Immunotherapy is an attractive option to extend remission rates in ovarian cancer. The use of adoptive cell transfer (ACT) of ex vivo generated tumor-antigen specific effector/memory CD8+ T cells circumvents the regulatory environment present in ovarian cancer patients and can mediate durable immunity. However, strategies to ex vivo generate effector/memory CD8+ T cells have not been described and the application of ACT to treat ovarian tumor remains untested. Based on our reported findings and new evidence generated by using both murine and human T cells, we hypothesize that the gamma chain cytokine;IL-21 in combination with mTOR inhibitor;rapamycin, will ex vivo generate tumor-antigen specific effector/memory CD8+ T cells that enable durable immunity to ovarian cancer patients by ACT. We have designed two specific aims to test the hypothesis and generate information that can support a phase 2 trial. First, to determine the combinatorial dose of Rapamycin and IL-21 that optimally produces human WT1 specific effector/memory CD8+ T cells with high replicative potential for adoptive cellular therapy and second to evaluate in a Phase I study, the safety, in vivo persistence and anti-tumor efficacy of IL-21/ Rapamycin conditioned WT-1 specific CD8+ T cells adoptively transferred to patients with advanced ovarian cancer. The completion of this study will identify a new strategy to generate antigen-specific CD8+ T cells for effector/memory function and test their efficacy in ACT, it is likely to establish a new approach to treat ovarian cancer.
The immune regulatory conditions limit efficacy of immune therapy in ovarian cancer. The successful use of ex vivo generated CD8+ T cells for adoptive cell transfer (ACT) therapy of various cancers have been noted, but it has never been applied to ovarian cancer patients. The use of IL-21 in combination with rapamycin is a novel method to generate effector/memory CD8+ T cells for ACT, that will harness the dual advantages of specificity and durability to establish a new paradigm for adoptive cell therapy in general and specifically for extending remission rates in ovarian cancer.
|Szender, J Brian; Eng, Kevin H; Matsuzaki, Junko et al. (2016) HLA superfamily assignment is a predictor of immune response to cancer testis antigens and survival in ovarian cancer. Gynecol Oncol 142:158-62|
|Kohrt, Holbrook E; Tumeh, Paul C; Benson, Don et al. (2016) Immunodynamics: a cancer immunotherapy trials network review of immune monitoring in immuno-oncology clinical trials. J Immunother Cancer 4:15|
|Chen, Yichao; Xia, Rui; Huang, Yixian et al. (2016) An immunostimulatory dual-functional nanocarrier that improves cancer immunochemotherapy. Nat Commun 7:13443|
|Wong, Jeffrey L; Obermajer, NataÅ¡a; Odunsi, Kunle et al. (2016) Synergistic COX2 Induction by IFNÎ³ and TNFÎ± Self-Limits Type-1 Immunity in the Human Tumor Microenvironment. Cancer Immunol Res 4:303-11|
|Shi, Liangrong; Chen, Lujun; Wu, Changping et al. (2016) PD-1 Blockade Boosts Radiofrequency Ablation-Elicited Adaptive Immune Responses against Tumor. Clin Cancer Res 22:1173-84|
|Cuellar-Partida, Gabriel; Lu, Yi; Dixon, Suzanne C et al. (2016) Assessing the genetic architecture of epithelial ovarian cancer histological subtypes. Hum Genet 135:741-56|
|Winham, Stacey J; Pirie, Ailith; Chen, Yian Ann et al. (2016) Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer. Cancer Epidemiol Biomarkers Prev 25:446-54|
|PrÃ¦stegaard, Camilla; Kjaer, Susanne K; Nielsen, Thor S S et al. (2016) The association between socioeconomic status and tumour stage at diagnosis of ovarian cancer: A pooled analysis of 18 case-control studies. Cancer Epidemiol 41:71-9|
|Earp, Madalene; Winham, Stacey J; Larson, Nicholas et al. (2016) A targeted genetic association study of epithelial ovarian cancer susceptibility. Oncotarget 7:7381-9|
|Zhao, Wenyuan; Chen, Beibei; Guo, Xin et al. (2016) A rank-based transcriptional signature for predicting relapse risk of stage II colorectal cancer identified with proper data sources. Oncotarget 7:19060-71|
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