Background: Adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TILs) holds the promise to markedly change the long-term prognosis of patients with metastatic melanoma, and modifications of the original protocol which can improve its clinical efficacy are highly desirable. 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 (NCT00937625) were associated with the number of tumor-reactive T cells infused. Subsequently, we assessed the ability of therapeutics to modulate the constitutive response of clinical grade TIL products to matched autologous short-term cultured melanoma cell lines from twelve patients. Results: Our data showed that a high absolute number of infused tumor-reactive T-cells is critical to achieve an objective response. In addition, we provided in vitro evidence that activation of apparently non-tumor reactive TILs could be strongly enhanced with autologous melanoma sensitization by pre-treatment with low dose IFN-gamma (evidence for both CD4+ and CD8+ TILs) or, in BRAFV600E mutant cell lines, with BRAF-signaling blockade (evidence for CD8+ TILs only). Modulation of TIL responses of defined specificity to differentiation, overexpressed and cancer-testis antigens was further characterized. Conclusions: Combination strategies represent the next frontier of cancer immunotherapy. Our studies indicate that ACT may act synergistically with new melanoma therapeutics, such as BRAF-blocking agents for tumors with BRAF constitutive activation, or low dose IFN-?gamma. The ability of anti-melanoma agents 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, clinical studies on the feasibility of a sequential combination of BRAF-blocking agents or low dose IFN-gamma and ACT are highly warranted.
|Titolo:||New melanoma therapeutics to improve adoptive T cell therapy - potential synergism of combinations|
|Data di pubblicazione:||2012|
|Appare nelle tipologie:||4.2 Abstract in Atti di convegno|