Enhancing responses to melanoma therapy with novel combinations of targeted therapy and immune checkpoint blockade


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Robert Szczepaniak Sloane1,Alexandre Reuben2,Ningping Feng2,Sarah Johnson2,Jill Garvey2,Jiong Chen2,Courtney Hudgens2,Luigi Nezi2,Teresa Manzo2,Mariana Pettaccia De Macedo2,John Miller2,Jianhua Hu2,Richard Davis2,Hong Jiang2,Peter Prieto2,Timothy Heffernan2,Elizabeth Burton2,Patrick Hwu2,Hussein Tawbi2,Alexander Lazar2,Michael T. Tetzlaff2,Joe Marszalek2,Willem Overwijk2,Zachary Cooper2,Michael A. Davies2,Jennifer A. Wargo2
1UT MD Anderson Cancer Center,2MD Anderson

Abstract

Background

Treatment with targeted therapy and immunotherapy have revolutionized melanoma treatment. However, only a subset of patients respond durably, and combination strategies are emerging as a clear choice. We now have strong data to support the use of combined targeted therapy and immunotherapy, and sought to investigate different combination regimens in a BRAF-mutant murine melanoma model to help rationally guide novel combination strategies.

Method

C57BL/6 mice were implanted with melanoma tumours (BRAFV600E/PTEN-/-) and were treated with immunotherapy combinations (α-CTLA-4, α-OX40, α-PD-1, α-CTLA-4/α-PD-1 and α-OX40/α-PD-1) with or without BRAF/MEK inhibitors (dabrafenib and trametinib - DT). Total treatment duration was limited to 19 days to test the hypothesis that a short burst of therapy could result in long-term control. Tumour growth and survival were monitored, and immune profiling and gene expression profiling were performed in tumours.

Results

In these studies, treatment with aPD-1 and aCTLA-4 monotherapy was relatively ineffective in controlling tumour growth, while aOX40 had a modest impact. Combination immunotherapy was more effective, with the best control observed in the α-OX40/α-PD-1 group (with 5/12 mice showing no evidence of disease). The addition of DT to immunotherapy improved tumour control in all groups. Immune profiling demonstrated increases in CD8 T cell number and function, as well as lower expression of TIM-3 and LAG-3 in all DT-treated groups. Gene expression corroborated these findings, with significant increases in immune-related genes in presence of DT, suggesting immune mechanisms to the enhanced responses.

Conclusion

We have shown that DT treatment can be used to effectively shape the tumour immune microenvironment and enhance responses to immunotherapy – even in the setting of a short burst of therapy. These studies provide rationale for clinical trials investigating these combination strategies in melanoma, and results may support further studies combining molecularly targeted therapy and immunotherapy for other cancer types.