Rhabdomyosarcoma (RMS), a rare cancer that forms in soft tissue, specifically skeletal muscle tissue and sometimes in hollow organs including the bladder or uterus, generally occurs in children. Disease prognosis and treatment decisions depend on the type of rhabdomyosarcoma, where it originated, tumor size, and whether the tumor has metastasized. In the majority of cases, treatment involves a combination of surgery, chemotherapy, and radiation therapy.
Decades of advancements in the treatment of rhabdomyosarcoma have significantly improved patient outcomes, and ongoing research is designed to further enhance treatment options. After treatment patients need lifelong monitoring for the potential of late effects of intense chemotherapy and radiation. In the refractory stage of metastatic rhabdomyosarcoma remains largely incurable. As a result, there is a major unmet medical need for patients diagnosed with the disease.
In a clinical trial with a novel form of immunotherapy consisting of chimeric antigen receptor (CAR) T cells that were engineered to target the HER2 protein on the surface of the cancer cells, a child diagnosed with rhabdomyosarcoma that had spread to the bone marrow, showed no detectable cancer after treatment.
As part of the study, a pediatric patient with refractory bone marrow metastatic rhabdomyosarcoma received three cycles of autologous HER2 CAR T-cells therapy after lymphodepleting chemotherapy-induced remission which was consolidated with four more CAR T-cell infusions without lymphodepletion. Following disease relapses in the bone marrow at six months off-therapy, a second remission was achieved after one cycle of lymphodepletion and HER2 CAR T-cells. Response consolidation with additional CAR T-cell infusions includes pembrolizumab (Keytruda®; Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.) to improve treatment efficacy.
The clinical trial, supported by Stand Up To Cancer© (SU2C) – St. Baldrick’s Pediatric Cancer Dream Team Translational Research Grant, Alex’s Lemonade Stand Pediatric Cancer Foundation, Cancer Prevention Research Institute of Texas, and others and conducted by researchers at Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, also provides new insights into how this exceptional recovery occurred.
The initial study results were published in the July 15 editions of Nature Communications.
A High-Risk Patient
“This child’s cancer was considered high risk because it had not responded to standard chemotherapy. As a result, this child was a candidate to receive a promising new CAR T-cell therapy, a personalized form of immunotherapy that redirects the patient’s own immune T-cells to recognize and fight the tumor,” explained Meenakshi G. Hegde, M.D., assistant professor of pediatric hematology-oncology at Baylor College of Medicine and Texas Children’s and the first and corresponding author of the study.
About 75% of the tumor cells in this patient displayed a protein on their surface called human epidermal growth factor receptor 2 or HER2.
In the trial, the investigators reprogrammed the T-cells to target the HER2 protein by genetically engineering them to express CAR molecules that recognize the HER2-expressing (HER2+) cancer cells.
In a previous clinical trial, the HEROS study, the researchers found that CAR T-cells directed at HER2+ tumor cells had a favorable safety profile. This early generation CAR T-cell treatment resulted in clinical benefit in a small subset of patients, but it did not eradicate their tumors.
“From the HEROS trial, we learned that HER2-CAR T-cells expanded but did not persist in the patients, which could in part explain the lack of anti-tumor responses,” said Hegde, who also works at Baylor’s Dan L Duncan Comprehensive Cancer Center.
To overcome this limitation, in the HEROS 2.0 trial Hedged and her colleagues added successive HER2-CAR T cell infusions along with low-dose chemotherapy to eliminate normal T cells as a strategy to improve the expansion and persistence of the infused HER2-CAR T. The T cell-depleting chemotherapy administered before transferring HER2-CAR T cells eliminated the patient’s existing immune cells, creating a space for the engineered CAR T cells to expand in the patient.
“Although the child had a lasting response to HER2-CAR T cells with no tumor detected, cancer returned six months after we stopped the T-cell infusions. Fortunately, the child achieved a second remission after retreatment with HER2-CAR T cells,” Hegde explained.
“Considering the several challenges in successfully treating solid tumors using CAR T-cells, achieving this exceptional tumor response is very encouraging,” she added.
At the time of this report, this pediatric patient is 20 months off T-cell treatment and remains healthy and cancer-free.
Exceptional recovery occurred
The sustained tumor response in this patient has provided the researchers with important insights into how rhabdomyosarcoma was eliminated. The CAR T-cells were engineered to recognize and attack HER2+ cancer cells. Although not all cancer cells expressed HER2 on the cell surface, the tumor was eliminated in its entirety. This prompted the question of how the HER2-negative cancer cells were eradicated.
“It is fascinating to see the remodeling of the patient’s T-cell compartment and the development of antibodies directed against proteins implicated in tumor survival and metastasis during the course of treatment in this child,” said Sujith K. Joseph, Ph.D., senior scientist at Baylor’s Center for Cell and Gene Therapy, who conducted an in-depth evaluation of the patient’s immune response.
“The immune activation mechanisms and associated tumor targets that unfolded during the acquired response could inform novel approaches to fight difficult-to-treat cancers,” Joseph further noted.
“This study shows that CAR T-cells could perhaps act as vaccines by exposing cancer proteins to the patient’s immune system. With more understanding and further refinement of their design, CAR T-cells could be effective against some incurable malignancies,” observed senior author Nabil M Ahmed, M.D., associate professor of pediatrics and immunology at Baylor and Texas Children’s Hospital.
Her2 Chimeric Antigen Receptor Expressing T Cells in Advanced Sarcoma – NCT00902044
 Hegde, M., Joseph, S.K., Pashankar, F. et al. Tumor response and endogenous immune reactivity after administration of HER2 CAR T cells in a child with metastatic rhabdomyosarcoma. Nat Commun 11, 3549 (2020). https://doi.org/10.1038/s41467-020-17175-8
Featured image: Group photo of the authors. Photo courtesy: © 2020 Paul Kuntz, TCH. Used with permission.