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Research Interests

Melanoma has become a target of immunotherapy because melanoma cells are somewhat susceptible to immune recognition (1-3).  Checkpoint inhibition with anti-CTLA-4 and anti-PD-1 antibodies is one type of immunotherapy that nonspecifically magnifies T cell responses against both tumor antigens and non-tumor antigens.  These antibodies now offer patients with advanced melanoma a chance for survival and even cures (4-6). More effective combinatorial approaches to checkpoint inhibition have resulted in improved response rates, but at the unsurprising cost of higher autoimmunity complications (7,8). 

Our laboratory efforts have focused on a type of immunotherapy called adoptive cell transfer (ACT) because of its intrinsic specificity (9-15). This technique traditionally involves the isolation of CD8+ T cells from tumor-infiltrating lymphocytes (TIL) followed by intense in vitro stimulation to generate large quantities of potent tumor-reactive effector CD8+ T cells. Typically infused after lymphodepletion therapy, these effector CD8+ T cells can cause a focused systemic immune response against tumor antigens that can be curative. However, the inconsistency and relative complexity of ACT have prevented its widespread clinical adoption.

We have previously shown that conventional ACT is handicapped by its reliance on effector CD8+ T cells, and that memory CD8+ T cells enable ACT to achieve maximal benefit. While they have the capacity to expand and kill cancer cells, effector CD8+ T cells are short-lived, terminally-differentiated cells whose proclivity for apoptosis is markedly accelerated by melanoma (16-20).  Memory CD8+ T cells are capable of durable survival, and are rapidly mobilized in response to antigen encounter (21,22). We have shown that, unlike effector CD8+ T cells, the survival and function of memory CD8+ T cells is completely unaffected by melanoma (20). Moreover, we have confirmed that memory T cell ACT establishes durable local and systemic immune responses far superior to traditional effector T cell ACT (23).

Memory T cell-based ACT has not been comprehensively pursued because there has been no practical way to prepare clinically relevant quantities of tumor-specific memory CD8+ T cells. Our current experiments are exploring ways to generate more tumor-specific memory CD8+ T cells by optimizing isolation and expansion protocols. 

(Picture courtesy of NIH NCI https://visualsonline.cancer.gov/collection.cfm?groupid=1)  

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15. Dudley ME, Gross CA, Somerville RP, et al. Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma. J Clin Oncol 2013;31:2152-2159. PMID: 23650429

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18. Russ AJ, Wentworth L, Xu K, et al. Suppression of T-cell expansion by melanoma is exerted on resting cells. Ann Surg Oncol 2011;18:3848-3857. PMID: 21465311

19. Russ AJ, Xu K, Wentworth L, et al. Melanoma-induced suppression of tumor antigen-specific T cell expansion is comparable to suppression of global T cell expansion. Cell Immunol 2011;271:104-109. PMID: 21741629

20. Wentworth L, Meyers AJ, Alam S, et al., Memory T cells are uniquely resistant to melanoma-induced suppression. Cancer Immunol Immunother 2013;62:149-159. PMID: 22865267

21. Wherry EJ, Teichgräber V, Becker TC, et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat Immunol 2003;4:225-234. PMID: 12563257

22. Sarkar S, Teichgräber V, Kalia V, et al. Strength of stimulus and clonal competition impact the rate of memory CD8 T cell differentiation. J Immunol 2007;179:6704-6714. PMID: 17982060 

23. Contreras A, Sen S, Tatar AJ, et al. Enhanced local and systemic anti-melanoma CD8+ T cell responses after memory T cell-based adoptive immunotherapy in mice. Cancer Immunol Immunother 2016;65:601-611. PMID: 27011014