BUFFALO (WHN) – Scientists at Roswell Park Comprehensive Cancer Center have reported preclinical findings detailing a novel approach to enhance chimeric antigen receptor (CAR) T-cell therapy for solid tumors, a notoriously difficult cancer type to treat with this modality.
The research, published today in Cancer Cell, centers on reprogramming neutrophils, a type of white blood cell, to mount an immune response against solid tumors. This strategy involves equipping CAR T cells with a specific cytokine, Interleukin-36 gamma (IL-36γ).
CAR T-cell therapy has demonstrated significant success in treating blood cancers, leading to high remission rates. However, its application to solid tumors has faced substantial hurdles. These include the diverse array of antigens on solid tumor cells, which can change during treatment, and the complex tumor microenvironment (TME) that can impede CAR T-cell infiltration and function.
Dr. Renier Brentjens, Deputy Director and Chair of the Department of Medicine at Roswell Park and a leader in CAR T-cell research, stated that the work reveals a new mechanism for CAR T cells to collaborate with a patient’s existing immune cells. “Our findings establish that the IL-36 gamma CAR T-cell platform holds promise as a possible treatment option for some advanced solid-tumor cancers for which there currently are no curative therapies,” Dr. Brentjens remarked. He was recognized with the 2024 Warren Alpert Foundation Prize for his contributions to CAR T-cell therapy development.
The study, led by Dr. Brentjens, with first author Yihan Zuo, PhD, and co-senior author Scott Abrams, PhD, evaluated CAR T cells engineered to target IL-36γ. This protein influences various immune cells, including neutrophils. Recent evidence suggests certain neutrophil subsets can directly kill tumors and foster adaptive anti-tumor immunity, potentially impacting immunotherapy outcomes.
Researchers worked with preclinical models of small cell lung cancer to assess the efficacy of these IL-36γ-armored CAR T cells. Their observations indicated that these modified CAR T cells could reprogram neutrophils, enabling them to present antigens and drive a potent anti-tumor immune response.
“Our study uncovers an unexpected level of immune collaboration activated by IL-36 gamma-armored CAR T cells,” said Yihan Zuo, PhD, a research scientist in Roswell Park’s Department of Medicine and the study’s first author. “We were excited to find that neutrophils can be reprogrammed to acquire antigen-presenting functions and drive potent antitumor immunity.”
This approach also bypasses the need for lymphodepletion, a standard preparatory step in CAR T-cell therapy that uses chemotherapy to reduce the patient’s own lymphocytes, creating space for the engineered CAR T cells. By not depleting neutrophils, the IL-36γ-armored CAR T cells can potentially recruit them into the anti-tumor effort.
Scott Abrams, PhD, Jacobs Family Endowed Chair of Immunology at Roswell Park and a co-senior author on the study, commented, “The discovery of this unique CAR T cell/IL-36 gamma pairing defines a breakthrough not only in our basic understanding of the immune-tumor interaction but also a key advance in attacking solid cancers, which has remained a longstanding paradox.”
The Roswell Park GMP Engineering & Cell Manufacturing Facility (GEM), which houses the research and development, is described as the largest at any academic center, featuring extensive clean rooms and quality control capabilities.
The findings, while significant in preclinical models, have not yet been evaluated in human subjects. Roswell Park is currently developing a clinical trial based on these research outcomes.
The research team included contributors from seven Roswell Park programs and Christopher Hackett, MD, PhD, from Weill Cornell Medicine. Funding for this work was provided, in part, by grants from the National Cancer Institute (NCI), including project numbers U01CA256801 and P30CA016056, which supports Roswell Park’s Cancer Center Support grant.