FDA Clears Trial of Dual-Target CAR T-Cell Therapy for Colorectal Cancer

The U.S. Food and Drug Administration has granted permission for investigators at the University of Colorado Anschutz Medical Campus to launch a clinical trial of a genetically engineered immune-cell therapy designed to attack colorectal cancer in a way that few current treatments can. The experimental approach, developed by researchers at CU Anschutz, will be tested in adults with advanced colorectal cancer and in pediatric patients with solid cancers who have run out of standard treatment options. The trial is expected to begin in December, and its approval marks a significant step for a therapy that began as a laboratory idea on the same campus where it will now be manufactured and delivered to patients.

The therapy belongs to a class of treatments known as CAR T-cell immunotherapy. The process begins with the collection of a patient’s own T cells, the immune system’s specialized killers. In the laboratory, those cells are genetically modified so that they carry engineered receptors capable of recognizing and binding to specific molecules on the surface of cancer cells. Once reprogrammed, the cells are expanded into large numbers and returned to the patient, where they circulate, seek out their targets and attack. The technique has already produced striking results in certain blood cancers, including leukemia and lymphoma, where engineered immune cells have driven durable remissions in patients who had exhausted every other option.

Translating that success to solid tumors such as colorectal cancer has proved far more difficult. Solid tumors are physically dense, immunologically hostile environments that engineered cells struggle to infiltrate and survive in. They deploy molecular defenses that suppress or redirect immune attacks, and they present a fundamental targeting problem: researchers must find a molecule that is abundant on cancer cells but scarce on healthy tissue, so that the therapy attacks the tumor without destroying vital organs. That targeting challenge has been one of the central obstacles holding back CAR T-cell therapy for the many cancers that form solid masses rather than circulating freely in the blood.

The CU Anschutz team believes it has found a way around that obstacle by aiming at two targets at once. The first is B7-H3, a protein found on the surface of most colorectal tumors and, importantly, on a wide range of other cancers as well. Researchers at several institutions have been investigating B7-H3 as a potential cancer target precisely because of its broad presence across tumor types. The second target is IL-8, a signaling protein that helps promote tumor growth, inflammation and the spread of cancer through the body. By simultaneously targeting B7-H3 and the IL-8 pathway, the engineered cells are designed to strike both the tumor itself and one of the biological systems it uses to grow and evade immune destruction. The researchers hope that this two-pronged strategy will give the engineered cells a better chance of overcoming the defenses that have limited earlier attempts to treat solid tumors with CAR T-cell therapy.

The dual-target design also reflects a deliberate strategic choice about which patients the therapy could eventually serve. Michael Verneris, MD, professor of pediatric oncology at CU Anschutz and program co-leader of Tumor-Host Interactions at the CU Anschutz Cancer Center, said the team wanted to move away from highly narrow approaches. “This is a very different way of thinking about how we treat cancer,” Verneris said. “We wanted to find targets that are present across many different cancers rather than developing a therapy that would only apply to a small number of patients.” If the trial demonstrates that the approach is safe and effective, the researchers say it could eventually be tested against other cancers in which these pathways play a role, including some breast, lung and ovarian cancers.

Christopher Lieu, MD, professor of medical oncology at CU Anschutz and associate director of clinical research at the CU Anschutz Cancer Center, is leading the trial. He framed the therapy as a potential alternative to the blunt instruments of conventional treatment. “Chemotherapy extends survival and helps cure people,” Lieu said. “At the same time, it’s like dropping an unguided bomb on a disease. Maybe you hit your target, but you are going to do a lot of collateral damage.” He is hoping the therapy, which has proven effective in animal models, will produce far longer-lasting results than current options typically deliver. “Immunotherapy gives us the opportunity to direct the immune system toward the cancer and potentially produce a much more durable response,” he said. The goal, he added, is not measured in months but in years.

The urgency behind the trial is underscored by troubling epidemiological trends. Colorectal cancer is increasingly affecting younger adults, with rates among people under 45 rising substantially over the past several decades while researchers continue to investigate the reasons behind the shift. For patients whose disease advances despite standard therapies, options narrow rapidly. Currently, only a small percentage of patients with colorectal and other gastrointestinal cancers qualify for certain forms of immunotherapy, because those treatments depend on specific tumor biomarkers that many patients do not have. Because B7-H3 is present in a much larger proportion of colorectal cancers, the researchers hope their approach could ultimately be applicable to a far broader patient population. “Given the number of patients we are seeing, we need new approaches,” Lieu said. But he and his colleagues are careful to note that the first step is determining whether the therapy is safe in people and whether it can effectively attack cancer in the human body, as it has in animal models.

The path from concept to clinical trial also highlights the structural advantages of the CU Anschutz campus, which brings together the university’s health professional schools, Children’s Hospital Colorado, UCHealth University of Colorado Hospital and the Gates Biomanufacturing Facility within easy walking distance of one another. The experimental cells for the trial will be manufactured at the Gates Biomanufacturing Facility, meaning the entire pipeline, from basic research to cell production to patient treatment, exists on a single campus. “The whole spectrum is right here,” Verneris said. “If we didn’t have the Gates Institute, we wouldn’t be able to make our own cells. This could have remained an interesting idea. Instead, it has become a clinical trial that could have a real impact on patients.” Philanthropic support has been essential to reaching this point, Verneris noted, because trials of this kind are expensive and private donations made it possible to move the therapy from the laboratory into patients. “We are incredibly grateful to the donors who have helped make this possible,” he said.

For the patients who enroll, the trial represents something that advanced colorectal cancer currently offers in short supply: a chance at a treatment designed to last. If the engineered cells can safely navigate the hostile terrain of solid tumors and dismantle the pathways that colorectal cancers use to grow and spread, the trial could open a new front against one of the most common and increasingly prevalent cancers, and potentially against several others beyond it. The FDA’s clearance now allows that hypothesis to be tested in the place it matters most, in the bodies of the patients the therapy was designed for.

Subject of Research: A first-in-human clinical trial of dual-target CAR T-cell immunotherapy for advanced colorectal cancer

Article Title: FDA clears CU Anschutz clinical trial using engineered immune cells to fight colorectal cancer

Article References: FDA clears CU Anschutz clinical trial using engineered immune cells to fight colorectal cancer. (n.d.). Original publication

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Keywords: CAR T-cell therapy, colorectal cancer, FDA clearance, clinical trial, immunotherapy, B7-H3, IL-8, solid tumors, CU Anschutz, pediatric cancer, engineered immune cells, Gates Biomanufacturing Facility