PHASE 1 ALEXANDER STUDY OF AUTO3 THE FIRST BICISTRONIC CHIMERIC ANTIGEN RECEPTOR (CAR) TARGETING CD19 AND CD22 WITH PEMBROLIZUMAB IN PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B CELL LYMPHOMA
Author(s): ,
Aravind Ramakrishnan
Affiliations:
Hem/Onc,Sarah Cannon Research Institute,Austin,United States
,
Maria Marzolini
Affiliations:
Hem/Onc,University College of London,London,United Kingdom
,
Wendy Osborne
Affiliations:
Freeman Hospital,Newcastle,United Kingdom
,
Eleni Tholouli
Affiliations:
Hem/Onc,Manchester Royal Infirmary,Manchester,United Kingdom
,
Carlos Bachier
Affiliations:
Hem/Onc,Sarah Cannon Research Institute,Nashville,United States
,
Peter McSweeney
Affiliations:
Hem/Onc,Sarah Cannon Research Institute,Denver,United Kingdom
,
David Irvine
Affiliations:
Hem/Onc,Queen Elizabeth Hospital,Glasgow,United Kingdom
,
Yiyun Zhang
Affiliations:
Autolus therapeutics,London,United Kingdom
,
Muhammad Al-Hajj
Affiliations:
Autolus Therapeutics,London,United Kingdom
,
Simon Thomas
Affiliations:
Autolus Therapeutics,London,United Kingdom
,
Martin Pule
Affiliations:
Autolus Therapeutics,London,United Kingdom
,
Vijay Peddareddigari
Affiliations:
Autolus Therapeutics,London,United Kingdom
,
Nushmia Khokhar
Affiliations:
Autolus Therapeutics,London,United Kingdom
,
Maud Jonnaert
Affiliations:
Autolus therapeutics,London,United Kingdom
,
Robert Chen
Affiliations:
Autolus Therapeutics,London,United Kingdom
Kirit Ardeshna
Affiliations:
Hem/Onc,University College of London,London,United Kingdom
EHA Library. Osborne W. 06/12/20; 295060; S240
Wendy Osborne
Wendy Osborne
Contributions
Abstract

Abstract: S240

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: Aggressive Lymphomas: Cellular and bispecific antibody therapies

Background
CD 19 CAR T cell therapies have shown significant activity in patients with relapsed/refractory (r/r) Diffuse Large B Cell Lymphoma (DLBCL), however relapses due to CD19 loss or PDL1 upregulation are common. In this study, we are evaluating the safety and efficacy of AUTO3, a CAR T cell therapy designed to target CD19 and CD22 simultaneously with limited duration of anti-PD1 blockade.

Aims
To determine the safety and efficacy of AUTO3 with limited duration of anti-PD1 blockade.  

Methods
We constructed a novel bicistronic retroviral vector encoding both an anti-CD19 CAR and an anti-CD22 CAR. Antigen binding domains were humanized incorporating an OX40 co-stimulatory domain for the CD19 CAR and a 41BB co-stimulatory domain for the CD22 CAR. The CD22 CAR was enhanced by incorporating a novel pentameric spacer. The cell product was manufactured in a semi-automated and closed process using CliniMACS Prodigy.

Patients (≥ 18 years) with r/r DLBCL not otherwise specified (NOS), high grade, or transformed from indolent histology; Eastern Cooperative Oncology Group Performance Status <2, adequate renal, hepatic, cardiac function and an absolute lymphocyte count ≥0.3 x 10e9/L are eligible. Patients with CNS disease, prior allogeneic stem cell transplant, prior CD19 or CD22 directed therapy are excluded, as well as patients with any contraindication to receiving Pem. Lymphodepletion was done with fludarabine and cyclophosphamide.  Bridging therapy was allowed. The three dose levels explored are 50, 150, and 450 x 106 CAR T-cells. Patients received AUTO3 alone, or with 3 doses of pembrolizumab (pem) 200 mg every 3 weeks starting on Day 14 (regimen A), or with a single dose of pem 200 mg on Day -1 (regimen B). The primary endpoint is frequency of dose-limiting toxicities (DLTs) and grade (G) 3-5 adverse events (AE) and secondary endpoints included overall response rate (ORR), complete response rate (CRR), duration of response, and relevant biomarkers

Results
As of Jan 21, 2020, 28 patients underwent leukapheresis, 27 successfully manufactured, 1 being manufactured, and 19 patients treated with AUTO3. The median age was 57 (28 - 71) and median number of prior therapies was 3 (2 - 10). 89% had refractory disease, 74% were DLBCL NOS, and 26% were tDLBCL. Dose escalation from 50 to 450 x 106 cells with pem regimen A and B have been completed without DLTs. G > 3 treatment emergent AEs that occurred > 15% were neutropenia (89%), thrombocytopenia (58%), anemia (47%), febrile neutropenia (16%), and hypophosphataemia (16%). Across all dose levels, there were 0% severe cytokine release syndrome (sCRS) with primary infusion and 5% severe neurotoxicity (sNT) (1/19), which resolved. There were no cases of sCRS and no neurotoxicity of any grade at > 50 x 106 cells.

Eighteen patients were evaluable for efficacy. Among the 11 treated at dose > 50 x 106, the ORR and CRR were 64% and 55%, and all CRs are ongoing (1-12 month). Two out of 3 patients achieved CR at 450 x 106 cells on pem regimen B. Additional patients and longer follow up, as well as biomarkers, will be presented.

Conclusion
AUTO3 at > 50 x 10CAR T cells with pembrolizumab induces CRs without severe CRS or neurotoxicities of any grade.

Session topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical

Keyword(s): B cell lymphoma, Cellular therapy

Abstract: S240

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: Aggressive Lymphomas: Cellular and bispecific antibody therapies

Background
CD 19 CAR T cell therapies have shown significant activity in patients with relapsed/refractory (r/r) Diffuse Large B Cell Lymphoma (DLBCL), however relapses due to CD19 loss or PDL1 upregulation are common. In this study, we are evaluating the safety and efficacy of AUTO3, a CAR T cell therapy designed to target CD19 and CD22 simultaneously with limited duration of anti-PD1 blockade.

Aims
To determine the safety and efficacy of AUTO3 with limited duration of anti-PD1 blockade.  

Methods
We constructed a novel bicistronic retroviral vector encoding both an anti-CD19 CAR and an anti-CD22 CAR. Antigen binding domains were humanized incorporating an OX40 co-stimulatory domain for the CD19 CAR and a 41BB co-stimulatory domain for the CD22 CAR. The CD22 CAR was enhanced by incorporating a novel pentameric spacer. The cell product was manufactured in a semi-automated and closed process using CliniMACS Prodigy.

Patients (≥ 18 years) with r/r DLBCL not otherwise specified (NOS), high grade, or transformed from indolent histology; Eastern Cooperative Oncology Group Performance Status <2, adequate renal, hepatic, cardiac function and an absolute lymphocyte count ≥0.3 x 10e9/L are eligible. Patients with CNS disease, prior allogeneic stem cell transplant, prior CD19 or CD22 directed therapy are excluded, as well as patients with any contraindication to receiving Pem. Lymphodepletion was done with fludarabine and cyclophosphamide.  Bridging therapy was allowed. The three dose levels explored are 50, 150, and 450 x 106 CAR T-cells. Patients received AUTO3 alone, or with 3 doses of pembrolizumab (pem) 200 mg every 3 weeks starting on Day 14 (regimen A), or with a single dose of pem 200 mg on Day -1 (regimen B). The primary endpoint is frequency of dose-limiting toxicities (DLTs) and grade (G) 3-5 adverse events (AE) and secondary endpoints included overall response rate (ORR), complete response rate (CRR), duration of response, and relevant biomarkers

Results
As of Jan 21, 2020, 28 patients underwent leukapheresis, 27 successfully manufactured, 1 being manufactured, and 19 patients treated with AUTO3. The median age was 57 (28 - 71) and median number of prior therapies was 3 (2 - 10). 89% had refractory disease, 74% were DLBCL NOS, and 26% were tDLBCL. Dose escalation from 50 to 450 x 106 cells with pem regimen A and B have been completed without DLTs. G > 3 treatment emergent AEs that occurred > 15% were neutropenia (89%), thrombocytopenia (58%), anemia (47%), febrile neutropenia (16%), and hypophosphataemia (16%). Across all dose levels, there were 0% severe cytokine release syndrome (sCRS) with primary infusion and 5% severe neurotoxicity (sNT) (1/19), which resolved. There were no cases of sCRS and no neurotoxicity of any grade at > 50 x 106 cells.

Eighteen patients were evaluable for efficacy. Among the 11 treated at dose > 50 x 106, the ORR and CRR were 64% and 55%, and all CRs are ongoing (1-12 month). Two out of 3 patients achieved CR at 450 x 106 cells on pem regimen B. Additional patients and longer follow up, as well as biomarkers, will be presented.

Conclusion
AUTO3 at > 50 x 10CAR T cells with pembrolizumab induces CRs without severe CRS or neurotoxicities of any grade.

Session topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical

Keyword(s): B cell lymphoma, Cellular therapy

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