AACR 2019: HER2-Targeted CAR T-Cell Therapy Plus Chemotherapy in Advanced Sarcoma
A small phase I study by Navai et al investigated a combination of lymphodepletion chemotherapy and HER2-specific chimeric antigen receptor (CAR) T-cell therapy for pediatric and adult patients with advanced HER2-positive sarcoma. The combination showed promising antitumor activity and was found to be well tolerated. Additional testing of HER2-specific CAR T cells in larger cohorts of patients is needed to define efficacy and optimal dosage, according to the study researchers. Led by Meenakshi Hegde, MD, of Baylor College of Medicine, Houston, the study was presented at the American Association for Cancer Research (AACR) Annual Meeting (Abstract LB-147).
Soft-tissue and visceral sarcomas represent a rare group of mesenchymal tumors, with more than 70 subtypes. Since treatment for these diverse neoplasms is challenging, prognosis for patients with advanced sarcoma is generally poor. According to Cancer.Net, this year, nearly 13,000 people will be diagnosed with soft-tissue sarcoma, and an estimated 5,270 adults and children are expected to die from the disease.
Study Methodology
Ten patients aged 4 to 54 years with refractory or metastatic HER2-positive sarcoma, 5 with osteosarcoma, 3 with rhabdomyosarcoma, 1 with Ewing sarcoma, and 1 with synovial sarcoma were enrolled in the study. The patients had received up to five prior salvage therapies for their cancer.
The patients were treated with up to three infusions of HER2-targeted CAR T cells after lymphodepletion with either fludarabine or fludarabine and cyclophosphamide. The patients who had responses to this initial treatment received up to five additional infusions of CAR T cells without lymphodepletion.
Study Results
The researchers found that the CAR T cells expanded in all but 2 patients, with a median peak expansion on day 7, and CAR T cells were detected in all patients 6 weeks after infusion. One pediatric patient whose rhabdomyosarcoma had metastasized to the bone marrow had a complete response for 12 months but relapsed and was retreated with CAR T cells, which resulted in a complete response that has been ongoing for 17 months. Additional analysis of the patient’s blood at different time points showed antibody responses against several intracellular proteins involved in the cell cycle, cell growth, cell signaling, and in tumor processes, such as invasion and metastasis.
One pediatric patient with osteosarcoma with metastasis to the lungs has had an ongoing complete response for 32 months. Three patients achieved stable disease, and five had progressive disease.
Overall, the patients experienced limited treatment-related toxicities. They all had expected decreases in their blood counts following chemotherapy, which subsequently improved, and none developed infections secondary to low blood counts. A total of 8 patients developed grade 1–2 cytokine-release syndrome within 24 hours of receiving CAR T cells and had complete resolution within 5 days of onset after receiving supportive care. None of the patients experienced decreased heart function or pulmonary toxicities.
Clinical Significance
Although clinical studies have shown that HER2-targeted antibodies such as trastuzumab are not effective for patients with HER2-positive sarcoma, HER2-specific CAR T cells appear to have antitumor activity in these patients. “Our group has previously shown in the laboratory that HER2-directed CAR T cells are better at targeting low levels of HER2 on tumor cells compared with trastuzumab,” said first author Shoba Navai, MD, Assistant Professor of Pediatrics at the Center for Cell and Gene Therapy at Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital. “So, these CAR T cells may have antitumor activity in patients with sarcoma even when HER2-antibody therapies do not.”
Disclosure: Funding for this study was provided by St. Baldrick’s–Stand Up to Cancer Dream Team Translational Research Grant, Cookies for Kids’ Cancer, and the Cancer Prevention and Research Institute of Texas. The study authors’ full disclosures can be found at abstractsonline.com.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
