17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Abstract

Introduction: Relapsed/refractory (r/r) peripheral T cell lymphomas (PTCL) are highly aggressive tumors associated with very poor prognosis. We recently described a new targeting strategy based on the mutually exclusive expression of T cell receptor beta-chain constant domains 1 and 2 (TRBC1 and TRBC2) (Maciocia, PM. et al. Nat Med, 2017) which can spare a proportion of the normal T cell compartment. Here we describe first in human clinical findings of AUTO4, a TRBC1 directed autologous CAR T cell therapy for patients with TRBC1-positive PTCL. Methods: NCT03590574 is an ongoing, multi-centre, single-arm phase 1/2 study of AUTO4 in r/r TRBC1-positive PTCL. Here we report the findings of the dose escalation. Four dose levels were explored: 25 × 106, 75 × 106, 225 × 106, and 450 × 106 CAR T cells were administered as a single dose. CAR T-cell products were generated using a semi-automated closed process. The initial AUTO4 manufacturing process A was optimized and is now being used in process B to define the recommended phase 2 dose. Primary endpoints in phase 1 are incidence of ≥Grade 3 toxicity occurring within 60 days of AUTO4 infusion and the frequency of dose limiting toxicities (DLT) within 28 days of AUTO4 infusion. Overall response (CR + PR) rate by Lugano PET-CT criteria is a secondary endpoint. Results: As of 8 February 2023, 12 patients (10 process A, 2 process B) have been treated with AUTO4. The median age was 57 years (range 34–72) with a median prior lines of 2 (range 1–5). 7 patients were diagnosed with PTCL-NOS, 4 with AITL (Angioimmunoblastic T-cell lymphoma) and 1 with ALCL (Anaplastic large cell lymphoma). Chemotherapy bridging was given to 70% of patients and 4/8 CD30+ patients recieved brentuximab as bridging or as prior line therapy. 3/12 patients had prior autoSCT. The most common treatment adverse events were transient Grade1–4 neutropenia, thrombocytopenia. Lymphopenia was observed with CD3+ lymphocytes recovering to baseline levels after pre-conditioning. No ≥Grade 3 infections were observed. Any grade CRS was observed in 6/12 patients (5 at 450 × 106, 1 at 250 × 106) and one patient developed Grade 3 CRS which resolved within 3 days. No ICANS or DLTs were observed. Response at month 1 was evaluable in 9/10 patients using process A. Five patients were in complete metabolic response (CMR) (1/5 was in CMR at the time of lymphodepletion), 1 patient achieved a partial response (PR) and 3 patients had no response. At the 450x106 dose level, 3/4 patients achieved CMR at month 1, and 2 of them are in ongoing remission at 12 and 15 months, respectively. The efficacy non-evaluable patient at month 1, due to COVID19 infection, showed no response at month 3 but achieved a delayed PR by month 9 without any further treatment. Conclusions: AUTO4 was well tolerated with no DLT. Ongoing CMR at months 12 and 15 are encouraging. Updated data and longer follow up using the improved manufacturing process B will be presented. The research was funded by: Autolus Ltd Keywords: aggressive T-cell non-Hodgkin lymphoma, cellular therapies, ongoing trials Conflicts of interests pertinent to the abstract J. Shang Employment or leadership position: Autolus Therapeutics E. Xue Employment or leadership position: Autolus Therapeutics M. Zhang Employment or leadership position: Autolus Therapeutics S. Basilico Employment or leadership position: Autolus Therapeutics M. Raymond Employment or leadership position: Autolus Therapeutics P. Lao-Sirieix Employment or leadership position: Autolus Therapeutics K. Lilova Employment or leadership position: Autolus Therapeutics W. Brugger Employment or leadership position: Autolus Therapeutics M. Pule Employment or leadership position: Autolus Therapeutics