UCLA researchers have developed a new kind of immunotherapy that harnesses the body’s immune system to fight cancer more effectively. The innovative cell therapy uses specially engineered immune cells—allogeneic CD70-directed CAR-engineered NKT (AlloCAR70-NKT) cells—equipped with built-in weapons to attack kidney cancer tumors and reprogram their protective tumor microenvironment (TME), but without the need to customize treatment for each individual patient.
Tests in cell lines and in preclinical mouse models of renal cell carcinoma (RCC)—including both orthotopic and metastatic in vivo xenograft models—showed that the AlloCAR70-NKT cells waged a multi-pronged attack against cancer cells and exhibited a high safety profile. This off-the-shelf approach, the researchers say, could 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,” said Lily Wu, MD, PhD, 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.”
Wu and colleagues reported on their developments in Cell Reports Medicine, in a paper titled “Multimodal targeting of metastatic renal cell carcinoma via CD70-directed allogeneic CAR-NKT cells,” in which they concluded, “Taken together, our findings support the therapeutic potential of AlloCAR70-NKT cells as a next-generation, off-the-shelf immunotherapy with dual tumor- and TME-targeting functionality and the added capacity to eliminate alloreactive T cells, which offers a compelling strategy for treating metastatic RCC.”
Renal cell carcinoma (RCC) represents about 90% of kidney cancers, with 30%–40% of patients developing metastatic disease despite current treatments, the authors wrote. And despite recent advances in targeted therapies, such as vascular endothelial growth factor (VEGF) and mammalian target of rapamycin inhibitors, many patients with metastatic renal cell carcinoma, which is aggressive and often fatal, either fail to respond or eventually relapse. “… approximately 33% of patients still progress to metastatic disease, with a five year survival of only 12%,” the team stated. “These limitations highlight the urgent need for more effective and innovative treatment options.”
Immunotherapy has exhibited some promise as a strategy against RCC, the team noted. In particular, “… chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy targeting CD70 is emerging as an attractive approach for RCC,” they pointed out. However, the team further explained, “… most CAR70-T cell products are autologous, necessitating patient specific manufacturing, which is labor intensive, time consuming, and financially burdensome.”
To address current treatment challenges, the researchers at the UCLA Health Jonsson Comprehensive Cancer Center and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research generated a new cell 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, but shows limited expression in normal tissues. These AlloCAR70-NKT cells were designed to resist immune rejection and remain active in the tumor environment. “…we employed our previously established hematopoietic stem and progenitor cell (HSPC) gene engineering technology and a clinically guided culture method to generate allogeneic CD70-directed CAR-engineered invariant natural killer T (AlloCAR70-NKT) cells,” they stated.
“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,” commented co-senior author Lili Yang, PhD, 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 mouse models of RCC, including orthotopic and metastatic xenograft models, the AlloCAR70-NKT cells demonstrated a multi-pronged attack against kidney cancer. 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. The AlloCAR70-NKT cells also 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.
AlloCAR70-NKT cell treatment in addition 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 the 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. The results of tests in mouse models, the investigators stated “… collectively highlight the favorable safety profile of AlloCAR70-NKT cells and support their potential as a durable and safe off-the-shelf cellular immunotherapy.”
In summary, they reported, “Through the use of a comprehensive array of experimental models, including primary RCC patient samples, patient-derived tumor cell lines, in vitro functional assays, and both orthotopic and metastatic in vivo xenograft models, we demonstrate that AlloCAR70-NKT cells effectively and concurrently eliminate RCC tumor cells, modulate the immunosuppressive TME, and deplete CD70-expressing alloreactive T cells.”
Co-senior author Arnold Chin, MD, PhD, professor of urology at the David Geffen School of Medicine at UCLA, commented, “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.” He added: “If the early promise translates to patients, it could offer a new lifeline for many.”
The post Off-the-Shelf Immunotherapy Demonstrates Multipronged Attack Against Cancer appeared first on GEN – Genetic Engineering and Biotechnology News.
