In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. CT130-CT130
Abstract:
Background: P-BCMA-101 is a novel chimeric antigen receptor (CAR)-T cell therapy designed to increase efficacy while minimizing toxicity through reduced immunogenicity, lack of tonic signaling, a safety switch, high purity ( & gt95% CAR+) and a Tscm phenotype (Tscm are long-lived lymphocyte stem cells that appear to gradually differentiate into effectors, improving efficacy, durability and safety of a CAR-T therapeutic). The P-BCMA-101 CAR utilizes an anti-BCMA (B-Cell Maturation Antigen) Centyrin™ fused to a second-generation CAR scaffold (a CARTyrin) rather than antibody fragments. Centyrins are fully human and have high binding affinities, but are smaller, more stable and potentially less immunogenic. This product is made using the piggyBac™ (PB) transposon system, requiring only mRNA and plasmid DNA. PB eliminates the need for virus, preferentially producing the desired Tscm phenotype and reducing manufacturing costs. The higher cargo capacity of PB also permits the incorporation of other genes, such as a safety switch and a selection gene in P-BCMA-101. The former allows for in vivo depletion of P-BCMA-101 if severe adverse events were to occur and the latter allows enrichment of CAR+ cells leading to greater consistency and purity to produce a better 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. Objectives & Methodology: Thus, a 3+3 dose escalation Phase 1 clinical trial was initiated in patients with r/r MM to assess the safety and efficacy of P-BCMA-101 (NCT03288493). Patients are apheresed to harvest T cells, then P-BCMA-101 CARTyrin T cells are manufactured and administered to patients as a single dose after a standard cyclophosphamide/fludarabine conditioning regimen. Preliminary Results: Two heavily pretreated patients are thus far evaluable at a dose of 0.75 x 106 CARTyrin+ cells / kg. P-BCMA-101 manufactured for patients were primarily Tscm, and demonstrated robust and specific in vitro killing and cytokine production against BCMA+ tumor cells. Both patients' MM was BCMA+. Patient 1, a 54yo female with λ light chain myeloma had rapid progression in spite of chemotherapy, with free light chains (FLC) spiking to 3290 mg/L and renal failure prior to P-BCMA-101 treatement. After P-BCMA-101 administration a partial response was reported, with FLC rapidly decreasing from 1308 mg/L at baseline to 305 mg/L. No cytokine release syndrome (CRS) was seen, though there were mild elevations in CRS markers. Patient 2 is a 50yo female with oligosecretory κ light chain myeloma with plasmacytomas. Likewise, no CRS was reported. PET/CT is pending. P-BCMA-101 CARTyrin T cells markedly expanded and persisted in both patients, comprising 14-40% of circulating T cells within 3 weeks of infusion. Both patients continue in good condition, and additional patients have been enrolled. Clinical trial data are early, but appear consistent with the preclinical findings for P-BCMA-101. Funding for this study was provided by Poseida Therapeutics and CIRM Citation Format: Tara K. Gregory, Jesus G. Berdeja, Krina K. Patel, Syed Abbas Ali, Adam D. Cohen, Caitlin Costello, Eric M. Ostertag, Nishan de Silva, Devon J. Shedlock, Michelle Resler, Matthew A. Spear, Robert Z. Orlowski. Clinical trial of P-BCMA-101 T stem cell memory (Tscm) CAR-T cells in relapsed/refractory (r/r) multiple myeloma (MM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT130.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2018-CT130
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2018
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2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
