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Allogeneic BCMA-targeting CAR T cells in relapsed/refractory multiple myeloma: phase 1 UNIVERSAL trial interim results

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Abstract

ALLO-715 is a first-in-class, allogeneic, anti-BCMA CAR T cell therapy engineered to abrogate graft-versus-host disease and minimize CAR T rejection. We evaluated escalating doses of ALLO-715 after lymphodepletion with an anti-CD52 antibody (ALLO-647)-containing regimen in 43 patients with relapsed/refractory multiple myeloma as part A of the ongoing first-in-human phase 1 UNIVERSAL trial. Primary objectives included determination of the safety and tolerability of ALLO-715 and the safety profile of the ALLO-647-containing lymphodepletion regimen. Key secondary endpoints were response rate and duration of response. Grade ≥3 adverse events were reported in 38 (88.0%) of patients. Cytokine release syndrome was observed in 24 patients (55.8%), with 1 grade ≥3 event (2.3%) and neurotoxicity in 6 patients (14%), with no grade ≥3 events. Infections occurred in 23 patients (53.5%), with 10 (23.3%) of grade ≥3. Overall, 24 patients (55.8%) had a response. Among patients treated with 320 × 106 CAR+ T cells and a fludarabine-, cyclophosphamide- and ALLO-647-based lymphodepletion regimen (n = 24), 17 (70.8%) had a response including 11 (45.8%) with very good partial response or better and 6 (25%) with a complete response/stringent complete response. The median duration of response was 8.3 months. These initial results support the feasibility and safety of allogeneic CAR T cell therapy for myeloma. See clinicaltrials.gov registration NCT04093596.

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Fig. 1: Consort diagram.
Fig. 2: Duration of response in patients who received 320 × 106 CAR+ T cells with an FCAa LD regimen.
Fig. 3: Subgroup analysis of response in patients who received 320 × 106 CAR+ T cells with an FCAa LD regimen.

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Data availability

This trial is currently ongoing. Subject to patient privacy and confidentiality obligations, access to patient-level data and supporting clinical documents may be available upon request and subject to review by the study sponsor on completion of the trial. Such requests can be made to Allogene Therapeutics, Inc., 210 East Grand Avenue, South San Francisco, CA 94080, USA or by email at info@allogene.com. A material transfer and/or data access agreement with the sponsor will be required to access the data.

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Acknowledgements

The study was sponsored and funded by Allogene Therapeutics. We thank the patients who participated in this trial and the family and friends who supported them through the process as well as S. Ghatta (Allogene) and Medical Leverage and E. MacLaren who assisted in the preparation of this manuscript. TALEN gene-editing is a technology owned by Cellectis. S.M. acknowledges funding support from the NCI Memorial Sloan Kettering Core grant (P30 CA008748).

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Authors and Affiliations

Authors

Contributions

E.E.K., W.L., W.Y., A.B. and S.K.K. provided the overall trial design. E.E.K., W.L. and W.Y. did the clinical analysis. S.M., J.V.M., S.C., M.L., S.S., O.O.O., S.A.M., R.N., F.A., J.C.C., M.H., E.E.K. and S.K.K. carried out the clinical interpretation. M.D. and E.B. did the translational experiments, planning, execution and analysis. S.M., M.L., S.S., R.N., F.A., E.E.K., E.B., M.D. and W.Y. drafted the manuscript. A.B. and E.E.K. ensured the integrity of the work as a whole.

Corresponding author

Correspondence to Sham Mailankody.

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Competing interests

S.M. received consulting fees from Evicore, Optum, BioAscend, Janssen Oncology and Legend Biotech. Memorial Sloan Kettering Cancer Center receives research funding from the NCI, Janssen Oncology, Bristol Myers Squibb, Allogene Therapeutics, Fate Therapeutics and Takeda Oncology for conducting research. S.M. received honoraria from OncLive, Physician Education Resource, MJH Life Sciences and Plexus Communications. C.S. received institutional research funding from Janssen, Bristol Myers Squibb, Amgen, Novartis, Syndax, Ionis, Allogene and Sanofi GSK and honoraria for advisory boards/speakers bureau from Sanofi, GSK and Omeros. J.V.F., S.A.M., J.C.C. and M.H. report no competing interests. L.M. received honoraria from Pfizer and clinical trial funding from Caelum. L.M. is a member of the Board of Directors or other advisory committees at Alnylam, Bristol Myers Squibb, Caelum, Celgene, GlaxoSmithKline, Janssen Pharmaceuticals, Karyopharm, Kite, Kura Oncology, Oncopeptides, Pfizer, Sanofi and Takeda. S.S. reports consultancy fees from Janssen, Magenta Therapeutics and Bristol Myers Squibb, as well as research funding from Magenta Therapeutics and Allogene. O.O.O. held consultancy and advisory board roles for Pfizer, Kite, Gilead, AbbVie, Janssen, TGR therapeutics, Novartis, curio science and Nekktar, and received institutional funding from Kite, Pfizer, Daichi Sankyo and Allogene and honoraria from Pfizer and Gilead. R.N. reports consultancy fees and honoraria from Actinium and Incyte. F.A. received personal fees from Bristol Myers Squibb as a speaker and a fee from Janssen pharmaceutical as an advisory board member. F.A. consulted or held an advisory role for Seattle Genetics, Incyte Corporation Speakers’ Bureau and Company: Incyte Corporation and received travel and accommodation expenses from Seattle Genetics and Incyte and honoraria from Incyte. Without receiving direct funding, F.A. served as the local principal investigator for Allogene Therapeutics, Celgene, GlaxoSmithKline, Bristol Myers Squibb, Seattle Genetics, Acetylon Pharmaceuticals, Millennium, Astellas Pharma and AbbVie. E.E.K., W.L., M.D. and A.B. are employees of Allogene Therapeutics. E.B. and W.Y. are consultants with Allogene Therapeutics who do not own stock. S.K.K. receives institutional funding for clinical trials from Abbvie, Amgen, Allogene, AstraZeneca, Bristol Myers Squibb, Carsgen, GlaxoSmithKline, Janssen, Novartis, Roche-Genentech, Takeda, Regeneron and Molecular Templates. S.K.K. also participated in consulting/advisory boards without personal payment for Abbvie, Amgen, Bristol Myers Squibb, Janssen, Roche-Genentech, Takeda, AstraZeneca, Bluebird Bio, Epizyme, Secura Biotherapeutics, Monterosa therapeutics, Trillium, Loxo Oncology, K36, Sanofi and ArcellX, and with personal payment for Oncopeptides, Beigene, Antengene and GLH Pharma.

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Nature Medicine thanks Katayoun Rezvani, Ying Yuan and Jay Spiegel for their contribution to the peer review of this work. Primary Handling Editors: Saheli Sadanand and Joao Monteiro, in collaboration with the Nature Medicine team

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Extended data

Extended Data Fig. 1 Diagram of the scFv in ALLO-715.

The major domains in ALLO-715 are shown schematically.

Extended Data Fig. 2 Flow Cytometry Gating Strategy.

After gating out dead cells and debris, single cells were defined using SSC peak height vs area. Lymphocytes were gated using a combination of side scatter and CD45. CAR T cells were separated from host lymphocytes using an anti-idiotype antibody developed at Allogene.

Extended Data Fig. 3 ALLO-715 in-vivo expansion by Dose Level in Patients Who Received a Fludarabine/Cyclophosphamide/ALLO-647 (FCA) Containing Lymphodepletion Regimen by Days Relative to CAR Dosing.

Data are presented as median values ± interquartile range. N = 43 independent study subjects. Results reported as ‘Not Quantifiable,’ ‘Reported and Unreliable,’ or below the lower limit of quantitation (LLOQ) value have been replaced with LLOQ value (50 Copies/ug).

Extended Data Fig. 4 CAR T Cell Concentrations Stratified by Response.

(a) CAR T cell concentrations among ALLO-715 DL3 patients that received any fludarabine/cyclophosphamide/ALLO-647 (FCA) lymphodepletion are shown in responders and non-responders. Error bars show the interquartile range (IQR) for each data point. (b) CAR T cell concentrations among ALLO-715 DL3 patients that received any FCA lymphodepletion in non-responders and those with very good partial responses or better (VGPR+). Error bars show the IQR for each data point. (c) Box plot of vector copy number (VCN) responders and non-responders for all patients with assay results between days 1-28. The boxes represent the first quartile (Q1), median, and third quartile (Q3). The lower and the upper whiskers extend to the most extreme points within 1.5 × IQR of Q1 and Q3 respectively, where IQR = Q3-Q1. N = 20 independent study subjects (N = 6 non-responders; N = 14 responders).

Extended Data Fig. 5 ALLO-647 Pharmacokinetics and Host Immune Cell Depletion and Reconstitution.

(a) Concentration vs time profile of ALLO-647 adopted from a population PK model, which used post-hoc concentrations for all subjects enrolled. The model-predicted exposure of ALLO-647 increased with administered dose and appeared to be greater than dose proportional. The geometric mean is shown, and the error bars represent the geometric standard error. N = 96 independent subjects including N = 13 from ALPHA2, N = 41 from ALPHA, and N = 42 from UNIVERSAL. (b) Host T cell counts per ul of whole blood relative to study day. Data are presented as median values ± interquartile range, and N = 43 independent study subjects. VGPR+= very good partial response or better. PR = partial response. NR=no response.

Extended Data Fig. 6 Host Immune Cell Counts Per µl Whole Blood Relative to Study Day.

Counts for the following immune cell types are shown: (a) CD45+ cells; (b) T cells; (c) B cells; (d) and NK cells. Data are presented as median values ± interquartile range. N = 43 independent study subjects. FCA = Fludarabine/Cyclophosphamide/ALLO-647.

Extended Data Table 1 Summary of infections by maximum CTCAE grade
Extended Data Table 2 Efficacy in patients who received CA LD regimens
Extended Data Table 3 ALLO-715 in vivo expansion by DL in patients who received an FCA-containing LD regimen

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Mailankody, S., Matous, J.V., Chhabra, S. et al. Allogeneic BCMA-targeting CAR T cells in relapsed/refractory multiple myeloma: phase 1 UNIVERSAL trial interim results. Nat Med 29, 422–429 (2023). https://doi.org/10.1038/s41591-022-02182-7

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