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Published on: February 17, 2022
TRBC1-CAR T cell therapy in peripheral T cell lymphoma: a phase 1/2 trial
Kate Cwynarski1,2, Gloria Iacoboni3, Eleni Tholouli4
1Department of Haematology, University College London, London, UK.
Abstract:
Relapsed/refractory peripheral T cell lymphomas (PTCLs) are aggressive tumors with a poor prognosis. Unlike B cell lymphomas, treatment of PTCL has not benefited from advances in immunotherapy. This is largely due to a lack of suitable target antigens that discriminate malignant from normal T cells, thus avoiding severe immunosuppression consequent to depletion of the entire T cell compartment. We recently described a targeting strategy based on the mutually exclusive expression of T cell antigen receptor beta-chain constant domain (TRBC) 1 and 2. Selective targeting of the T cell antigen receptor beta-chain expressed by the (clonal) malignancy spares normal T cells expressing the other chain. The LibraT1 study is an ongoing, multicenter, international, single-arm phase 1/2 study of TRBC1-directed autologous chimeric antigen receptor (CAR) T cells (AUTO4) in relapsed/refractory TRBC1-positive PTCL. Primary objectives were assessment of safety and tolerability of AUTO4 infusion. Key secondary endpoints included efficacy, CAR T cell expansion and persistence. Here we describe the findings from dose escalation in LibraT1 in the first ten patients, in a non-prespecified interim analysis. AUTO4 resulted in low frequency of severe immunotoxicity, with one of ten patients developing grade 3 cytokine release syndrome. Complete metabolic response was observed in four of ten evaluable patients, with remissions being durable beyond 1 year in two patients. While an absence of circulating CAR T cells was observed, CAR T cells were readily detected in lymph node biopsy samples from sites of original disease suggesting homing to tumor sites. These results support the continuing exploration of TRBC1 targeting in PTCL. ClinicalTrials.gov registration: NCT03590574 .
Insights
Peripheral T cell lymphomas (PTCLs) show poor prognosis. A new therapy targeting T cell receptor beta-chain constant domain 1 (TRBC1) CAR T cells shows promise, with some patients achieving durable remissions and manageable side effects.
Area of Science:
- Oncology
- Immunotherapy
- Hematology
Background:
- Relapsed/refractory peripheral T cell lymphomas (PTCLs) have a poor prognosis and limited treatment options.
- Current immunotherapies for PTCLs are hindered by the lack of specific target antigens, leading to severe immunosuppression.
- A novel strategy targets mutually exclusive T cell receptor beta-chain constant domain (TRBC) 1 and 2 expression to spare normal T cells.
Purpose of the Study:
- To evaluate the safety, tolerability, and preliminary efficacy of TRBC1-directed chimeric antigen receptor (CAR) T cells (AUTO4) in patients with relapsed/refractory PTCL.
- To assess CAR T cell expansion, persistence, and tumor homing.
- To describe findings from the dose escalation phase of the LibraT1 study.
Main Methods:
- Phase 1/2, single-arm, multicenter study of AUTO4 in relapsed/refractory TRBC1-positive PTCL.
- Dose escalation in the first ten patients.
- Assessment of safety (including cytokine release syndrome), efficacy (complete metabolic response), CAR T cell expansion, persistence, and tumor infiltration via biopsy.
Main Results:
- AUTO4 demonstrated a low frequency of severe immunotoxicity, with one of ten patients experiencing grade 3 cytokine release syndrome.
- Four of ten evaluable patients achieved a complete metabolic response, with two experiencing durable remissions exceeding 1 year.
- CAR T cells were detected in lymph node biopsies, indicating homing to tumor sites, despite absence in circulation.
Conclusions:
- TRBC1-directed CAR T cell therapy (AUTO4) shows potential for treating relapsed/refractory PTCL with manageable safety.
- The observed durable responses and tumor homing support further investigation of this targeted approach.
- This strategy offers a promising avenue for PTCL immunotherapy by selectively targeting malignant T cells.
