Roswell Park Researchers Develop IL-36 Gamma 'Armored' CAR T Cells to Eradicate Solid Tumors
核心洞察
Roswell Park researchers led by CAR T-cell therapy pioneer Renier Brentjens have developed IL-36 gamma (搜索) 'armored' CAR T cells that can reprogram neutrophils (搜索) to activate innate immune responses against solid tumors (搜索).
The breakthrough study demonstrates the first mechanism by which CAR T cells can engage a patient's own immune cells to target solid-tumor malignancies, potentially overcoming the challenges that have limited CAR T therapy success in solid cancers.
The IL-36 gamma (搜索) CAR T-cell platform eliminates the need for lymphodepletion prior to treatment, allowing neutrophils (搜索) to be recruited for anti-tumor responses rather than being eliminated.
Researchers at Roswell Park Comprehensive Cancer Center have achieved a significant breakthrough in CAR T-cell therapy for solid tumors (搜索), developing "armored" CAR T cells that can eradicate solid-tumor cancers by reprogramming the patient's own immune cells. The laboratory study, led by CAR T-cell therapy pioneer Renier Brentjens, MD, PhD, represents a major advance toward achieving in solid tumors the same therapeutic success that CAR T-cell therapy has realized in blood cancers.
Revolutionary Immune Cell Collaboration
The research team, including first author Yihan Zuo, PhD, and co-senior author Scott Abrams, PhD, is the first to demonstrate that CAR T cells armored with the cytokine IL-36 gamma (搜索) can reprogram white blood cells known as neutrophils (搜索) to activate an innate immune response against solid tumors (搜索). Their findings, published in Cancer Cell, establish a new mechanism by which CAR T cells can engage a patient's own immune system to target solid-tumor malignancies.
"What's so exciting about this work is that it demonstrates a new mechanism by which CAR T cells can engage a patient's own immune cells to go after solid-tumor malignancies," says Dr. Brentjens, who holds The Katherine Anne Gioia Endowed Chair in Cancer Medicine at Roswell Park and was recognized with the 2024 Warren Alpert Foundation Prize for his contributions to CAR T-cell therapy development.
Overcoming Solid Tumor Challenges
While CAR T-cell therapies have achieved high remission rates for blood-based cancers, solid tumors (搜索) present greater therapeutic challenges. Solid tumor cells display many different antigens on their surface and can stop producing targeted antigens to "hide" from CAR T cells during treatment. Additionally, the protective tissue surrounding tumors and the overall tumor microenvironment make it difficult for CAR T cells to infiltrate the tumor.
Working with preclinical models of small cell lung cancer (搜索), the research team evaluated CAR T cells designed to target Interleukin 36 gamma (搜索) (IL-36γ), a protein with broad impact on immune cells, including neutrophils (搜索) that are key to establishing the cancer-immunity cycle. Recent studies have shown that neutrophil subsets can kill tumors directly and induce adaptive anti-tumor immunity while affecting immunotherapy outcomes.
Unexpected Immune Collaboration
"Our study uncovers an unexpected level of immune collaboration activated by IL-36 gamma (搜索)-armored CAR T cells," explains study first author Yihan Zuo, PhD, research scientist in Roswell Park's Department of Medicine. "We were excited to find that neutrophils (搜索) can be reprogrammed to acquire antigen-presenting functions and drive potent antitumor immunity. These insights open new possibilities for developing next-generation cell therapies for solid tumors (搜索)."
The treatment strategy eliminates the need for lymphodepletion prior to treatment, a standard step in CAR T-cell therapy that uses chemotherapy to eliminate the patient's own lymphocytes to make room for CAR T cells. By sparing neutrophils (搜索), the armored IL-36 gamma (搜索) CAR T cells can recruit them to the anti-tumor response instead.
Clinical Translation in Development
"The discovery of this unique CAR T cell/IL-36 gamma (搜索) 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," notes study co-senior author Scott Abrams, PhD, Jacobs Family Endowed Chair of Immunology at Roswell Park.
Dr. Brentjens emphasizes the clinical potential: "Our findings establish that the IL-36 gamma (搜索) 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."
A clinical trial based on these findings is now in development at Roswell Park. The research was funded in part by two National Cancer Institute grants (project numbers U01CA256801 and P30CA016056) and involved contributors from seven Roswell Park programs as well as Christopher Hackett, MD, PhD, of Weill Cornell Medicine.