Humans
- Immunotherapy, Adoptive
- Measles virus/physiology
- Mice
- Mice, Inbred ICR
- Mice, SCID
- Multiple Myeloma/immunology
- Multiple Myeloma/pathology
- Multiple Myeloma/radiotherapy
- Multiple Myeloma/therapy
- NK Cell Lectin-Like Receptor Subfamily K/immunology
- Oncolytic Virotherapy
- RNA, Messenger/biosynthesis
- RNA, Messenger/genetics
- Random Allocation
- Stromal Cells/transplantation
- Virus Replication
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Chunsheng Liu
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
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Sarhan D, D'Arcy P, Wennerberg E, Lidén M, Hu J, Winqvist O, Rolny C, Lundqvist A. Activated monocytes augment TRAIL-mediated cytotoxicity by human NK cells through release of IFN-γ. Eur J Immunol 2012; 43:249-57. [PMID: 22996291 DOI: 10.1002/eji.201242735] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2012] [Revised: 08/29/2012] [Accepted: 09/11/2012] [Indexed: 12/23/2022]
Abstract
Natural killer (NK) cells are innate lymphocytes that are able to directly kill tumor cells through different mechanisms including ligation of TNF-related apoptosis-inducing ligand (TRAIL) receptors. Zoledronic acid (ZA) is a bisphosphonate known to upregulate the expression of TRAIL on human γδ T cells. Here, we investigated whether exposure to ZA would upregulate TRAIL expression on human NK cells and augment their cytotoxicity against tumor cells. When cocultured with monocytes, treatment with ZA and IL-2 resulted in a significant upregulation of TRAIL expression on human NK cells (p = 0.002). Consequently, ZA-primed NK cells were significantly more cytotoxic against TRAIL sensitive tumor cells (p < 0.0001). In the presence of ZA and IL-2, monocytes produced high levels of IFN-γ; when cultured in the presence of neutralizing antibodies to IFN-γ, TRAIL expression and TRAIL-mediated cytotoxicity of NK cells were significantly reduced. Furthermore, in tumor-bearing SCID/Beige mice, a significant delayed tumor progression and prolonged survival was observed after infusion of ZA-primed NK cells compared with that observed in mice infused with unprimed NK cells. These findings represent a novel approach to potentiate TRAIL-mediated apoptosis by adoptively infused NK cells that could improve the outcome in patients with cancer.
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Affiliation(s)
- Dhifaf Sarhan
- Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden
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Thanendrarajan S, Nowak M, Abken H, Schmidt-Wolf IGH. Combining cytokine-induced killer cells with vaccination in cancer immunotherapy: more than one plus one? Leuk Res 2011; 35:1136-42. [PMID: 21652069 DOI: 10.1016/j.leukres.2011.05.005] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2010] [Revised: 03/08/2011] [Accepted: 05/09/2011] [Indexed: 12/20/2022]
Abstract
The immune system can be harnessed to fight cancer by active (stimulating the patient's intrinsic immune response to cancer) and by passive (transfer of active humoral or cellular immunity) immunotherapy. While for each strategy proof-of-principle was provided, clinical benefit was limited likely due to malfunction of lymphocytes. Increasing knowledge of both the mechanism of vaccination through dendritic cells (DCs) and the potency of a subset of natural killer T lymphocytes termed cytokine-induced killer (CIK) cells led to new strategies through combining adoptive and passive immunotherapy. This review summarizes most recent clinical trials indicating that CIK cells can substantially enhance the effect of tumor vaccines and discusses the potential therapeutic benefit in the long-term control of tumor progression.
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Affiliation(s)
- Sharmilan Thanendrarajan
- Medizinische Klinik und Poliklinik III, Center for Integrated Oncology (CIO), University of Bonn, Bonn, Germany
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