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 (ClinicalTrials.gov identifier: NCT00902044) were presented at the 2019 American Association for Cancer Research (AACR) Annual Meeting, held March 29–April 3 in Atlanta, Georgia (
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
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
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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