For Advanced Sarcoma, Adding Lymphodepletion to HER2-Targeted CAR T-Cell Therapy Excites


A phase I trial evaluated the safety and efficacy of adding lymphodepletion to HER2-targeted T-cell therapy in patients with advanced HER2-positive sarcoma.

The addition of lymphodepletion to autologous human epidermal growth factor receptor 2 (HER2)-targeted chimeric antigen rector (CAR) T-cell therapy appeared safe and showed clinical activity in a small group of patients with advanced HER2-positive sarcoma. The results of the open-label phase I clinical trial ( identifier: NCT00902044) were presented at the 2019 American Association for Cancer Research (AACR) Annual Meeting, held March 29–April 3 in Atlanta, Georgia (LB-147).

The trial was designed to evaluate HER2-targeted CAR T-cell therapy in children and adults with refractory/metastatic HER2-positive sarcoma. The trial first conducted a dose-escalation group in which 19 patients received HER2-targeted CAR T-cell therapy alone at various doses. The results from this group were reported in a 2015 article published in the Journal of Clinical Oncology and indicated acceptable safety. Here, the results of the patients who received lymphodepletion before CAR T-cell therapy are reported.

In total, 10 pediatric and adult patients with refractory/metastatic HER2-positive sarcoma received either fludarabine for lymphodepletion (3 patients) or fludarabine and cyclophosphamide for lymphodepletion (8 patients). Following lymphodepletion, patients received a maximum of 3 infusions with CAR T cells. Patients who achieved stable disease or a response were permitted to receive up to 5 additional infusions with CAR T cells without lymphodepletion.

Overall, 5 patients had osteosarcoma, 3 had rhabdomyosarcoma, 1 had Ewing sarcoma, and 1 had synovial sarcoma. Patients had a median age of 14 years (range, 4 to 54 years) and received as many as 5 prior salvage therapies. One patient with rhabdomyosarcoma was re-enrolled and received treatment again.

A total of 4 patients had disease progression, 4 had stable disease, and 2 had complete responses. One complete response occurred in an 8-year-old boy with rhabdomyosarcoma that had metastasized to the bone marrow. The response lasted for 12 months until disease relapse. The patient was then re-enrolled and received CAR T-cell therapy again, which led to a complete response that is ongoing at 17 months. The other complete response occurred in a patient with osteosarcoma that had metastasized to the lungs; the response is ongoing at 32 months.

No dose-limiting toxicity, neurotoxicity, transfusions, or lasting pulmonary or cardiac toxicities were observed. Grade 1 or 2 cytokine release syndrome developed in 8 of 11 patients within 24 hours of CAR T-cell therapy infusion and resolved via supportive care within 5 days.

“Overall, the safety is not going to be an issue, hopefully, but definitely needs to be tested in a bigger cohort of patients,” said Zahra Ghiassi-Nejad, MD, PhD, assistant professor of radiation oncology at the Icahn School of Medicine at Mount Sinai, during an interview with Cancer Network. She was not involved in the study.

Compared with the previously reported results for the HER2-targeted CAR T-cell therapy alone group, Ghiassi-Nejad said that in this study, the researchers “were able to show better expansion of the CAR T cells when they gave that induction lymphopenia,” and “the T cells were actually able to expand in the patient’s body much more effectively.” T-cell expansion occurred in 9 of 11 patients, and CAR T cells were detectable in 10 of 10 patients at 6 weeks after CAR T-cell infusion.

“The previous study had failed to show any complete responses,” Ghiassi-Nejad said. “This [study] is exciting.”

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