EHA Library - The official digital education library of European Hematology Association (EHA)

SAFETY AND PRELIMINARY EFFICACY FINDINGS OF AUTO4, A TRBC1-TARGETTING CAR, IN RELAPSED/REFRACTORY TRBC1 POSITIVE SELECTED T CELL NON-HODGKIN LYMPHOMA
Author(s): ,
Kate Cwynarski
Affiliations:
Haematology,University College London,London,Royaume-uni;Haematology,University College London,London,Vereinigtes Königreich;Haematology,University College London,London,Regno Unito;Haematology,University College London,London,United Kingdom;Haematology,University College London,London,Reino Unido;Haematology,University College London,London,Verenigd Koninkrijk;Haematology,University College Londo
,
Eleni Tholouli
Affiliations:
Manchester Royal Infirmary,Manchester ,Royaume-uni;Manchester Royal Infirmary,Manchester ,Vereinigtes Königreich;Manchester Royal Infirmary,Manchester ,Regno Unito;Manchester Royal Infirmary,Manchester ,United Kingdom;Manchester Royal Infirmary,Manchester ,Reino Unido;Manchester Royal Infirmary,Manchester ,Verenigd Koninkrijk;Manchester Royal Infirmary,Manchester ,Reino Unido;Manchester Royal Infi
,
Gloria Iacoboni
Affiliations:
VHIO Vall d'Hebron Hospital,Barcelona,Espagne;VHIO Vall d'Hebron Hospital,Barcelona,Spanien;VHIO Vall d'Hebron Hospital,Barcelona,Spagna;VHIO Vall d'Hebron Hospital,Barcelona,Spain;VHIO Vall d'Hebron Hospital,Barcelona,España;VHIO Vall d'Hebron Hospital,Barcelona,Spanje;VHIO Vall d'Hebron Hospital,Barcelona,Espanha;VHIO Vall d'Hebron Hospital,Barcelona,Испания;VHIO Vall d'Hebron Hospital,Barcelona
,
Tobias Menne
Affiliations:
Freeman Hospital Newcastle,Newcastle,Royaume-uni;Freeman Hospital Newcastle,Newcastle,Vereinigtes Königreich;Freeman Hospital Newcastle,Newcastle,Regno Unito;Freeman Hospital Newcastle,Newcastle,United Kingdom;Freeman Hospital Newcastle,Newcastle,Reino Unido;Freeman Hospital Newcastle,Newcastle,Verenigd Koninkrijk;Freeman Hospital Newcastle,Newcastle,Reino Unido;Freeman Hospital Newcastle,Newcastl
,
David Irvine
Affiliations:
University of Glasgow,Glasgow,Royaume-uni;University of Glasgow,Glasgow,Vereinigtes Königreich;University of Glasgow,Glasgow,Regno Unito;University of Glasgow,Glasgow,United Kingdom;University of Glasgow,Glasgow,Reino Unido;University of Glasgow,Glasgow,Verenigd Koninkrijk;University of Glasgow,Glasgow,Reino Unido;University of Glasgow,Glasgow,Соединённое Королевство;University of Glasgow,Glasgow,
,
Leigh Wood
Affiliations:
Cancer Clinical Trials Unit,University College London Hospitals,London,Royaume-uni;Cancer Clinical Trials Unit,University College London Hospitals,London,Vereinigtes Königreich;Cancer Clinical Trials Unit,University College London Hospitals,London,Regno Unito;Cancer Clinical Trials Unit,University College London Hospitals,London,United Kingdom;Cancer Clinical Trials Unit,University College London
,
Nivetha Balasubramaniam
Affiliations:
Cancer Clinial Trials Unit,University College London,London,Royaume-uni;Cancer Clinial Trials Unit,University College London,London,Vereinigtes Königreich;Cancer Clinial Trials Unit,University College London,London,Regno Unito;Cancer Clinial Trials Unit,University College London,London,United Kingdom;Cancer Clinial Trials Unit,University College London,London,Reino Unido;Cancer Clinial Trials Unit
,
Justin Shang
Affiliations:
Autolus Therapeutics,Rockville,États-unis;Autolus Therapeutics,Rockville,Vereinigte Staaten;Autolus Therapeutics,Rockville,Stati Uniti;Autolus Therapeutics,Rockville,United States;Autolus Therapeutics,Rockville,Estados Unidos;Autolus Therapeutics,Rockville,Verenigde Staten;Autolus Therapeutics,Rockville,Estados Unidos;Autolus Therapeutics,Rockville,United States;Autolus Therapeutics,Rockville,USA
,
Michael Zhang
Affiliations:
Autolus Therapeutics,Rockville,États-unis;Autolus Therapeutics,Rockville,Vereinigte Staaten;Autolus Therapeutics,Rockville,Stati Uniti;Autolus Therapeutics,Rockville,United States;Autolus Therapeutics,Rockville,Estados Unidos;Autolus Therapeutics,Rockville,Verenigde Staten;Autolus Therapeutics,Rockville,Estados Unidos;Autolus Therapeutics,Rockville,United States;Autolus Therapeutics,Rockville,USA
,
Kevin Duffy
Affiliations:
Clinical Development,Autolus Therapeutics,London,Royaume-uni;Clinical Development,Autolus Therapeutics,London,Vereinigtes Königreich;Clinical Development,Autolus Therapeutics,London,Regno Unito;Clinical Development,Autolus Therapeutics,London,United Kingdom;Clinical Development,Autolus Therapeutics,London,Reino Unido;Clinical Development,Autolus Therapeutics,London,Verenigd Koninkrijk;Clinical Dev
,
Birgit Huber
Affiliations:
Autolus Therapeutics,Munich,Allemagne;Autolus Therapeutics,Munich,Deutschland;Autolus Therapeutics,Munich,Germania;Autolus Therapeutics,Munich,Germany;Autolus Therapeutics,Munich,Alemania;Autolus Therapeutics,Munich,Duitsland;Autolus Therapeutics,Munich,Alemanha;Autolus Therapeutics,Munich,Германия;Autolus Therapeutics,Munich,Tyskland
,
Mary Vinson
Affiliations:
Autolus Therapeutics,London,Royaume-uni;Autolus Therapeutics,London,Vereinigtes Königreich;Autolus Therapeutics,London,Regno Unito;Autolus Therapeutics,London,United Kingdom;Autolus Therapeutics,London,Reino Unido;Autolus Therapeutics,London,Verenigd Koninkrijk;Autolus Therapeutics,London,Reino Unido;Autolus Therapeutics,London,Соединённое Королевство;Autolus Therapeutics,London,Storbritannien
,
Wolfram Brugger
Affiliations:
Clinical Development,Autolus Therapeutics,London,Royaume-uni;Clinical Development,Autolus Therapeutics,London,Vereinigtes Königreich;Clinical Development,Autolus Therapeutics,London,Regno Unito;Clinical Development,Autolus Therapeutics,London,United Kingdom;Clinical Development,Autolus Therapeutics,London,Reino Unido;Clinical Development,Autolus Therapeutics,London,Verenigd Koninkrijk;Clinical Dev
Martin Pule
Affiliations:
Research & Development,Autolus Therapeutics,London,Royaume-uni;Research & Development,Autolus Therapeutics,London,Vereinigtes Königreich;Research & Development,Autolus Therapeutics,London,Regno Unito;Research & Development,Autolus Therapeutics,London,United Kingdom;Research & Development,Autolus Therapeutics,London,Reino Unido;Research & Development,
(Abstract release date: 05/12/22) EHA Library. Cwynarski K. 06/11/22; 357125; S261
Kate Cwynarski
Kate Cwynarski
Contributions
Abstract
Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S261

Type: Oral Presentation

Session title: Gene therapy and cellular immunotherapy - Clinical 2

Background

Peripheral T cell lymphomas (PTCL) are typically aggressive, treatment resistant and associated with poor prognosis. Clinical application of immunotherapy is limited by a lack of target antigens that discriminate malignant from normal T cells. Unlike B cell depletion, pan–T cell aplasia is prohibitively toxic. We recently described a 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.

Aims

Here we describe early clinical findings of AUTO4, a TRBC1 directed autologous CAR T cell therapy, tested against relapsed/refractory (r/r) TRBC1+ PTCL. 

Methods

NCT03590574 is multi-centre, single-arm study of AUTO4 with a phase I dose escalation component and a phase II expansion cohort. Here we report the initial findings of the phase I component. Biopsies from patients >18 years of age were screened for TRBC1-positive PTCL using next-generation sequencing. Four flat dose levels were explored: 25 x 106, 75 x 106, 225 x 106, and 450 x 106 CAR T cells administered as a single dose. CAR T-cell products are generated using a semi-automated closed process. Patients received lymphodepletion with fludarabine (30mg/m2 x4, day-6 to day-3) and cyclophosphamide (500mg/m2 x2 on day-6 and day-5) (Flu/Cy) prior to AUTO4 infusion on Day 0. Primary endpoints were incidence of Grade 3 to 5 toxicity occurring within 60 days of AUTO4 infusion and the frequency of dose limiting toxicities within 28 days of AUTO4 infusion (DLT period). Overall response (CR+PR) rate post AUTO4 infusion by PET-CT (Lugano 2014 criteria) was a secondary endpoint.

Results

As of 09-FEB-2022, n=64 patients consented for screening of TRBC1-positive PTCL. N=24 samples were TRBC1-positive; 7 patients were screen failures including 1 patient who died during screening. 11 products were manufactured; one patient relapsed prior to AUTO4 infusion, and one patient screen failed after product manufacture. To date 9 patients have been treated with AUTO4. The median age in these 9 patients was 57 years (range 34 to 63 years). The T-cell lymphoma subtypes treated were PCTL-NOS (n=4), ALCL (n=1), and AITL (n=4). Two patients had prior stem cell transplantation. The median number of prior treatment lines was 3 (range 1-5). After lymphodepletion with Flu/Cy, 3 patients received 25 × 106 CAR T cells, 2 patients received 75 × 106 CAR T cells, 1 patient received 225 × 106 CAR T cells and 3 patients received 450 × 106 CAR T cells. No patient experienced any dose limiting toxicities. The median (range) number of CD3+ T-cells/µl in blood prior to lymphodepletion and at the end of the DLT period (Day 28) was 204 (94-698) and 123 (19-458), respectively. 3 patients (33%) experienced CRS (1 patient with Grade 1, 1 patient with Grade 2, and 1 patient with Grade 3). None of the patients experienced neurotoxicity/ICANS. The most common treatment-emergent adverse events were cytopenias (anemia and neutropenia). Of the 9 patients treated, 5 patients had achieved complete metabolic responses (CMR) by PET-CT at Month 1, one patient remains with a PR 6 months post AUTO4 infusion, and 3 patients did not respond. All 3 patients at the 450x106 cell dose achieved a CMR at Month 1.

Conclusion

AUTO4 has a tolerable safety profile in patients with r/r TRBC1+ peripheral T-cell lymphoma. Early data shows encouraging response rates. Updated data and longer follow up will be presented.

Keyword(s): Autologous, CAR-T, Peripheral T-cell lymphoma

Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S261

Type: Oral Presentation

Session title: Gene therapy and cellular immunotherapy - Clinical 2

Background

Peripheral T cell lymphomas (PTCL) are typically aggressive, treatment resistant and associated with poor prognosis. Clinical application of immunotherapy is limited by a lack of target antigens that discriminate malignant from normal T cells. Unlike B cell depletion, pan–T cell aplasia is prohibitively toxic. We recently described a 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.

Aims

Here we describe early clinical findings of AUTO4, a TRBC1 directed autologous CAR T cell therapy, tested against relapsed/refractory (r/r) TRBC1+ PTCL. 

Methods

NCT03590574 is multi-centre, single-arm study of AUTO4 with a phase I dose escalation component and a phase II expansion cohort. Here we report the initial findings of the phase I component. Biopsies from patients >18 years of age were screened for TRBC1-positive PTCL using next-generation sequencing. Four flat dose levels were explored: 25 x 106, 75 x 106, 225 x 106, and 450 x 106 CAR T cells administered as a single dose. CAR T-cell products are generated using a semi-automated closed process. Patients received lymphodepletion with fludarabine (30mg/m2 x4, day-6 to day-3) and cyclophosphamide (500mg/m2 x2 on day-6 and day-5) (Flu/Cy) prior to AUTO4 infusion on Day 0. Primary endpoints were incidence of Grade 3 to 5 toxicity occurring within 60 days of AUTO4 infusion and the frequency of dose limiting toxicities within 28 days of AUTO4 infusion (DLT period). Overall response (CR+PR) rate post AUTO4 infusion by PET-CT (Lugano 2014 criteria) was a secondary endpoint.

Results

As of 09-FEB-2022, n=64 patients consented for screening of TRBC1-positive PTCL. N=24 samples were TRBC1-positive; 7 patients were screen failures including 1 patient who died during screening. 11 products were manufactured; one patient relapsed prior to AUTO4 infusion, and one patient screen failed after product manufacture. To date 9 patients have been treated with AUTO4. The median age in these 9 patients was 57 years (range 34 to 63 years). The T-cell lymphoma subtypes treated were PCTL-NOS (n=4), ALCL (n=1), and AITL (n=4). Two patients had prior stem cell transplantation. The median number of prior treatment lines was 3 (range 1-5). After lymphodepletion with Flu/Cy, 3 patients received 25 × 106 CAR T cells, 2 patients received 75 × 106 CAR T cells, 1 patient received 225 × 106 CAR T cells and 3 patients received 450 × 106 CAR T cells. No patient experienced any dose limiting toxicities. The median (range) number of CD3+ T-cells/µl in blood prior to lymphodepletion and at the end of the DLT period (Day 28) was 204 (94-698) and 123 (19-458), respectively. 3 patients (33%) experienced CRS (1 patient with Grade 1, 1 patient with Grade 2, and 1 patient with Grade 3). None of the patients experienced neurotoxicity/ICANS. The most common treatment-emergent adverse events were cytopenias (anemia and neutropenia). Of the 9 patients treated, 5 patients had achieved complete metabolic responses (CMR) by PET-CT at Month 1, one patient remains with a PR 6 months post AUTO4 infusion, and 3 patients did not respond. All 3 patients at the 450x106 cell dose achieved a CMR at Month 1.

Conclusion

AUTO4 has a tolerable safety profile in patients with r/r TRBC1+ peripheral T-cell lymphoma. Early data shows encouraging response rates. Updated data and longer follow up will be presented.

Keyword(s): Autologous, CAR-T, Peripheral T-cell lymphoma

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