Autologous CD30.CAR-T-cell therapy in patients with relapsed or refractory classical Hodgkin lymphoma – long term update of the chariot trial

Abstract Introduction Autologous CD30-directed chimeric antigen receptor T-cell (CD30.CAR-T) therapy has demonstrated favorable safety and promising antitumor activity in relapsed or refractory (r/r) classical Hodgkin lymphoma (cHL) patients (pts) (Ramos et al., 2020; Ahmed et al., 2022). The phase 2 CHARIOTclinical trial, sponsored by Tessa Therapeutics (company dissolved in 2023), of autologous CD30.CAR-T in pts with r/r cHL (NCT#04268706) continued to show a manageable safety profile and encouraging anti-tumor responses of CD30.CAR-T therapy in pts with heavily pretreated r/r cHL (Ahmed et al., 2021). Herein, we report the long term outcomes of pts treated on this trial. Methods The phase 2 trial was a single arm, multi-center study, enrolling pts (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. Pts were treated with CD30.CAR-T cells, after bendamustine and fludarabine lymphodepletion. The median CD30.CAR-T dose was 2.4 (range: 2.0-2.7) × 108 cells/m2. Pt variables were retrospectively collected by treating centers. Overall survival (OS) and progression-free survival (PFS) were estimated using the KM method, Fischer's exact test or Wilcoxon rank-sum test were used for univariate associations of categorical and continuous variables, and median follow-up time was calculated using the reverse KM method. Results Between 2021-2022, 17 pts were screened, 15 pts were enrolled on trial and underwent apheresis and 14 pts had a cell product infused. Among pts treated on trial; information for 12 pts were available for analysis, the following data details the outcomes for the 12 pts with obtainable data. A CD30.CAR-T product was successfully manufactured for all patients with a median manufacturing time of 6.3 weeks (range: 5.9-8.0) The median age at the time of CAR-T was 35 years (range: 28-39), 75% of pts were male, and 50% were Caucasian. Eight pts (66%) had stage III/IV disease at the time of CAR-T and 66% (n=8) had primary refractory disease to frontline therapy as well as refractory disease to last line of therapy. Median time from first relapse to CD30.CAR-T was 60 months (range: 39 - 93). Sixty seven percent (n=8) of pts had received a prior autologous stem cell transplant. ECOG performance status was 0/1 for 92% (n=11) of pts. The median number of prior therapies was 6 (range: 3-17). Thirty-three percent (n=4) of pts received bridging therapy prior to CAR-T. ORR after CD30.CAR-T single infusion was 75% (n=9) with complete response (CR) rate of 50% (n=6). CD30.CAR-T treatment was well toleratedwith only one pt experiencing grade 1 CRS which resolved with 1 dose of tocilizumab. There was no reported neurotoxicity. One patient had a respiratory viral infection in the 6 months after CAR-T infusion and there were no prolonged cytopenias beyond 3 months after CAR-T infusion. With a median follow-up time of 45 months, of the 12 pts, 9 had relapse/progression while 1 pt died without progression. The median progression-free survival time was 7.1 months (95%CI: 4.0 – NA, months). The 36 month PFS was 17% (95% CI 4.7- 59.1). The median OS was not reached with the 36 month OS rate of 91% (95% CI 75.4 - 100.0). The estimated median duration of response was 8.8 months for all pts. Four pts received consolidative allogeneic stem cell transplant and of those 1 pt has had a continued response without relapse. One pt has maintained their response after CD30.CAR-T infusion without further therapy. Conclusions CD30.CAR-T was well tolerated in this small cohort, with no treatment related deaths, dose-limiting toxicities, high grade CRS or neurotoxicity. It demonstrated a high ORR of 75% in a heavily pretreated cohort, though the durability of response is disappointing. Potential strategies to improve long term responses could include increasing cell doses, alternative lymphodepletion regimens, further engineering of the product or the addition of novel therapeutic agents to enhance CD30.CAR-T effectiveness in r/r cHL. Further data on CAR-T kinetics will be available at presentation.