Harnessing Senescence Biology for Immune Oncology

Endeavor Award (2023-Present)

Memorial Sloan Kettering Cancer Center: Scott Lowe, PhD; Paul Romesser, MD; Michel Sadelain, MD, PhD; Julio Garcia-Aguilar, MD; Andrea Schietinger, PhD; Dana Pe’er, PhD

Scott Lowe, PhD

Paul Romesser, MD

Michel Sadelain, MD, PhD

Julio Garcia-Aguilar, MD

Andrea Schietinger, PhD

Dana Pe’er, PhD

In the realm of cancer treatment, immune oncology (IO) has emerged as a game-changer, offering enduring anti-tumor responses for a subset of patients. Within this arena, two standout methods are immune checkpoint blockade, which reignites the innate immune system, and CAR T cell therapies, which programs custom-engineered synthetic immune cells to seek out and destroy tumor cells. Nonetheless, despite this progress, a significant portion of patients remains unresponsive to these and other IO strategies.

This project is rooted in a discovery made by this team, who found that therapeutic agents capable of inducing tumor cell senescence hold the potential to significantly enhance the vulnerability of cancer cells to immune attacks. Cellular senescence is a stress response program that halts cell cycle progression and releases factors that can significantly reshape the tissue environment. Although cellular senescence has been studied for decades, our understanding of the role of senescence in modulating IO is still in its infancy. Now, this Endeavor team will begin to unravel the intricacies of senescence biology and leverage this understanding to broaden the reach of immune oncology to encompass a more diverse and broader set of cancer patients.

The team is made up of a diverse array of investigators boasting expertise in senescence biology, immunology, computational biology, radiation oncology, and cell-based therapies. They will initially focus on rectal cancer, as it is accessible for repeat biopsies, allowing longitudinal monitoring of treatment effects on senescence and the tumor microenvironment. The team will characterize the impact of radiation-induced senescence on tumor cell immunogenicity and therapeutic outcome, investigate the immunomodulatory effect of senescence to enhance the anti-tumor immune response, and harness senescence to enhance cell therapy in solid tumors, particularly focusing on CAR T cell therapy. Additionally, the hypothesis that senescence-induced alterations could amplify the potency of CAR T cells and other similar treatments will be rigorously tested. Armed with these insights, the researchers plan to devise strategies that steer the immune response towards rejecting the tumor cells.

By understanding the mechanisms underlying senescence induction and its impact on the immune microenvironment, the researchers hope to identify potential biomarkers and patient populations that will benefit from senescence-modulating therapies. Ultimately, the implications of this Endeavor award extend beyond rectal cancer. Given that numerous traditional and targeted anti-cancer agents can also induce tumor cell senescence, this program establishes a framework for propelling senescence-inducing therapies to enhance immune oncology across diverse cancer types.