Abstract 3476: TAK-243 increases tumor immunogenicity enhancing systemic anti-tumor immune response and tumor regression in combination with immune checkpoint inhibition in a syngeneic model of lymphoma
Authors: Klinghoffer Richard , Burns Connor , Merrell Angela , Grenley Marc 
Published: April 2023

Abstract
Agents that induce a shift in the activity state of the immune tumor microenvironment (TME) from “cold-to-hot” may increase response to immune checkpoint inhibitors. Here we examined whether TAK-243, a small molecule inhibitor of the ubiquitin activating enzyme (UAE), could heighten tumor immunogenicity and increase response to checkpoint inhibition. Our hypothesis was based on previous studies showing that TAK-243 induces ER stress (Hyer et al.) a phenomenon that can influence the status of the immune TME. While TAK-243 has previously shown anti-tumor potential, these studies were largely performed in immune-deficient models of cancer leaving potential influence on immune response in question. We first examined this potential using multiplexed trackable intratumor microdosing (CIVOTM, Presage Biosciences) to introduce TAK-243 alone or in combination with an anti-PD1 antibody (RPM1-14) to distinct localized positions within in a syngeneic model of lymphoma (A20). Response to localized drug exposure was then evaluated by immunohistochemistry and in situ hybridization biomarker analysis. TAK-243 induced elevation of multiple immune response biomarkers including 1) dendritic cell enrichment, 2) chemokine elevation, 3) TNFa elevation, and 4) CD8/Granzyme B elevation. We next examined whether TAK-243 could act as an “in situ vaccine” upon intratumor delivery and increase response to systemically delivered anti-PD1. Consistent with this potential, intratumor injection of TAK-243 resulted in greater regression of tumors in a dual flanked A20 xenograft model (ie one tumor on each flank of the host) when combined with systemically delivered anti-PD1 compared to either TAK-243 or anti-PD1 treatment alone. Importantly clear abscopal effects were induced as tumor regression was observed in both TAK-243 injected and non-injected tumors from subjects treated with the combination of TAK-243 and anti-PD1, 60% of which showed complete loss of tumor. Inhibition of the anti-tumor response was observed upon introduction of the drug combination with a CD8-depleting antibody. Furthermore, re-inoculation of subjects that exhibited complete regression of tumor masses with A20 cells showed no growth of new tumors. Taken together, these data suggest that intratumor injection of TAK-243 has potential to act as an in situ vaccine which increases anti-tumor immunogenicity and primes tumors for response to ICIs.
Citation Format: Richard Klinghoffer, Connor Burns, Angela Merrell, Marc Grenley. TAK-243 increases tumor immunogenicity enhancing systemic anti-tumor immune response and tumor regression in combination with immune checkpoint inhibition in a syngeneic model of lymphoma [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 3476.