From bench to bedside and back: CAR T cells armed with IL-15 show promise in treating solid cancers

Chimeric antigen receptor (CAR) T cell therapy has been a breakthrough success in treating some hematologic malignancies, but this therapy has not shown sustained clinical efficacy in solid tumors. More information is needed to explain why; however, limits in technology previously prevented scientists from studying how CAR T cells evolve post-infusion in humans, which could help in engineering more effective therapies.

Researchers at Baylor College of Medicine, Texas Children’s Cancer Center, the Center for Advanced Innate Cell Therapy and the Center for Cell and Gene Therapy at Baylor, Houston Methodist Hospital and Texas Children’s have found a promising method to address these challenges. A study published in the journal Nature reports results of the first-in-human phase 1 clinical trials of a novel immunotherapy approach for solid tumors expressing glypican-3 (GPC3). The study tested CAR T cells enhanced with the protein interleukin-15 (IL-15), which helps T cells survive and multiply.

Led by corresponding author Dr. Andras Heczey, Baylor researchers were at the forefront in developing and testing CAR T cells targeting the GPC3 cell surface proteoglycan in preclinical studies. However, to date, clinical studies of targeting GPC3 with CAR T cells have not shown antitumor efficacy. To address this issue, researchers studied GPC3-CAR T cells in combination with IL-15 and interleukin-21 (IL-21). Preclinical studies showed that adding IL-15 alone and in combination with IL-21 enhanced the expansion and antitumor activity of GPC3-CAR T cells.

As the time came to move these therapies to clinical trials, Heczey and Dr. Pavel Sumazin, a co-author of the Nature paper, found a solution to another challenge. “The technology became available to look at what happens to these cells in patients post-infusion at the single cell resolution, and we were able to implement that in these clinical studies,” said Heczey, associate professor of pediatrics – hematology and oncology at Baylor and director of the Liver Tumor Program at Texas Children’s Cancer Center.

Testing the therapy in clinical trials

In four clinical trials, conducted at Houston Methodist for adult patients and at Texas Children’s for pediatric patients, researchers studied GPC3-CAR T cells alone or GPC3-CAR T cells co-expressing IL-15. In the first cohort of adults with hepatocellular carcinoma (NCT02905188) and children with GPC3 expressing solid tumors (NCT02932956), treatment with GPC3-CAR T cells alone was found to be safe, with CAR T cell expansion peaking at two weeks post-infusion; however, no objective antitumor responses were observed. In the second cohort of adults (NCT05103631) and children (NCT04377932), treatment with GPC3-CAR T cells armed with IL-15 led to significantly increased CAR T cell expansion. 33% (4/12) of patients demonstrated an objective-antitumor response and 66% (8/12) experienced disease control for a minimum of four weeks.

Patients receiving the GPC3-CAR T cells armed with IL-15 had a higher incidence of cytokine release syndrome. Those symptoms were quickly resolved with standard management with modulation of IL1 and IL6 and in resistant cases with the activation of the inducible caspase 9 (IC9) safety switch. This genetic switch, previously studied and optimized in Dr. Cliona Rooney’s lab at the Center for Cell and Gene Therapy, has been shown to control CAR T cell expansion.

“Uncontrolled CAR T activation is toxic to the patient, but we don’t want to treat it by wiping out all the modified T cells,” said Dr. Malcolm Brenner, a senior author on the Nature study, founding director of the Center for Cell and Gene Therapy and Fayez Sarofim Chair at Baylor. “In a previous study, we showed that the IC9 safety switch can eliminate 90% of the modified T cells within 30 minutes, reversing toxic side effects. In this study, we demonstrate that iC9 can control GPC3-CAR T cells while maintaining substantial benefit of the therapy.”

Studying CAR T cell evolution post-infusion

A key part of this study was examining how CAR T cells evolved in the patient post-infusion. To do this, researchers examined peripheral blood and tumor-infiltrating CAR T cells at multiple time points.

This is perhaps one of the only studies to track changes in both the CAR T cells and the tumor before and after treatment.

These findings helped us understand the key players and the differences in the physical process between patients who respond to treatment and those who do not,” said Sumazin, associate professor of pediatrics – hematology and oncology at Baylor and director of the Bioinformatics Core Laboratory at Texas Children’s Cancer Center.

Researchers found certain gene signatures in patients who responded to therapy associated with antitumor activity. Tumor-infiltrating CAR T cells from responders showed repression of SWI/SNF epigenetic regulators and upregulation of FOS and JUN family members, as well as of genes related to Type I interferon signaling.

“In my lab, we are now trying to recapitulate these CAR T cell programs in preclinical studies to determine if these gene signatures are causal for enhanced antitumor activity,” Heczey said. “If they actually cause antitumor activity in the preclinical setting, we want to move these redesigned CAR T cell programs back into the clinical setting to see if we can create sustained responses in patients.”

Next, the team is studying the efficacy of GPC3-CAR T cells armed with both IL-15 and IL-21 in patients. Clinical trials for pediatric patients (NCT04715191) and adults (NCT06198296) with GPC3-positive solid tumors are actively recruiting.

“Our goal is to understand how we can optimize these therapies so that we can treat patients with more effective, less toxic cellular immunotherapies,” said first author Dr. David Steffin, assistant professor of pediatrics – hematology and oncology at Baylor and associate chief of the Cell Therapy and Bone Marrow Transplant Program at Texas Children’s Cancer Center. “These studies are highly complex, and the findings published in this paper are the result of a dedicated team effort from everyone in our labs.”

Other authors that contributed to this work include Nisha Ghatwai, Antonino Montalbano, Purva Rathi, Amy N. Courtney, Azlann B. Arnett, Julien Fleurence, Ramy Sweidan, Tao Wang, Huimin Zhang, Prakash Masand, John M. Maris, Daniel Martinez, Jennifer Pogoriler, Navin Varadarajan, Sachin G. Thakkar, Deborah Lyon, Natalia Lapteva, Mei Zhuyong, Kalyani Patel, Dolores Lopez-Terrada, Carlos A. Ramos, Premal Lulla, Tannaz Armaghany, Bambi J. Grilley, Stephen Gottschalk, Gianpietro Dotti, Leonid S. Metelitsa and Helen E. Heslop.

The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Texas Children’s Cancer Center, Dan L Duncan Comprehensive Cancer Center, Center for Cell and Gene Therapy, Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, University of Houston, St. Jude Children’s Research Hospital and Lineberger Comprehensive Cancer Center, University of North Carolina.

See the publication for a full list of funding for this work.

By Molly Chiu

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