Kepeng Wang

UConn Health, USA

Title: CARG-2020, an engineered trivalent immune-modulating oncolytic virus for treatment of cancers and their recurrence

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Biography

Research in Dr. Kepeng Wang’s lab focuses on the role of inflammation in colorectal cancer development and therapeutic intervention. Among the inflammatory signals that have been characterized in tumor microenvironment, IL-17 has been shown to play important roles in immunity against invading pathogens and in chronic inflammation of autoimmune diseases. IL-17 signaling also drives the development of colorectal, breast, pancreatic, and prostate cancers. His research showed that IL-17 signals to both tumor cells and other cell types within tumor. Direct engagement of IL-17 promotes tumor cell proliferation and survival, whereas IL-17 signaling on stromal and immune cells regulates tumor-associated inflammation and anti-tumor immunity. Dr. Kepeng Wang also collaborated with CaroGen Corp at Connecticut, USA for the development of novel oncolytic viruses for the treatment of cancers. 

Abstract

Tumors are adept at escaping the immune response through multiple mechanisms that disrupt key processes. This is observed with immune checkpoint blockade therapies that are only effective in limited numbers of cancer patients. Therapies targeting other immune pathways have shown promise for those who do not respond to certain immune checkpoint therapies, but these have efficacy in limited numbers of patients as well. Thus, developing a rational approach to combination therapy that targets multiple mechanisms will help build upon the successes of cancer immunotherapy. Here we describe the use of virus-like vesicles (VLV)—a hybrid alphavirus-rhabdovirus vector—as a trivalent combination cancer therapy. This high-capacity oncolytic vector was adapted to simultaneously and synergistically stimulate immune cell activation, inhibit an immune checkpoint pathway, and disrupt a pro-tumor pathway by co-delivering interleukin (IL)-12, short-hairpin RNA (shRNA) targeting programmed death ligand 1 (PD-L1), and a dominant-negative form of IL-17 receptor A (dn-IL17RA), respectively. Intratumoral injections of CARG-2020 eradicated large established tumors in mice. The concurrent modulation of IL-12, IL-17, and PD-L1 pathways by CARG-2020 prolonged overall survival and suppressed tumor recurrence. Treatment of primary tumors by CARG-2020 also resulted in marked inhibition of distal tumors, demonstrating a strong abscopal effect of the agent. CARG-2020 is also effective against MC38 tumors when delivered intravenously. CARG-2020 potently activates Th1-armed immunity in primary tumors and the spleen, and inhibits the expression of genes related to T cell exhaustion and cancer-promoting inflammation. In conclusion, CARG-2020 is a novel and first-in-class agent that combines oncolytic viral platform with trivalent immune modulation payloads working through multiple mechanisms of action. CARG-2020 is safe in animals when delivered intratumorally or intravenously, and is effective against both local and distal tumors in mice. Further development and pre-IND validation of this agent may warrant its potential use in human cancer immunotherapy