Selective BRAF inhibitors and immunomodulatory antibodies have advanced clinical treatment of metastatic melanoma. However, efficacy of these therapies is limited. BRAF inhibitors achieve high response rates, but effects are short-lived. In contrast, immunotherapies deliver durable responses but only in a small subset of patients. Combining these treatments may allow BRAF inhibition to augment immunotherapy, by improving immune system targeting of tumours. The success of this approach depends upon fully elucidating immunological interactions of BRAF inhibitors, and optimizing combination strategies.
Using a subcutaneous BRAFV600E melanoma model, we have investigated host immune involvement in the anti-tumour effects of the BRAF inhibitor, PLX4720, in NOD/Scid versus C57Bl/6 mice. PLX4720 control of tumour growth was significantly less effective in immunocompromised than immunocompetent mice, resulting in a reduced survival advantage. This demonstrates that PLX4720 efficacy is partially immune dependent, and further work is being done to characterize immunological involvement. We have also established that BRAF inhibition can directly affect immune responses. In vitro both human and murine T cell activation can be boosted by low concentrations of PLX4720. Furthermore, we have shown in vivo that antigen-specific T cell proliferation is significantly increased by PLX4720 treatment in an OTI/OVA model. Applying the knowledge generated from these experiments of optimal dosing strategies, we are investigating combining PLX4720 with immunotherapy.Using an irradiated whole tumour cell vaccine, which slows BRAFV600E melanoma growth, we have preliminary evidence showing increased benefit of combination treatment over single-agent therapy.
In conclusion, selective BRAF inhibitors can boost T cell responses, and their anti-tumour efficacy is partially immune dependant, which can be maximised in combination with immunotherapy.