Abstract 3973: Effects of anti-PD-1 and anti-4-1BB antibody treatment on melanoma-specific T cells in a murine model of melanoma.

Abstract

Abstract Adoptive cell therapy with tumor infiltrating lymphocytes (TIL) is a promising immunotherapeutic approach and has resulted in durable response rates of 20-30% in patients with metastatic melanoma. However, several limitations exist to prevent the widespread implementation of adoptive cell therapy, including inadequate infiltration of tumor-specific T cells into tumors and anemic expansion of tumor-specific T cells in vitro. One such factor is PD-1 expression on T cells that plays an important role in T cell exhaustion. Agonistic co-stimulatory molecules such as 4-1BB which is transiently expressed on activated T cells can reverse T cell exhaustion and enhance anti-tumor immune response. In this study, we have examined two approaches to improve the frequency of tumor-specific T cells in tumors and TIL cultures. First, we examined whether blocking PD-L1/PD-1 signaling increased the infiltration of tumor-specific T cells in the murine B16 melanoma model. Mice bearing B16 tumors were treated with NrIgG or anti-PD-1 antibodies. T cells were isolated from B16 tumors on day 18 after tumor injection. Increased IFN-γ production following B16 restimulation was observed in TIL isolated from mice treated with anti-PD-1 antibody (1445 ± 48 pg/ml) compared to TIL isolated from mice treated with control antibody (748 ± 25 pg/ml, p<0.001). In addition, we examined whether the expansion of T cells during TIL culture in vitro could be augmented by targeting the co-stimulatory molecule, 4-1BB. T cells were isolated from B16 tumors and cultured in vitro with 10 mcg/mL anti-4-1BB antibody. After 5 days, increased B16-specific IFN-γ was measured in TIL cultured with anti-4-1BB antibody (1865 ± 64 pg/ml, p<0.001 compared to TIL cultured with control antibody). Combination treatment with anti-PD-1 antibody therapy in vivo and anti-4-1BB antibody in vitro demonstrated synergistic effects, with increased levels of IFN-γ (4440 ± 486 pg/ml) produced by B16-specific TIL. These findings suggest that anti-PD-1 antibody treatment in combination with in vitro 4-1BB antibody treatment can enhance the frequency of tumor-specific T cells isolated from B16 melanoma. This may represent a potential strategy to increase the effectiveness of TIL therapy in patients with melanoma. Citation Format: John L. Robinson, Krithika Kodumudi, Amy Weber, Amod Sarnaik, Shari Pilon-Thomas. Effects of anti-PD-1 and anti-4-1BB antibody treatment on melanoma-specific T cells in a murine model of melanoma. [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 3973. doi:10.1158/1538-7445.AM2013-3973