Abstract 4114: Can exosomal cargoes predict checkpoint inhibitor response in melanoma, and can we overcome drug resistance

Abstract Immune check point inhibitor(s) have become a main stay of treatment for melanoma regardless of its mutational status. However, not all patients respond to treatment. In fact, only 40-60% respond to treatment. Currently, only PD-L1/PD-1 expression and mutational burden can predict response to treatment. Published data have shown that exosomal PD-L1 is an important factor contributing to response/failure to checkpoint inhibitor treatment. Exosome is known to carry several types of cargoes and is one of the important delivery systems in the body. We have begun to examine the role of exosomal PD-L1, PD-1 in predicting response, and as well as how to overcome drug resistance. We initiated an institutional study in metastatic melanoma patients who underwent immunotherapy treatment (anti-PD-1 + anti-CTLA 4 drugs). Blood samples were obtained at baseline and at subsequent treatment. Both serum and plasma exosomes were isolated. Eighteen patients were entered in the study. We have found that 1) Patients with PD-L1 negative tumor can have high exosomal PD-L1 expression, 2) all patients had exosomal PD-L1, and 3) all patients with decreased exosomal PD-L1 expression after treatment showed antitumor response [partial response (PR) or complete response (CR)]. In contrast, patients who had consistently high exosomal PD-L1 expression post-treatment showed no response, and this can be seen after the third cycle of treatment. Patients who achieved CR showed low exosomal PD-L1 and no exosomal PD-1 post-treatment. Importantly, we have also found that exosomes carry antiapoptotic protein and proapoptotic protein, as well as ATG family protein, which is related to autophagy. Whether these proteins also play a role in determining the cell fate in the metastatic sites is not known and will need future investigation. Interestingly, the two patients who showed no response also had high p-AKT. Since traditional anti PD-1 and anti-PD-L1 drugs do not have effect on exosomal PD-L1 and PD-1, we formed a collaboration with Dr. Stephane Roche at Florida Atlantic University, who has designed novel peptides by exploiting the innate plasticity of the PD-1 receptor (pembrolizumab H3 loop mimics). Thus far, we have screened many compounds and have selected 2 compounds for further testing. Together, we have also designed new PD-L1 peptides that can inhibit both PD-L1 and PI3K/AKT pathways simultaneously. Hence one can overcome checkpoint inhibitor resistance due to exosomal PD-L1/PD-1. Supported by grant from Sylvester Comprehensive Cancer Center and R21GM132754. Citation Format: Pablo Eduardo Puente, Dan Nguyen, Niramol Savaraj, Chunjing Wu, Medhi Wangpaichitr, Stephane Roche, Guangkuan Zhao, Alexis Richaud, Jose Lutzky, Leonel Hernandez Aya, Mecker Moller, Jessica Crystal, Neha Goel, Lynn Feun. Can exosomal cargoes predict checkpoint inhibitor response in melanoma, and can we overcome drug resistance. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4114.