New off-the-shelf immunotherapy for metastatic kidney cancer could help improve outcomes

UCLA researchers have developed a new kind of immunotherapy that uses specially engineered immune cells equipped with built-in weapons to attack kidney cancer tumors and reprogram their protective environment - all without the need to customize treatment for each individual patient.

This "off-the-shelf" approach, called AlloCAR70-NKT, could help improve outcomes, reduce complications and expand access for patients with limited treatment options. 

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. This approach overcomes the time delays and safety risks of traditional immunotherapies, especially for patients with aggressive, late-stage disease."

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

Despite recent advances in immunotherapy and targeted therapies, many patients with metastatic renal cell carcinoma, an aggressive and often fatal form of kidney cancer, either fail to respond or eventually relapse. The five-year survival rate remains just 12%. Given the disease's resistance to current treatments, there is an urgent need for new and more effective therapeutic strategies. 

To address these challenges, researchers at the UCLA Health Jonsson Comprehensive Cancer Center and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research developed AlloCAR70-NKT, an innovative cell therapy that harnesses the body's immune system to fight cancer more effectively. 

In the study, published in Cell Reports Medicine, researchers created the therapy 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 designed to resist immune rejection and remain active in the tumor environment. 

"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."

When tested in preclinical models, AlloCAR70-NKT cells demonstrated what researchers call a multi-pronged attack against kidney cancer. First, the cells directly killed cancer cells through both the engineered CAR and their NKT receptors, even when the 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, which often 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. 

"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 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. A full list of authors is included in the study. 

Wu, Yang and Chin are all members of the UCLA Health Jonsson Comprehensive Cancer Center and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research. Yang is also a member of the Goodman-Luskin Microbiome Center and the Parker Institute for Cancer Immunotherapy (PICI). 

The research was supported in part by grants from the California Institute for Regenerative Medicine, PICI, and a Kidney Cancer Research Program Award from the Department of Defense.