UCLA researchers have developed a groundbreaking off-the-shelf immunotherapy called AlloCAR70-NKT that could transform treatment for metastatic kidney cancer patients. The therapy uses specially engineered immune cells equipped with built-in weapons to attack kidney cancer tumors and reprogram their protective environment without requiring customization for individual patients.
The research, published in Cell Reports Medicine, addresses a critical unmet need in oncology. Despite recent advances in immunotherapy and targeted therapies, many patients with metastatic renal cell carcinoma either fail to respond or eventually relapse, with the five-year survival rate remaining just 12%.
Novel Engineering Approach
"We successfully turned stem cells into powerful cancer-fighting immune cells that can be ready to use for any patient, bypassing the need to engineer each patient's own cells," said Dr. Lily Wu, professor of molecular and medical pharmacology and urology at the David Geffen School of Medicine at UCLA and co-senior author of the study. "This approach overcomes the time delays and safety risks of traditional immunotherapies, especially for patients with aggressive, late-stage disease."
The therapy was created by genetically engineering natural killer T (NKT) cells derived from stem cells to express a chimeric antigen receptor (CAR) that targets CD70, a protein commonly found on kidney cancer cells. These AlloCAR70-NKT cells were specifically designed to resist immune rejection and remain active in the tumor environment.
Overcoming CAR-T Limitations
"This approach tackles a challenge in cancer immunotherapy: developing an off-the-shelf cell therapy that can persist and function effectively in patients without causing serious immune complications," said Dr. Lili Yang, professor of microbiology, immunology and molecular genetics at UCLA and co-senior author of the study. "Traditional CAR-T therapies often fall short in solid tumors like kidney cancer due to limited durability, poor tumor penetration and immune suppression. AlloCAR70-NKT cells are specifically engineered to overcome those obstacles."
Multi-Pronged Attack Mechanism
When tested in preclinical models, AlloCAR70-NKT cells demonstrated a sophisticated multi-pronged attack against kidney cancer. First, the cells directly killed cancer cells through both the engineered CAR and their NKT receptors, even when tumors had low levels of the CD70 protein, which usually makes them harder to treat.
Second, they disrupted the tumor's microenvironment, a protective barrier made up of suppressive immune cells that typically shields the tumor from immune attack and helps cancer resist treatment.
Third, they eliminated CD70-positive host immune cells that would normally reject the donor cells, allowing the therapy to persist longer in the body and sustain its anti-tumor activity. Since these cells don't remain in the body indefinitely, they are less likely to cause long-term immune system problems, such as chronic immune suppression or graft-versus-host disease.
Clinical Promise
"This multi-pronged approach helps them attack both the tumor and its surrounding support system, making them a potent, multifunctional and safer immunotherapy option for metastatic kidney cancer," said Dr. Arnold Chin, professor of urology at the David Geffen School of Medicine at UCLA and co-senior author of the study. "If the early promise translates to patients, it could offer a new lifeline for many."
The research was conducted at the UCLA Health Jonsson Comprehensive Cancer Center and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research. The study's first authors are Yan-Ruide Li, a postdoctoral scholar in the Lili Yang laboratory, and Junhui Hu, an assistant project scientist in the department of molecular and medical pharmacology at UCLA.
The research was supported in part by grants from the California Institute for Regenerative Medicine, the Parker Institute for Cancer Immunotherapy, and a Kidney Cancer Research Program Award from the Department of Defense.
