Phase 1 First-in-Human Study of AUTO2, the First Chimeric Antigen Receptor (CAR) T Cell Targeting APRIL for Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Autor: Vijay G R Peddareddigari, Simon Thomas, Jim Faulkner, Sonja Zweegman, Tobias Menne, Ekaterini Kotsopoulou, Lydia Lee, Shaun Cordoba, Martin Pule, Virginie Cerec, Kwee Yong, Nushmia Z. Khokhar, Jim Cavet, Muhammad Al-Hajj, Rakesh Popat
Rok vydání: 2019
Předmět:
Zdroj: Blood. 134:3112-3112
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood-2019-126689
Popis: Introduction: Chimeric antigen receptor (CAR) T cell therapies directed against B cell maturation antigen (BCMA) have shown significant activity in patients with RRMM, however single antigen targeting with CAR-T cells can result in antigen negative relapse. Dual antigen targeting increases targetable tumor antigens and may reduce the risk of antigen negative disease escape. 'A proliferation-inducing ligand' (APRIL) is a natural high affinity ligand for BCMA and transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI). Like BCMA, TACI is also a tumor necrosis factor receptor and is involved in maturation of B-cells, including their maturation to plasma cells. Importantly, TACI is expressed on MM cells. In this study, we are evaluating the safety and efficacy of AUTO2, a CAR-T cell therapy designed to target BCMA and TACI. Methods: We designed a novel CAR construct using a truncated form of APRIL as the tumor-targeting domain which recognizes both BCMA and TACI on MM cells. AUTO2 is retrovirally transduced to express APRIL CAR and the RQR8 safety switch. The APRIL CAR construct is in a third-generation format with composite endodomains of CD28, OX40 and CD3 zeta. The cell product was manufactured on a semi-automated and closed process. Patients (≥ 18 years) with RRMM; Eastern Cooperative Oncology Group Performance Status Results: As of the data cut-off date (July 03, 2019), 12 patients have been enrolled. Eleven patients have been dosed on study, 1 at 15 x10e6, 3 at 75x10e6, 3 at 225x10e6, 3 at 600x10e6 and 1 at 900x10e6 CAR-T cells. Two patients have been retreated. All patients were successfully manufactured and received target dose. Median age was 61 years (range 45-69 years), median 5 prior lines of treatment (range 3-6) ,73% had prior autologous transplant, 100% were refractory to a PI or IMiD, 80% were refractory to both and 45% were refractory to daratumumab. Eleven patients had a minimum of 4 week follow up and were evaluable for safety analysis. No AUTO2 related deaths were observed and no DLTs were observed. The most frequent ≥ Grade 3 adverse events (>30%) were anemia (82%), neutrophil count decreased (73%). Five patients (45%) experienced CRS, all were grade 1, no ≥ G2 CRS was noted. Tocilizumab was given to 3 patients (27%). No cases of neurotoxicity occurred. Seven patients were dosed, in the ≥ 225x10e6 dose cohorts, the ORR was 43% (28% PRs and 14% VGPRs). Interestingly the patient dosed at 15x10e6 CAR-T cells maintained stable disease (SD) for a year and was retreated at higher dose of 225x10e6 CAR-T cells and continues with SD without further treatment. This patient had the highest baseline levels of TACI and was previously primary refractory to treatment. Another patient initially treated at 75 x10e6 CAR -T cells was retreated with 225x 10e6 CAR-T cells and achieved a partial response. Updated data as well as cellular kinetics, product characteristics and additional biomarker analysis including BCMA and TACI will be presented. Conclusions: AUTO2 is a novel CAR-T therapy, with a manageable safety profile at doses up to 900x10e6 CAR-T cells. Disclosures Popat: Janssen: Honoraria, Other: travel support to meetings; GSK: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Other: travel, accommodations, expenses. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cavet:Amgen: Other: congress support , Research Funding, Speakers Bureau; Oncopeptide: Other: congress support , Research Funding, Speakers Bureau; EUSA: Other: congress support , Research Funding, Speakers Bureau; GSK: Other: congress support, Research Funding, Speakers Bureau; Celgene: Other: congress support , Research Funding, Speakers Bureau; Janssen: Other: Congress support , Research Funding, Speakers Bureau; Takeda: Other: congress support , Research Funding, Speakers Bureau. Yong:Autolus: Consultancy; Sanofi: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Lee:Autolus Therapeutics: Equity Ownership, Research Funding. Faulkner:Autolus Therapeutics: Employment, Equity Ownership. Kotsopoulou:Autolus Therapeutics: Employment, Equity Ownership. Al-Hajj:Autolus Therapeutics: Employment, Equity Ownership. Thomas:Autolus: Employment, Equity Ownership. Cordoba:Autolus: Employment, Equity Ownership. Pule:Autolus: Employment, Equity Ownership, Patents & Royalties. Cerec:Autolus Therapeutics: Employment, Equity Ownership. Peddareddigari:Autolus Therapeutics: Employment, Equity Ownership. Khokhar:Autolus Therapeutics: Employment, Equity Ownership. Menne:Kyowa Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant.
Databáze: OpenAIRE
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