IFN-γ to improve immunotherapy for melanoma.

Abstract

2565 Background: Adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TILs) holds the promise to change the long-term prognosis of patients with metastatic melanoma. In this study we have explored strategies to improve the efficacy of cell products for infusion through tumor immune-sensitization. Methods: We examined whether objective responses in our pilot ACT trial (NCT937625) were associated with the number of tumor-reactive T cells infused. Subsequently, we assessed the ability of immune-sensitizing agents to modulate the constitutive response of 12 clinical grade TIL products to matched autologous short-term cultured melanoma cell lines. Results: Our data showed that a high absolute number of infused tumor-reactive T cells is critical to achieve an objective response. In addition, a defective population of tumor-specific CD8+ and CD4+ T cells unable to exert antitumor effector functions ex vivo was detected in most TIL products. However, an antitumor specific response could be restored by pretreatment of the autologous tumor cells with low dose IFN-γ. Of note, IFN-γ treatment was invariably associated with increased cancer immunogenicity as demonstrated by up-regulation of MHC molecules. Conclusions: Combination strategies represent the next frontier of cancer immunotherapy. Although previous trials in melanoma showed that IFN-γ does not mediate clinical benefit when used as monotherapy, our findings show that its ability to increase tumor cell immunogenicity may enhance the efficacy of current immune-based therapies such as ACT through improved activation of pre-existing but unresponsive tumor specific lymphocytes. Therefore, additional studies on the possibility of a sequential combination of low dose IFN-γ and ACT are highly warranted.