Updated Results and Correlative Analysis: Autologous CD30.CAR-T-Cell Therapy in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma (CHARIOT Trial)

Abstract

Introduction Early results from the Pilot segment of a Phase 2 trial of autologous CD30.CAR-T in patients with relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL) (NCT#04268706) demonstrated a favorable safety profile and excellent anti-tumor responses of CD30.CAR-T in patients with heavily pretreated r/r cHL (Ahmed et al., 2021). We report here updated clinical data and exploratory biomarker analysis from the Pilot segment. Methods This is a Phase 2 single arm, multi-center study, enrolling patients (12-75 years) with cHL progression after at least 3 lines of therapy, including chemotherapy, brentuximab vedotin, and anti-programmed cell death (PD)-1 antibodies. The pilot segment of this study has fully enrolled with safety as the primary endpoint and overall response rate (ORR) as assessed centrally according to Lugano Classification Revised Response System for malignant lymphoma (Cheson et al., 2014) as a secondary endpoint. The patients were treated with CD30.CAR-T cells, after lymphodepletion chemotherapy using bendamustine and fludarabine, with an allowable dose range of 2.0 to 2.7 × 108 CD30.CAR-T cells per m2. Second CD30.CAR-T infusion is allowed if the patients show progression after initial response to first CD30.CAR-T infusion. Exploratory objectives include assessment of expansion and persistence of autologous CD30.CAR-T, cytokine profiling, immunological parameters, circulating tumor DNA (ctDNA), and other biomarkers in blood and tumor tissue. Results As of 22 July 2022, 17 patients were screened and 15 patients enrolled in the Pilot segment (median age: 35 years [21-57], 66.7% male). The median number of prior therapies was 6 (range: 3-18). All 15 patients were treated with CD30.CAR-T single infusion, and 7 patients received a second CD30.CAR-T infusion. ORR after CD30.CAR-T single infusion was 73.3% (n=11) with complete response (CR) rate of 60% (n=9). ORR in 5 patients with available response assessment after the second infusion was 100%, with CR of 60% (n= 3). CD30.CAR-T treatment was well tolerated with one grade 1 Cytokine Release Syndrome (CRS) and no neurotoxicity. CD30.CAR-T cells in peripheral blood peaked at 7 days after first CAR-T infusion with median Cmax (peak exposure) of 6964.7 copies/µg DNA.There was no correlation observed between response and Cmax, or AUC (area under the curve) 0-42 days, 0-90 days, 0-180 days after the first CD30.CAR-T infusion. Biopsies obtained at the time of screening and relapse were reviewed by an independent pathologist with 100% concordance of CD30 positivity between local and central testing. HAMA (Human Anti-Mouse Antibody) in serum was negative after first and secondCD30.CAR-T infusion in all patients. An increase of the homeostatic cytokines interleukin (IL)-7 and IL-15 was detected after lymphodepletion chemotherapy. Serum CCL17 (Thymus and Activation Regulated Chemokine; TARC), a predictive marker of early response assessment in HL (Guidetti et al., 2017) was elevated before CD30.CAR-T infusion and had a dramatic decrease after treatment in responding patients. Conclusions Overall, CD30.CAR-T therapy was well tolerated with no unexpected safety signal and showed excellent anti-tumor efficacy with an ORR of 73.3% in heavily pretreated r/r cHL patients. The CD30.CAR-T cells showed good expansion and persistence after infusion. The efficacy, safety and exploratory biomarkers of CD30.CAR-T will be further evaluated in the Pivotal segment of this Phase 2 study.