Oncolytic Adenoviruses: The Cold War against Cancer Finally Turns Hot

SIMPLE SUMMARY: Immunotherapy has revolutionized cancer treatment, as demonstrated by the tremendous success of checkpoint inhibitors in different tumor types. Unfortunately, most patients, particularly patients with non-responsive “cold” tumors, do not benefit from checkpoint inhibitors. Enter “armed” oncolytic viruses, which “cooperate” with checkpoint inhibitors to improve anticancer responses. These are genetically engineered viruses that selectively infect, replicate in, and kill cancer cells but not cells from healthy tissues; in the process, oncolytic viruses express the therapeutic proteins that they are armed with or carry. This effectively turns the infected tumors “hot” and makes them suitable for treatment with checkpoint inhibitors. The most well-studied of all the oncolytic viruses are adenoviruses. These are agents of the common cold, which makes them remarkably safe for clinical use. This review article summarizes the oncolytic adenoviruses in advanced clinical trials and presents strategies to improve their anticancer activity. ABSTRACT: Oncolytic viruses, colloquially referred to as “living drugs”, amplify themselves and the therapeutic transgenes that they carry to stimulate an immune response both locally and systemically. Remarkable exceptions aside, such as the recent 14-patient trial with the PD-1 inhibitor, dostarlimab, in mismatch repair (MMR) deficient rectal cancer, where the complete response rate was 100%, checkpoint inhibitors are not cure-alls, which suggests the need for a combination partner like oncolytic viruses to prime and augment their activity. This review focuses on adenoviruses, the most clinically investigated of all the oncolytic viruses. It covers specific design features of clinical adenoviral candidates and highlights their potential both alone and in combination with checkpoint inhibitors in clinical trials to turn immunologically “cold” and unresponsive tumors into “hotter” and more responsive ones through a domino effect. Finally, a “mix-and-match” combination of therapies based on the paradigm of the cancer-immunity cycle is proposed to augment the immune responses of oncolytic adenoviruses.