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.

Improving Biologics’ Effectiveness in Clinical Oncology: From the Combination of Two Monoclonal Antibodies to Oligoclonal Antibody Mixtures

“…In mice treated with this combination, CD8 + T cells, natural killer (NK) and γδ T cells with cytolytic activity were increased as well as plasma antitumor IgGs, leading to better overall survival [ 40 ]. Similar results were described recently by another group using the TA99 mAb with the anti-CTLA-4 mAb or the agonist anti-CD137 mAb in the B16F10 mouse melanoma model [ 46 ]. In both cases, treatment with the TA99 mAb resulted in an increased expression of the secondary targets CTLA-4, PD1 or CD137, leading to an optimal combinatorial effect of the anti-PD1 or anti-CD137 mAbs.…”

Bispecific antibodies redirect synthetic agonistic receptor modified T cells against melanoma

“…Real-time PCR reactions were performed using SYBR Green PCR Master Mix (Applied Biosystems) and sequence specific primers for human MCSP, human and murine TYRP1. [28][29][30] The amplification was performed with CFX Connect Real-Time PCR Detection System (Bio-Rad Laboratories) running up to 50 cycles of 5 s at 95°C followed by 30 s at 60°C after an initial step of 95°C for 2 min. Melting curves from 65°C to 95°C were performed to evaluate the specificity of the PCR.…”