Abstract 697: Defining anti-tumor immune stimulatory mechanisms of MEM-288, a CD40 ligand and IFN-beta dual-transgene armed oncolytic adenovirus
Authors: Zheng Hong , Powell Chase D. , Antonia Scott , Cantwell Mark J. , Perez Bradford A. , Beg Amer A. 
Published: July 2021

Abstract
MEM-288 is a dual-transgene armed oncolytic adenovirus being developed for cancer treatment as a standalone agent or in combination with immune checkpoint inhibitors (ICI). MEM-288 is armed with two potent immune agonist transgenes: MEM40, a novel chimeric CD40 ligand (CD40L) designed for stable cell surface expression of CD40L that functions as a potent activator of CD40 expressing dendritic cells (DCs), and the DC and T cell activating cytokine IFNβ. We have evaluated MEM-288 activity in multiple in vivo immunocompetent mouse models to determine impact on systemic antitumor T cell activity after intratumoral virus injection. We were able to readily detect both tumor and immune cell infection and transgene expression following MEM-288 intratumoral administration in mouse tumor models and freshly resected human NSCLC tumors. MEM-288 injection in the syngeneic mouse lung metastatic model 344SQ demonstrated anti-metastatic activity that correlated with a significant enhancement in tumor infiltrating lymphocytes (TILs) and an increase in the systemic antitumor CD8 T cell response. MEM-288 also generated a highly efficacious response against both injected and distant non-injected contralateral tumors in the B16-F10 melanoma model, both as a monotherapy and in combination with ICI. These antitumor and immune responses were only found with MEM-288 as compared to the base adenovirus vector encoding only GFP transgene, indicating the observed effects were highly transgene-dependent. Dissecting the immune stimulatory effects further, we found MEM-288 injection in B16 tumors led to a significant increase in DC activation markers CD80 and CD86 suggesting that DCs may represent a key target of MEM-288 encoded transgenes leading to systemic T cell responses. In support of this hypothesis, we found the MEM-288 CD8 T cell response was completely abolished in BATF3 knockout (KO) mice which lack the cDC1 DC subset (CD8α conventional DC deficient). This suggests that cDC1s are a key mediator of MEM-288 activity. Furthermore, MEM-288 activity was also impaired in both CD40 and type 1 IFN receptor (IFNAR1) KO mice suggesting that both transgenes mediate MEM-288 immune stimulation. In summary, these results demonstrate MEM-288's capacity to induce a potent increase in systemic T cell responses through transgene-mediated stimulation of tumor DCs. This immune stimulatory capacity complements the additional mechanistic features of MEM-288, including enhanced tumor-specific viral replication, oncolysis, and tumor antigen release. MEM-288 is currently being prepared for first-in-human clinical testing in solid tumors as a monotherapy and in combination with ICI.
Citation Format: Hong Zheng, Chase D. Powell, Scott Antonia, Mark J. Cantwell, Bradford A. Perez, Amer A. Beg. Defining anti-tumor immune stimulatory mechanisms of MEM-288, a CD40 ligand and IFN-beta dual-transgene armed oncolytic adenovirus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 697.