Combined autologous CD30.CAR‐T cells and nivolumab in patients with relapsed or refractory classical Hodgkin Lymphoma after failure of frontline therapy (ACTION study)

Introduction: Autologous CD30.CAR-T therapy has demonstrated promising antitumor activity with favorable safety profile in relapsed or refractory (r/r) classical Hodgkin Lymphoma (cHL) patients. Hodgkin Reed-Sternberg cells, the target of CD30.CAR-T, frequently overexpress PD-L1/PD-L2. Checkpoint inhibitors (CPI) of PD-1, including nivolumab (nivo), have shown effective and safe in r/r cHL. Pre-clinical studies suggest that combination of CPI and CAR-T therapy could enhance the survival of CAR-T cells and promote tumor cell death. Methods: A single-arm, phase 1b, multicenter study (NCT# 05352828) is being conducted to evaluate safety and antitumor activity of combined CD30.CAR-T and nivo in r/r cHL patients after frontline therapy failure, with 15 patients to be enrolled. Patients are treated with 2 cycles of nivo, followed by a single infusion of CD30.CAR-T preceded by lymphodepletion (LD) chemotherapy. An additional 2 cycles of nivo are then given, followed by response assessment by PET/CT per Lugano 2014 criteria. Patients without progressive disease may undergo either autologous stem cell transplant or continue nivo up to 6 additional cycles per physician and patient preference. Results: A total of 15 patients were enrolled (Table 1). To date, all patients were treated with at least 2 cycles of nivo, and 10 patients treated with CD30.CAR-T (median dose: 2.4 [range: 2.0–2.7] ×108 cells/m2). Combined therapy was well tolerated. 86.7% (13/15) patients experienced at least one AE with 46.7% patients having grade ≥3 AEs which were hematologic toxicities mainly due to LD chemotherapy. Two patients had cytokine release syndrome (Grade 1), which resolved without use of steroid or tocilizumab. No neurotoxicity was observed. Among 5 patients treated with CD30.CAR-T and 4 cycles of nivo, there were 4 complete response (CR) and one stable disease (SD). ctDNA-MRD was assessed with PhasED-Seq (Foresight Diagnostics) in 3 patients where samples were available to date, all with radiographic CR. All 3 patients (100%) had undetectable ctDNA-MRD at this timepoint, demonstrating deep molecular response. Conclusion: Preliminary data demonstrated favorable safety profile and promising anti-tumor responses of CD30.CAR-T combined with nivo in r/r cHL patients after failure of frontline therapy. Evaluation of 15 patients enrolled is ongoing, and the clinical and ctDNA-MRD data will be presented at the meeting. The research was funded by: Tessa Therapeutics Keywords: Cellular therapies, Hodgkin lymphoma Conflicts of interests pertinent to the abstract. S. Ahmed Consultant or advisory role: Chimagen, Tessa Therapeutics, Myeloid Therapeutics, ADC therapeutics, KITE/Gilead Research funding: Seattle Genetics, Merck, Xencor, Chimagen, Tessa Therapeutic M. Mei Honoraria: Novartis Research funding: BMS Other remuneration: Speaker Bureau: Morphosys, SeaGen D. M. Kurtz Consultant or advisory role: Foresight Diagnostics, Genentech, Roche, Adaptive Biotechnologies Stock ownership: Foresight Diagnostics A. Beitinjaneh Consultant or advisory role: Kite/Gilead N. S. Grover Consultant or advisory role: Novartis, Tessa Therapeutics, ADC Therapeutics, Kite, Caribou Research funding: Genentech C. A. Ramos Consultant or advisory role: Tessa Therapeutics, Athenex Therapeutics, Genentech, Novartis, CRISPR Therapeutics Research funding: Tessa Therapeutics, Athenex Therapeutics Other remuneration: Royalties & Patents: Tessa Therapeutics, J. J. Chabon Employment or leadership position: Foresight Diagnostics Stock ownership: Foresight Diagnostics A. Schultz Employment or leadership position: Foresight Diagnostics C. Ding Employment or leadership position: Tessa Therapeutics A. Myo Employment or leadership position: Tessa Therapeutics A. A. Alizadeh Consultant or advisory role: Foresight Diagnostics, Cibermed, Adaptive Biotechnologies, Gilead, Roche, BMS, Genentech, Karyopharm Stock ownership: Foresight Diagnostics, Cibermed, Gilead, Syncopation Research funding: BMS I. D. Horak Employment or leadership position: Tessa Therapeutics H. E. Heslop Consultant or advisory role: Ankarys, Fresh Wind Biotechnologies, Gilead Biosciences, GlaxoSmithKline, Millenium, Novartis, Tessa Therapeutics Stock ownership: Allovir, Marker Therapeutics, Coregen, Fresh Wind Biotechnologies Research funding: Kuur Therapeutics, Tessa Therapeutics