Cancer cells have several ways of evading the immune system. Some conceal the molecular features that treatments are designed to recognize, while others form solid tumors that immune cells struggle to penetrate. Scientists are now exploring whether immune cells equipped with more than one way to identify cancer could overcome some of those obstacles.
"This dual targeting could help address antigen heterogeneity and antigen escape, two major barriers that have limited the effectiveness of conventional single-target cellular therapies in solid tumors," co-senior author Dr. Yan-Ruide (Charlie) Li, a postdoctoral scholar at UCLA, told Newsweek. Li said the experimental platform may be particularly useful against solid tumors that express validated intracellular antigens, including subsets of ovarian cancer, melanoma and prostate cancer.
In the study, published in Cell Reports Medicine, researchers developed “off-the-shelf” immune cells called AlloESO-T cells from gene-engineered blood-forming stem and progenitor cells. The cells were designed to attack tumors through two distinct biological routes. The first involves an engineered T-cell receptor, or TCR, that recognizes NY-ESO-1, a tumor-associated protein found in several solid cancers.
Unlike CAR-T cells, which generally recognize targets on cancer-cell surfaces, TCR-engineered cells can detect fragments from proteins originating inside tumor cells when those fragments are presented on the surface. The AlloESO-T cells also use natural killer receptors to detect stressed malignant cells independently of NY-ESO-1. This second line of attack could allow them to continue recognizing some cancer cells even if the original targeted antigen is absent or lost.
Li stressed that considerable work remains before the cells could be tested in patients, including establishing the appropriate dose and studying where the cells travel in the body, how long they persist and whether they successfully reach tumors. "The key next step is to show that AlloESO-T cells can be manufactured reproducibly at clinical grade while retaining their uniform engineered TCR, natural killer receptor activity, potency, and stability after cryopreservation," he said. Compared with conventional TCR-engineered cells derived from peripheral blood, the experimental cells demonstrated stronger cancer-cell killing, selective movement toward solid tumors, sustained activity and greater resilience to immune evasion in preclinical models.
The researchers also reported low risks of graft-versus-host disease and cytokine release syndrome in their laboratory and animal testing. The approach could also dramatically reduce manufacturing costs compared with existing personalized cell therapies. Unlike conventional treatments that are made individually from a patient's own immune cells, AlloESO-T cells are generated from blood-forming stem cells and can be produced in large batches.
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