Improved therapeutic efficacy of unmodified anti-tumor antibodies by immune checkpoint blockade and kinase targeted therapy in mouse models of melanoma

Abstract

The use of specific anti-tumor antibodies has transformed the solid cancer therapeutics landscape with the relative successes of therapies such as anti-HER2 in breast cancer, and anti-EGFR in HNSCC and colorectal cancer. However, these therapies result in toxicity and the emergence of resistant tumors. Here, we showed that removing immune suppression and enhancing stimulatory signals increased the anti-tumor activity of unmodified TA99 antibodies (anti-TYRP1) with a significant reduction of growth of solid tumors and lung metastases in mouse models of melanoma. Immune checkpoint blockade enhanced the efficacy of TA99, which was associated with greater CD8⁺/Foxp3⁺, NK1.1⁺ and dendritic cell infiltrates, suggestive of an increased anti-tumor innate and adaptive immune responses. Further, MEK inhibition in melanoma cell lines increased the expression of melanosomal antigens in vitro, and combining TA99 and MEKi in vivo resulted in enhanced tumor control. Moreover, we found an improved therapeutic effect when YUMM tumor-bearing mice were treated with TA99 combined with MEKi and immune checkpoint blockade (anti-PD1 and anti-CTLA4). Our findings suggest that MEKi induced an increased expression of tumor-associated antigens, which in combination with anti-tumor antibodies, generated a robust adaptive anti-tumor response that was sustained by immune checkpoint inhibition therapy. We postulate that combining anti-tumor antibodies with standard-of-care strategies such as immune checkpoint blockade or targeted therapy, will improve therapeutic outcomes in cancer.