Abstract IA31: Combining targeted therapy and immune checkpoint blockade to improve responses

Abstract

Abstract There have been significant advances in treatment of metastatic melanoma over the past several years through the use of targeted therapy and immune checkpoint blockade. Oncogenic mutations in the BRAF gene occur in over half of melanoma tumors, and treatment with agents targeting this mutation results in objective responses in the majority of patients. However significant limitations exist as responses are not durable, with the majority of patients progressing on therapy within 6-10 months. Another area of significant progress involves the use of immune checkpoint blockade, such as with monoclonal antibodies blocking CTLA-4 and the PD-1 pathway. In contrast, treatment of patients with immune checkpoint inhibitors results in a lower response rate than those observed with targeted therapy, but ones that tend to be more durable. With these advances, we are posed with therapeutic dilemmas with regard to timing and sequence of therapy. Namely, there is significant debate as to whether to begin treatment with targeted therapy versus immune checkpoint blockade upfront, and at which point to change treatment strategy. There is growing evidence of potential synergy in combining treatment with BRAF-targeted therapy and immune checkpoint blockade, and this concept is being empirically tested in clinical trials. There a strong scientific rationale for combining these therapies, as treatment with BRAF inhibitors is associated with increased immunogenicity of melanoma tumors within 2 weeks of therapy - with increased melanoma antigens and CD8+ T cell infiltrate, and decreased immunosuppressive cytokines and VEGF. BRAF inhibitors may also directly activate T cells through paradoxical activation of the MAPK pathway. However there is a concurrent increase in expression of immunomodulatory molecules (such as PD-L1) within 2 weeks of therapy which is likely related to T cell infiltrate, though also suggest a possible immune mechanism of resistance. Clinical trials and studies in murine models are currently underway to explore synergy between these therapies, and insights gained will be discussed herein. It is becoming increasingly apparent that complexities exist regarding appropriate timing and sequence in these combination strategies to optimize responses and minimize toxicity. Ultimately, ideal approaches using combined BRAF-targeted therapy and immune checkpoint blockade will be built on a deep understanding of the molecular and immune effects of each of these therapies in isolation, as well as in combination. Citation Format: Jennifer A. Wargo. Combining targeted therapy and immune checkpoint blockade to improve responses. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr IA31.