New Roswell Park Strategy for Overcoming Resistance to Immunotherapy Unleashes Power of Dendritic Cells

Team outlines 3-step approach that could expand benefits of checkpoint inhibitors; breast cancer study planned

BUFFALO, N.Y. — Many of the most aggressive and hard-to-treat cancers are highly effective at blocking T cells, known as the foot soldiers of the immune system, from reaching and responding to tumors. It’s a cancer defense mechanism that even groundbreaking immunotherapies have not yet broken through. Research led by a team from Roswell Park Comprehensive Cancer Center details a promising new strategy for overcoming this treatment resistance by zeroing in on dendritic cells and enhancing their function as “accessory cells” supporting other immune cells.

Based on their findings, a Roswell Park team led by Dr. Fumito Ito plans to study a new immunotherapy combination in patients with advanced breast cancer.

The new work, led by Fumito Ito, MD, PhD, FACS, of Roswell Park’s Center for Immunotherapy and published today in the journal Nature Communications, documents successful laboratory studies of a three-pronged approach for activating cross-presenting conventional type 1 dendritic cells (cDC1s) and reversing poor T-cell infiltration in even “cold” tumors that don’t typically respond to immunotherapy.

“Despite the unprecedented clinical activity on various cancers with PD-1/PD-L1 blockade immunotherapy, the majority of cancer patients will not experience long-term protection from these treatments, and we know that this is due in large part to poor T-cell infiltration into the tumor microenvironment,” says Dr. Ito, who is also Associate Professor of Oncology in the Department of Surgical Oncology at Roswell Park.

To overcome this obstacle, the team proposed a previously untried combination of three intratumoral methods for stimulating immune responses: (1.) administration of the cytokine protein Flt3L, to mobilize cDC1s and recruit them to the tumor microenvironment; (2.) radiotherapy, or radiation therapy, to promote immunogenic death of cancer cells and maturation of the dendritic cells; and (3.) dual stimulation of two key proteins, TLR3 and CD40, to activate antigen-loaded cDC1s for priming and expansion of tumor-specific CD8+ T cells.

“Our findings in multiple preclinical models of immunotherapy-resistant cancers, including melanoma and breast tumors, show that this novel combination increases the infiltration of tumor-killing T cells, triggers rapid regression of both primary and distant tumors and renders even tumors with poor T-cell penetration responsive to anti-PD-L1 immunotherapy,” says Dr. Ito. “Our approach overcame both primary, or initial, and acquired resistance, and we also saw evidence of tumor-specific systemic immunological memory, suggesting that this strategy may generate long-term anticancer responses even against hard-to-treat melanoma and breast tumors.”

A phase I clinical study of this approach in patients with advanced breast cancer is planned at Roswell Park.

Co-authors include Takaaki Oba, MD, PhD, who was a postdoctoral researcher in Dr. Ito’s lab when this work was conducted, and Roswell Park faculty members Mark Long, PhDHans Minderman, PhDScott Abrams, PhD, and Song Liu, PhD, as well as collaborators from Celldex Therapeutics Inc.

This work was supported by several National Cancer Institute (NCI) grants (project numbers P30CA016056, R50CA211108, R01CA172105, U24CA232979 and K08CA197966), as well as by funds from the Melanoma Research Alliance, Sarcoma Foundation of America and Uehara Memorial Foundation.