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1012 Efficacy and Safety of P-Bcma-101 CAR-T Cells in Patients with Relapsed/Refractory (r/r) Multiple Myeloma (MM)

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation: Immunotherapy
Hematology Disease Topics & Pathways:
multiple myeloma, Adult, Biological, Diseases, Therapies, CAR-Ts, Biological Processes, gene therapy, Study Population, immunotherapy, Plasma Cell Disorders, Lymphoid Malignancies, Clinically relevant, immune mechanism, stem cells
Monday, December 3, 2018: 7:00 PM
Ballroom 20D (San Diego Convention Center)

Tara Gregory, MD1*, Adam D. Cohen, MD2, Caitlin L. Costello, MD3, Syed Abbas Ali, MD4, Jesus G. Berdeja, MD5, Eric M Ostertag, MD6*, Christopher Martin, PhD6*, Devon J Shedlock, PhD6*, Michelle Lynn Resler, BS7*, Matthew A. Spear, MD8, Robert Z. Orlowski, MD, PhD9 and Krina K. Patel, MD, MSc10

1Colorado Blood Cancer Institute, Denver, CO
2Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
3Division of Blood and Marrow Transplant, Moores Cancer Center, University of California, San Diego, La Jolla, CA
4Johns Hopkins University, Baltimore
5Sarah Cannon Research Institute, Nashville, TN
6Poseida Therapeutics, Inc., San Diego, CA
7Poseida Therapeutics, Inc., SAN DIEGO, CA
8Poseida Therapeutics, San Diego, CA
9Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX
10Department of Lymphoma and Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX

P-BCMA-101 is a novel chimeric antigen receptor (CAR)-T cell therapeutic targeting BCMA, which is highly expressed on MM cells. It is designed to increase efficacy while minimizing toxicity through reduced immunogenicity, lack of tonic signaling, a safety switch, and a product comprised predominantly of early memory T cells that are effectively all CAR-positive. Rather than using a traditional antibody-based binder, P-BCMA-101 utilizes an anti-BCMA Centyrin™ fused to a CD3ζ/4-1BB signaling domain. Centyrins are fully human and have high binding affinities, but are smaller, more stable and potentially less immunogenic. P-BCMA-101 is produced using the piggyBac™ (PB) DNA Modification System instead of a viral vector, and requires only plasmid DNA and mRNA. This eliminates the need for virus, is less costly, and produces a purified population of CAR+ cells with a preponderance of the favorable stem cell memory T phenotype (TSCM). The higher cargo capacity permits the incorporation of other genes, a safety switch that allows for rapid depletion of product in vivo if indicated by adverse events, and a selection gene that allows for enrichment of CAR+ cells. These features are predicted to result in a greater therapeutic index. Efficacy of P-BCMA-101 in NSG mice bearing aggressive human MM.1S and p53 -/- MM.1S MM was reported (Hermanson, AACR 2016). Whereas control animals died early, tumor burden was reduced to the limit of detection after P-BCMA-101 treatment, and recurrences were spontaneously re-controlled without re-administration of product.

A Phase 1, 3+3 dose escalation trial is being conducted in patients with r/r MM (≥ 3 prior lines, including a proteasome inhibitor and an IMiD, or double refractory) to assess the safety and efficacy of P-BCMA-101 (NCT03288493). No pre-specified level of BCMA expression was required. Patients are apheresed to harvest T cells, P-BCMA-101 is then manufactured and administered to patients as a single intravenous (IV) dose after a standard 3-day cyclophosphamide (300 mg/m2/day) / fludarabine (30 mg/m2/day) conditioning regimen.

As of 31Jul18, 12 patients have been treated with 48, 50, 55, 118, 122, 124, 143, 155, 164, 238, 324 and 430 x 106 P-BCMA-101 CAR-T cells in 3 weight-based cohorts. Patients were heavily pre-treated (3-9 prior therapies), 100% had failed IMiDs, proteasome inhibitors and daratumumab, and 64% had high-risk cytogenetics. Nine patients have yet reached their first 2-week response assessment. All patients have shown some improvement in myeloma assessments on study, yet only 1 patient (8%) has developed any cytokine release syndrome (CRS) (limited Grade 2). Of 3 patients in the first cohort 1 attained a PR and 1 with non-secretory disease near CR of her plasmacytomas on PET/CT. Of the subsequent 6 patients, 3 patients have thus far reached a PR, 1 a VGPR, and 1 a sCR. Thus of the yet evaluable patients treated above Cohort 1, the overall response rate (ORR) is 83% (5/6), in spite of only one experiencing CRS. This CRS was scored as Grade 2, based on short-lived fever and hypotension managed with IV fluids and antibiotics, with minimal CRS marker elevations. Likewise, CRS markers were minimally elevated in other patients. The maximal IL-6 level in any patient was 86 pg/mL, which is orders of magnitude lower than levels generally reported in patients experiencing meaningful CRS after treatment with CAR-T products. No patients required treatment with tocilizumab or safety switch activation. There have been no patient deaths, and no neurotoxicity, DLTs or unexpected/off-target toxicities related to treatment. Generally, infusions were well-tolerated, with cytopenias, including transfusion requiring cytopenias and febrile neutropenia, being the most common Grade 3+ adverse events. Consistent with the hypothesis of the early memory phenotype conveying durability, circulating P-BCMA-101 cells were detected in the blood by flow and PCR, peaking at 2-3 weeks, and remaining detectable at the last timepoint tested in all patients (3 patients thus far assessed at 3 months).

In conclusion, current clinical trial data in patients with r/r MM support preclinical findings that the novel design of P-BCMA-101 can produce significant efficacy, comparing favorably with other anti-BCMA CAR-T products at similar doses, with notably less CRS and no neurotoxicity, consistent with the hypothesis of an improved therapeutic index.

Funding by Poseida Therapeutics and CIRM.

Disclosures: Gregory: Poseida Therapeutics, Inc.: Research Funding. Cohen: Seattle Genetics: Consultancy; Kite Pharma: Consultancy; Oncopeptides: Consultancy; Poseida Therapeutics, Inc.: Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; Celgene: Consultancy; Janssen: Consultancy; Novartis: Research Funding. Costello: Poseida Therapeutics, Inc.: Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Ali: Aduro Biotech: Consultancy, Research Funding; Celgene Inc: Consultancy, Research Funding; Poseida Therapeutics: Research Funding; Juno: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda Oncology: Consultancy; Amgen Inc: Consultancy. Berdeja: Genentech: Research Funding; Bluebird: Research Funding; Glenmark: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Teva: Research Funding; Janssen: Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding. Ostertag: Poseida Therapeutics, Inc.: Employment, Equity Ownership. Martin: Poseida Therapeutics, Inc.: Employment, Equity Ownership. Shedlock: Poseida Therapeutics, Inc.: Employment, Equity Ownership. Resler: Poseida Therapeutics, Inc.: Employment, Equity Ownership. Spear: Poseida Therapeutics, Inc.: Employment, Equity Ownership. Orlowski: Genentech: Consultancy; Poseida: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy. Patel: Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

*signifies non-member of ASH