Journal
CLINICAL CANCER RESEARCH
Volume 21, Issue 3, Pages 611-621Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-14-1934
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Funding
- Developmental Research Program of the Melanoma SPORE [5 P50 CA093459-05-DRP21]
- Team Science Award from the Melanoma Research Alliance (MRA)
- Dr. Miriam and Sheldon Adelson Medical Research Foundation (AMRF)
- NCI-K23 award [AAS 1 K23 CA178083-01]
- University of Texas Health Innovation for Cancer Prevention Research Pre-Doctoral Fellowship
- University of Texas School of Public Health-Cancer Prevention
- Research Institute of Texas [RP101503]
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Purpose: Cultured tumor fragments from melanoma metastases have been used for years as a source of tumor-infiltrating lymphocytes (TIL) for adoptive cell therapy (ACT). The expansion of tumor-reactive CD8(+) T cells with interleukin-2 (IL2) in these early cultures is critical in generating clinically active TIL infusion products, with a population of activated 4-1BB CD8(+) T cells recently found to constitute the majority of tumor-specific T cells. Experimental Design: We used an agonistic anti-4-1BB antibody added during the initial tumor fragment cultures to provide in situ 4-1BB costimulation. Results: We found that addition of an agonistic anti-4-1BB antibody could activate 4-1BB signaling within early cultured tumor fragments and accelerated the rate of memory CD8(+) TIL outgrowth that were highly enriched for melanoma antigen specificity. This was associated with NFkB activation and the induction of T-cell survival and memory genes, as well as enhanced IL2 responsiveness, in the CD8(+) T cells in the fragments and emerging from the fragments. Early provision of 4-1BB costimulation also affected the dendritic cells (DC) by activating NFkB in DC and promoting their maturation inside the tumor fragments. Blocking HLA class I prevented the enhanced outgrowth of CD8(+) T cells with anti-4-1BB, suggesting that an ongoing HLA class I-mediated antigen presentation in early tumor fragment cultures plays a role in mediating tumor-specific CD8(+) TIL outgrowth. Conclusions: Our results highlight a previously unrecognized concept in TIL ACT that the tumor microenvironment can be dynamically regulated in the initial tumor fragment cultures to regulate the types of T cells expanded and their functional characteristics. (C) 2014 AACR.
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