Costimulation through 4-1BB/CD137 improves the expansion and function of CD8+ melanoma tumor-infiltrating lymphocytes for adoptive T-cell therapy (66.21)

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Abstract Adoptive T-cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) is a powerful therapy for Stage IV melanoma patients who have failed first and second line therapies. TIL for adoptive transfer are expanded from melanoma surgical specimens with IL-2 followed by a “rapid expansion protocol” (REP), where the cells are activated with anti-CD3 antibody, PBMC feeder cells and IL-2 for two weeks, generating a final infusion product. The REP yields billions of highly-differentiated cytolytic CD8+ T cells that lose costimulatory molecules CD28 and CD27, and are hyporesponsive to further proliferative signals. We found “post-REP” CD8+ TIL express an alternative costimulatory molecule of the TNF-R family, 4-1BB. Our study tests the effects of an agonistic anti-4-1BB antibody added at the time of initiating the REP. We found adding an agonistic anti-4-1BB antibody increased CD8+ T-cell recovery, antigen specificity, BCL-2 gene expression and increased the frequency of CD28+ cells in the recovered CD8+ post-REP TIL. Adding anti-4-1BB improved post-REP TIL survival capacity in the absence of cytokine, with TIL continuing to divide even without added IL-2. Our findings suggest adding an agonistic anti-4-1BB antibody during the time of TIL REP initiation produces a CD8+ T cell population capable of improved effector function and survival. This may greatly improve TIL persistence and anti-tumor activity in vivo after adoptive transfer into patients.