In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3759-3759
Abstract:
Chimeric antigen receptor (CAR) T cells have been extremely effective in treating acute lymphoblastic leukemia and have shown promise against other malignancies including multiple myeloma (MM). However, relatively poor potency and durability continue to limit efficacy. Addressing these shortcomings, we have developed a novel CAR-T cell therapeutic with enhanced stem cell memory phenotype, reduced immunogenicity, and no evidence of tonic activity. P-BCMA-101 employs a BCMA-specific Centyrin rather than a single chain variable fragment (scFv) for antigen detection and is engineered using piggyBac (PB). Centyrins are fully human and have similar binding affinities but are smaller, more thermostable and predicted to be less immunogenic than a scFv. Furthermore, PB modification of human T cells requires only in vitro transcribed mRNA and plasmid DNA, eliminating the need for lentivirus or γ–retrovirus and resulting in time and cost savings. Additionally, the increased cargo capacity of PB permits the incorporation of a safety switch and a selectable gene into the product. The former is incorporated for optional depletion in vivo in case of adverse events and the latter allows enrichment of CARTyrin+ cells using the non-genotoxic drug methotrexate (MTX), leading to greater consistency in patient product material. Characterization of P-BCMA-101 revealed & gt; 70% of cells possessed a stem-cell memory phenotype (i.e. CD45RA+ CCR7+ CD62L+ CD95+) and & gt;95% of the cells were CARTyrin+. In addition, no tonic signaling or T cell exhaustion was observed, highlighted by low levels of PD-1, Lag3, and Tim-3. Cells exhibit specific and robust in vitro target-cell killing, cytokine production, and proliferation in response to BCMA+ tumor cells. In vivo anti-tumor efficacy of P-BCMA-101 has been evaluated in NSG mice bearing luciferase+ MM.1S cells, an aggressive human MM-derived cell line, monitoring tumor growth by bioluminescent imaging (BLI). Following tumor implantation, animals received a single IV administration of either 4 x 106 or 12 x 106 P-BCMA-101 cells. All untreated control animals succumbed to disease within four weeks of the treatment date. Conversely, tumor burden was reduced to the limit of detection by BLI within 7 days of p-BCMA-101 treatment. As opposed to lentivirus-based products in the same animal model, P-BCMA-101 persists and expands in the animals, eliminates tumors from relapse and prolong survival, with most animals surviving 100 days post-tumor implant. Finally, the effectiveness of the safety switch has been demonstrated both in vitro and in vivo. P-BCMA-101 is the first-in-class of Centyrin-based CAR therapeutics modified using PB and is predicted to have improved potency and durability given the phenotype and non-immunogenic properties of Centryrins. We plan to initiate a phase I clinical trial of P-BCMA-101 for the treatment of patients with relapsed and/or refractory MM. Citation Format: David Hermanson, Burton E. Barnett, Srinivas Rengarajan, Rebecca Codde, Christopher E. Martin, Xinxin Wang, Yening Tan, Jenessa B. Smith, Jin He, Rohit Mathur, Sattva S. Neelapu, Jing Yang, Eric M. Ostertag, Shedlock J. Devon. PiggyBac-manufactured anti-BCMA Centyrin-based CAR-T therapeutic exhibits improved potency and durability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3759. doi:10.1158/1538-7445.AM2017-3759
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2017-3759
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2017
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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