Long term follow up autologous CD30.CAR-T cells in combination with nivolumab in patients with relapsed or refractory classical Hodgkin lymphoma after failure of frontline therapy Free

Sairah Ahmed1*, Matthew Mei2*

*co-first authors

Introduction

Classical Hodgkin lymphoma (cHL) is characterized by the presence of malignant Hodgkin Reed-Sternberg (HRS) cells, which harbor amplifications in chromosome 9p24.1, leading to overexpression of programmed death-ligand 1 (PD-L1). Autologous CD30-directed chimeric antigen receptor T-cell (CD30.CAR-T) therapy has demonstrated favorable safety profile and promising antitumor activity in relapsed or refractory (r/r) cHL patients (Ramos et al., 2020; Ahmed et al., 2022). Preclinical studies demonstrated potential synergism between PD-1 checkpoint inhibitors and CAR-T cell therapy. While the standard for relapsed cHL after frontline therapy is salvage chemotherapy followed by autologous stem cell transplant (ASCT), this approach is associated with short-term toxicity, long-term morbidity and non-lymphoma-related mortality.

Tessa Therapeutics (company dissolved in 2023) sponsored the ACTION trial to evaluate safety and antitumor activity of CD30.CAR-T cells combined with nivolumab (nivo) in pts with r/r cHL after standard frontline chemotherapy. Herein, we report long term outcomes of pts treated on this trial.

Methods

The ACTION trial was a single-arm, phase 1b, multicenter study (NCT# 05352828) evaluating combination of CD30.CAR-T and nivo in r/r cHL pts after frontline therapy failure. Eligibility included cHL that was either primary refractory to frontline therapy or relapsed after initial response, inclusive of receipt of novel agents including prior PD-1 inhibitor therapy. Trial design was treatment with 4 cycles of nivo, followed by a single infusion of CD30.CAR-T preceded by lymphodepletion with bendamustine and fludarabine. Response assessment per Lugano 2014 criteria was done at ~day 28-30 post infusion. Pts without progressive disease underwent either ASCT or continued nivo up to 6 additional cycles per physician and pt preference. Pt variables were retrospectively collected by treating centers under umbrella of a multi-institutional retrospective study. Overall survival (OS) and progression-free survival (PFS) were estimated using the KM method, and median follow-up time was calculated using the reverse KM method. 

Results

Eighteen pts with r/r cHL were screened, 15 were enrolled and 14 pts were infused with CD30.CAR-T. Of the 15, 1 pt had a manufacturing failure of the cell product. Herein, we report outcomes of 13 pts who were treated with at least 2 cycles of nivo and CD30.CAR-T for whom data was available from participating centers.

Median CD30.CAR-T dose was 2.4 (range: 2.0-2.7) ×108 cells/m2and median age at time of CAR-T was 35 years (range: 29-76), 54% of pts were female, and 77% were Caucasian. Four pts (31%) had primary refractory disease and median time from relapse to CD30.CAR-T was 3.9 months (range 2.7-6.4). ECOG performance status was 0/1 for all pts and 23% (3) pts received a consolidative ASCT, while 77% (10) received 6 cycles of nivo as maintenance.

This combined therapy was well tolerated without immunotoxicity associated with nivo. Grade 1 CRS was observed in 1 pt (8%), resolving without use of steroid or tocilizumab. No neurotoxicity was observed. One pt (8%) reported infection after CD30.CART and 1 pt reported a second primary malignancy.

ORR was 92% (n=12); complete response (CR) as best response was 77% (n=10), partial response 15% (n=2) and stable disease 8% (n=1). With median follow-up of 24.3 months (95%CI:17.8 – NA, months), none of the 3 pts who received consolidative ASCT has relapsed. Of the 10 who received maintenance nivo, 4 progressed or relapsed (with 1 pt dying from disease), while 6 continue to have an ongoing response beyond 18 months. Median PFS was not reached [95%CI: 18.2 – NA, months] and PFS at 24 months was 67% (95%CI: 45 -100). Median OS was not reached, and OS at 24 months was 90%.

Conclusion

This study demonstrates the efficacy of CD30.CAR-T combined with nivolumab as a potential ASCT sparing modality in r/r cHL pts after failure of frontline therapy. No new significant safety signal was seen, and the combination therapy showed low incidence of low grade CRS. Further larger studies are needed for confirmation; however, for a carefully selected pt population, CD30.CAR-T with nivo shows a favorable duration of response. Correlative data will be available at time of presentation.