Novel immunotherapy shows promise for high-risk sarcomas: results of the HEROS 2.0 study published

Novel immunotherapy shows promise for high-risk sarcomas: results of the HEROS 2.0 study published

Researchers from the Texas Children's Cancer Center and the Center for Cell and Gene Therapy at Baylor College of Medicine, Texas Children's Hospital and Houston Methodist published results from a Phase I clinical trial of a novel immunotherapy for high-risk sarcomas in the journal Nature Cancer.

The therapy uses chimeric antigen receptor (CAR) T cells that specifically target the HER2 protein, which is overexpressed on the surface of sarcoma cells. The HEROS 2.0 study demonstrated that this therapeutic approach is safe and associated with clinical benefit.

CAR-T cell therapy has been a highly successful strategy for recurrent or high-risk leukemias or lymphomas, but the application of this therapy to solid tumors continues to present challenges. The results of this study show that we are taking a step further in harnessing the power of CAR-T cells as an effective cancer therapy for sarcomas.”

Dr. Meenakshi Hegde, first and corresponding author, associate professor of pediatrics - hematology and oncology at Baylor and pediatric oncologist at Texas Children's Cancer Center

In a previous clinical trial, the HEROS trial, researchers found that CAR-T cells targeting HER2+ tumor cells had a favorable safety profile, but clinical benefit was limited by poor CAR-T expansion and persistence. In HEROS 2.0, researchers gradually added HER2-CAR-T cell infusions after lymphodepletion, in which the patient's own T cells are depleted by chemotherapy to make room for the expansion of the infused therapeutic HER2-CAR-T cells.

“We also increased the number of allowed HER2-CAR-T infusions to maintain the exposure time of the CAR-T cells, with the aim of increasing the anti-tumor effect,” said Hegde. “This study showed that CAR-T expansion and persistence were improved by lymphodepletion and repeated cycles of treatment.”

Thirteen patients were enrolled in the HEROS 2.0 trial at Texas Children's Cancer Center and Houston Methodist Hospital, and seven patients received multiple CAR-T infusions. HER2-CAR-T expansion occurred after 19 of 21 total infusions and clinical benefit was observed in 50% of treated patients. An extraordinary reaction in a patient with metastatic rhabdomyosarcoma was detailed in a 2020 publication in Nature Communications. The patient remains healthy and cancer-free for more than five years after treatment.

Nine patients in the first two cohorts developed low-grade cytokine release syndrome (CRS), an acute inflammatory reaction considered a side effect of CAR-T treatment. Two patients in the third cohort experienced dose-limiting CRS, requiring discontinuation of dose escalation.

“We are now studying the tumors and how we manipulate the CAR-T cells to better enable the safe delivery of higher doses, thereby increasing anti-tumor activity by increasing the level of CAR-T cell expansion and persistence,” Hegde said.

“HEROS 2.0, the second edition of the HEROS trials, exemplifies how laboratory-bedside interaction leads to refinement of first-in-child studies and more durable clinical benefit,” said lead author Dr. Nabil Ahmed, professor of pediatrics – hematology and oncology at Baylor and pediatric oncologist at Texas Children’s Cancer Center.

Researchers are currently recruiting for the HEROS 3.0 trial, which will evaluate the safety of administering HER2 CAR T cells in combination with chemotherapy and an immune checkpoint inhibitor drug. Further information about the process can be found here.

Hegde and Ahmed are both members of the Dan L Duncan Comprehensive Cancer Center at Baylor. Additional study authors include Shoba Navai, Christopher DeRenzo, Sujith K. Joseph, Khaled Sanber, Mengfen Wu, Ahmed Z. Gad, Katherine A. Janeway, Matthew Campbell, Dolores Mullikin, Zeid Nawas, Catherine Robertson, Pretty R. Mathew, Huimin Zhang, Birju Mehta, Raksha R. Bhat, Angela Major, Ankita Shree, Claudia Gerken, Mamta Kalra, Rikhia Chakraborty, Sachin G. Thakar, Olga Dakhova, Vita S. Salsman, Bambi Grilley, Natalia Lapteva, Adrian Gee, Gianpietro Dotti, Riyue Bao, Ahmed Hamed Salem, Tao Wang, Malcolm K. Brenner, Helen E. Heslop, Winfried S. Wels, M. John Hicks and Stephen Gottschalk. They are affiliated with one or more of the following institutions: Baylor College of Medicine, Texas Children's Cancer and Hematology Center, Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Dana Farber Cancer Institute, University of North Carolina Chapel Hill, University of Pittsburgh, UPMC Hillman Cancer Center, Ain Shams University, Georg Speyer Haus Institute for Tumor Biology and Experimental Therapy, German Cancer Consortium, Frankfurt Cancer Institute and St. Jude Children's Research Hospital.

This work was supported in part by Stand Up To Cancer (SU2C) – St. Baldrick's Pediatric Cancer Dream Team Translational Research Grant (SU2C-AACR-DT1113), the V Foundation for Cancer Research, the Triumph Over Kids Cancer Foundation (TOKC), and Cookies for Kids' CancerTM Foundation, Alex's Lemonade Stand Pediatric Cancer Foundation, the Faris Foundation, the National Cancer Institute, and the Cancer Prevention and Research Institute of Texas. A full list of funding sources can be found in the publication.

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