Safety and Efficacy of CD30-Directed Chimeric Antigen Receptor T Cell Therapy Plus Camrelizumab in Patients with Relapsed/Refractory CD30+ Lymphoma

Introduction: CD30-directed chimeric antigen receptor (CAR)-T cell therapy offers a potent candidate therapy for relapsed/refractory (r/r) CD30+ lymphomas. However, although well tolerated, the anti-tumor activity of CD30 CAR-T cells needed to be improved. PD-1/PD-L1 blockade may enhance the function and anti-tumor activity of CAR-T cells. Herein, we conducted a prospective study (ChiCTR2100046763) of CD30-targeted CAR-T cell combined with camrelizumab, an anti-PD-1 monoclonal antibody, in patients with r/r CD30+ lymphomas.

Methods: All patients received lymphodepletion with cyclophosphamide and fludarabine followed by CD30 CAR-T cell infusion (1×10⁷/kg). Camrelizumab was administrated at 2-week intervals from day 15 after patients received infusion of CD30 CAR-T cells until toxicity or disease progression. Adverse events (AEs) were collected from the first day of preconditioning chemotherapy to 1 year after CAR-T cell infusion. AEs were graded by CTCAE 5.0, except for cytokine release syndrome (CRS), which was graded according to Lee’s grading system. Response was reported according to 2014 Lugano criteria.

Results: Between Jan 1, 2022, and Dec 30, 2023, 17 patients were screened for eligibility in this study. A total of 11 patients (64.7%) finished the CD30 CAR-T cell infusion and were included in the analysis, including 7 patients with classical Hodgkin lymphoma (cHL) and 4 patients with T-cell lymphoma (peripheral T cell lymphoma, non-specific type and anaplastic large cell lymphoma (ALCL) in 2 cases respectively). The median age of the patients was 30 years (range 14-67). The median number of prior lines of therapy was 3 (range 2-5). Resistance to anti-PD-1 antibody was reported in 5 patients with cHL, before enrolled in this study. No patients were lost to long-term follow-up.

Six (85.7%) patients in the disease cohort of cHL were evaluated for efficacy. One patient died of septic shock and severe CRS within the first month were excluded from response evaluation but were included in the toxicity and survival assessments. With a median follow-up was 23.4 months (range, 16-32), the median duration of camrelizumab treatment was 19.2 months (range, 9-31). Overall response was achieved in all evaluable patients (6/6, 100%), including 2 (33.3%) with a complete remission (CR) and 4 (66.7%) with a partial response (PR). The median time to best response was 3 months (range, 1-3 months). Five patients (83.3%) who were previously resistant to the PD-1 blockade, 4 achieved PR and the other showed CR. Of all the 6 patients who initially had a response, 4 patients (2 with CR and 2 with PR) continued to respond until the end of follow-up. The median persistence of response was 19.2 months. The median PFS was not reached (95% CI not estimable to not estimable) and the estimated 2-year PFS was 60.0%. The estimated 2-year overall survival (OS) was 100% and the median OS for all cHL patients has not been reached. Expansion and/or persistence of circulating CAR-T cells peaked at days 14-21 and became undetectable beyond 2 months. Significant expansion of CD30 CAR-T cell was not observed after camrelizumab treatment.

For patients with T-cell lymphoma, results were more disappointing, with no patient achieving objective response out of 4 patients, including 2 ALCL patients with high CD30 expression. This cohort was halted early due to low efficacy. Secondary outcomes included median OS of 7.3 months (95% CI: 4.4-10.2 ).

The combination of CD30 CAR-T cells and camrelizumab appeared to be well tolerated in this small cohort, with no treatment related deaths, dose-limiting toxicities and toxicity-related discontinuations were observed. The most common AEs reported were CRS and hematological toxicity. Seven patients experienced CRS (63.5%) and most were mild to moderate (85.7%). Regardless of causality, fatal AEs within the first month occurred in one patient, who died of CRS (grade 4) and pneumonia, despite receiving tocilizumab, glucocorticoid, and intensive care treatment.

Conclusions: Our results suggest that the combination of CD30 CAR-T cells and camrelizumab elicit a safe and durable response in r/r cHL, even in anti-PD-1 refractory patients. For patients with T-cell lymphoma, this regimen is safe but, given the lack of durable efficacy, indicates a need to consider alternative strategies.