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)

Abstract

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 <2, who have had at least 3 prior lines of therapy or have double refractory disease to proteasome inhibitors (PI) and immunomodulatory agents (IMiD), adequate hepatic and cardiac function and an absolute lymphocyte count ≥0.5 x 10e9/L are eligible. Patients with CNS disease, prior allogeneic stem cell transplant, are excluded. All patients receive lymphodepletion with 30 mg/m2/day fludarabine and 300 mg/m2/day cyclophosphamide for 3 days prior to AUTO2 infusion. Five dose levels are being explored (15 x 10e6; 75 x 10e6 ;225 x 10e6; 600 x10e6 x and 900x 10e6 transduced CAR-T cells). The primary endpoint of this phase 1 study is incidence of Grade 3 to 5 toxicity occurring within the DLT period (28 days post AUTO2 infusion), frequency of DLTs and the persistence of AUTO2. Key secondary endpoints include overall response rate, duration of response, and overall survival, as well as biomarker endpoints such as AUTO2 levels in blood. 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.

Overcoming Chimeric Antigen Receptor (CAR) Modified T-Cell Therapy Limitations in Multiple Myeloma

“…Relapsed/refractory MM patients were infused with 15 × 10 6 (1/11 pts), 75 × 10 6 (3/11 pts), 225 × 10 6 (3/11 pts), 600 × 10 6 (3/11 pts), and 900 × 10 6 (1/11 pts) APRIL CAR T-cells. The ORR was 43% (28 PRs and 14% VGPRs) in patients receiving ≥ 225 × 10 6 CAR T-cells (134). Long-term follow up is needed to assess the efficacy of this…”

“…In the preclinical setting, APRIL CAR T-cells have been successfully developed targeting both BCMA and TACI (133). Consequently, a clinical trial phase I/II is ongoing to evaluate the safety and efficacy of APRIL CAR T-cells in myeloma patients (NCT03287804) (134). Relapsed/refractory MM patients were infused with 15 × 10 6 (1/11 pts), 75 × 10 6 (3/11 pts), 225 × 10 6 (3/11 pts), 600 × 10 6 (3/11 pts), and 900 × 10 6 (1/11 pts) APRIL CAR T-cells.…”

CAR T-Cells in Multiple Myeloma: State of the Art and Future Directions

“…This resulted in the prevention of a BCMA negative relapse in a preclinical in vivo model of MM, whereas CAR T-cells targeting solely BCMA did not ( 175 ). The APRIL-based CAR T-cell product is currently investigated in the AUTO2 trial (NCT03287804) ( 133 ). As mentioned previously, other multispecific CAR T-cell products containing a bicistronic BCMA and SLAMF7-directed CAR ( 176 , 177 ) or simultaneously manufactured BCMA- and GPRC5D-directed CAR T-cells ( 121 ) have been investigated preclinically, and clinical testing of bispecific CAR T-cells targeting BCMA and CD38 ( 132 ) or BCMA and CD19 ( 178 ) are ongoing in China.…”

Bispecific Chimeric Antigen Receptor T Cell Therapy for B Cell Malignancies and Multiple Myeloma

“…A total of five patients had grade 1 CRS and there were no cases of neurotoxicity. Among patients who received ≥225 × 10 6 cells dose, the ORR was 43% in this early phase trial [ 49 ]. Table 1 summarizes dual targeted CAR approaches in multiple myeloma.…”