Adoptive Immunotherapy for the Treatment of Glioblastoma: Progress and Possibilities
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Patients with glioblastoma have a very poor prognosis. Adoptive cellular therapy (ACT) is defined as the collection of circulating or tumor-infiltrating lymphocytes, their selection, modification, expansion and activation, and their re-administration to patients in order to induce antitumor activity. Although various ACTs have been attempted, most failed to improve the outcome. Immune checkpoint blockade antibodies and T cell engineering with tumor-specific chimeric antigen receptors suggest the emergence of a new era of immunotherapy. Here, we summarize approaches with ACTs using genetically modified T cells, which have been improved by enhancing their antitumor activity, and discuss strategies to develop these therapies. The mechanisms by which gliomas modulate and evade the immune system are also discussed.Keywords:
Adoptive Cell Transfer
Adoptive immunotherapy
Immune checkpoint
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<p>PDF file - 59K, Combined anti-tumor activity of adoptive cell transfer (ACT) immunotherapy and PLX3397 in SM1 and B16 murine melanoma.</p>
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T cell adoptive immunotherapy has been employed to treat a variety of malignant diseases,especially tumors.Adoptive transfer of tumor-specific T cells induces the death of tumor cells in vitro,and has been applied to treat certain clinical patients and obtained successful therapeutic effects.Now,T cell adoptive therapy may become one of frontier weapons for treating tumors.
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AbstractMurine models of pulmonary tumors have long provided investigators a reliable and reproducible method of testing the therapeutic efficacy of adoptive immunotherapy. Adoptive immunotherapy involves the generation of tumor-specific immune cells which, following activation and culture in vitro, can mediate regression of established tumors following transfer into a tumor-bearing host. KeywordsPulmonary MetastasisAdoptive TransferLymph Node CellAdoptive ImmunotherapyEstablished TumorThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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Abstract Adoptive immunotherapy with CD8+ T cells has achieved some success in treating established cancer. Response rates are increased by preconditioning the patient with lymphodepleting whole body irradiation (WBI) prior to T cell transfer, including an increased fraction of complete responses. Using a mouse model of autochthonous brain cancer, we previously demonstrated that adoptive transfer of tumor-specific T cells following WBI promotes complete regression of established tumors and long-term survival. However, the mechanisms required to achieve complete responses remain to be defined. Here we investigate kinetic requirements for adoptive T cell transfer to achieve tumor control following WBI. To test the hypothesis that adoptive transfer early after irradiation is required for maximum long-term tumor control, we delayed adoptive transfer of T cells to tumor-bearing mice at varying intervals following irradiation. We show that delay of adoptive transfer did not affect initial T cell priming or the timing of initial appearance of activated T cells at the tumor site. However, we observed a modest decrease in T cell accumulation at the earliest appearance of cells in the brain (5 days post-transfer). Tumors were completely eliminated within 10 days in mice that received T cell transfer one day following WBI, while delayed transfer abrogated this effect. When adoptive transfer was delayed by one week following WBI, incomplete tumor regression was observed at 10 days post-transfer. Although mice in this group lived significantly longer than control animals, they eventually succumbed to lethal tumor recurrence. Our data suggest that lymphodepleting doses of WBI promote a prolonged window for effective T cell priming against the endogenous tumor antigen, but that optimal therapeutic potential requires T cell transfer early after irradiation conditioning. Supported by research grant CA02500 from the National Cancer Institute/National Institutes of Health. Citation Format: Eugene M. Cozza, Lynn R. Budgeon, Neil D. Christensen, Todd D. Schell. Regression of established tumors requires timely adoptive T cell transfer following whole body irradiation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3975. doi:10.1158/1538-7445.AM2013-3975
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Adoptive immunotherapy is an approach to cancer treatment that has not received significant evaluation in cancer patients. Recent developments in modern cellular immunology have expanded the opportunities for utilizing adoptive immunotherapy in humans. A variety of animal models have been developed utilizing the adoptive transfer of immune cells that can mediate the regression of established murine tumors. Analyses of these models are defining the important criteria necessary for the application of this approach to humans. Studies of the immune response of human cells to autologous tumors are identifying cells with antitumor reactivity that may be of value in the treatment of human malignancy. Preliminary clinical studies have been performed demonstrating the feasibility of infusing large numbers of activated lymphoid cells into humans. Adoptive immunotherapy is an approach to the treatment of cancer that deserves further study.
Adoptive immunotherapy
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Cancer Immunotherapy
Cell therapy
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Adoptive Cell Transfer
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The immunoprophylactic and immunotherapeutic effects of LAK cells transferred adoptively on L615-suffering mice were studied. The results showed that adoptive transfer of LAK cells could increase the survival rate of the mice and prolong the mean survival time of mice with advanced L615 leukemia. IL-2 in appropriate concentration was required in the adoptive immunotherapy, and the combined use of LAK cells with 5-FU or IFN-r had no additive immunotherapeutic effects. The results also revealed that the immunotherapeutic activity of the transferred LAK cells maintained a relatively long period of time in the host body.
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Abstract The passive transfer of immune lymphocytes into the tumor- bearing host or cancer patient is known as ‘ adoptive immunotherapy’ . The requirements for successful adoptive immunotherapy in animal models involve the ability to generate tumor-reactive cells in sufficient quantities to cause tumor rejection in vivo (Greenberg 1991; Chang and Shu 1992). Compared with other immunotherapeutic modalities, such as cytokines, vaccines, or antibodies, adoptive immunotherapy has been significantly more effective in mediating regression of advanced tumor burdens in animal models (Chou et al. 1988a; Rosenberg et al. 1986). The translation of animal studies to the clinical setting required the development of methods to culture lymphocytes in bulk quantities.
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