Autologous HER2-specific CAR T-cells after lymphodepletion for advanced sarcoma

Purpose To determine the maximum tolerated dose (MTD) of autologous chimeric antigen receptor T cells (HER2-CART) after lymphodepletion and to describe the cellular kinetics, safety, feasibility of repeat treatment cycles, and antitumor activity of HER2-CART in patients with advanced sarcoma. Patients and Methods On this phase I study, 13 patients with progressive, metastatic HER2+ sarcoma were treated in 14 enrollments; one patient who achieved complete remission was re-enrolled because of disease recurrence. Lymphodepletion consisted of fludarabine (Flu) 25 mg/m2/dose x 5 days with or without cyclophosphamide (Cy) 30 mg/kg/dose x 2 days. The dose cohorts evaluated include 1x108 total T-cells/m2 after Flu (cohort A); 1x108 total T-cells/m2 after Flu/Cy (cohort B) and 1x108 CAR-positive T-cells/m2 after Flu/Cy (cohort C). The evaluation of safety was the primary endpoint. Secondary outcomes included assessment of cellular kinetics and antitumor activity. Results All study participants received at least one infusion of HER2-CART after lymphodepletion and were included in the analysis (median age 14 years; range 4-55 years). Seven received multiple HER2-CART infusions. CART expansion was observed after all but two of 21 total infusions given after lymphodepletion. Nine of 12 (75%) patients in cohorts A and B developed grade 1-2 CRS. Two patients in cohort C experienced dose limiting toxicity (DLT) with grade 3-4 CRS. All patients recovered from treatment-related adverse events during study follow-up. Median OS was 8.2 months (95% CI, 4.4-17 months). Antitumor activity was observed at the MTD (cohort B), with 1-year OS and PFS of 62.5% (95% CI, 22.9%-86.1%) and 33.3% (95% CI, 7.8-62.3%), respectively. Three patients remain alive, with one in long-term remission at the sixth year of follow-up. While infused CART products did not exhibit a distinct immunophenotype by sarcoma histology, we observed different trends in expression of immune checkpoints when compared by disease and by treatment response. Conclusion and Relevance: Autologous HER2-CART can be infused safely after lymphodepletion in patients with progressive sarcoma, and the preliminary evidence of antitumor activity observed supports testing their efficacy in a phase II trial. Trial Registration: ClinicalTrials.gov identifier: NCT00902044