Bispecific antibody does not induce T-cell death mediated by chimeric antigen receptor against disialoganglioside GD2 Journal Article

Authors: Hoseini, S. S.; Dobrenkov, K.; Pankov, D.; Xu, X. L.; Cheung, N. K. V.
Article Title: Bispecific antibody does not induce T-cell death mediated by chimeric antigen receptor against disialoganglioside GD2
Abstract: Chimeric antigen receptors (CAR) and bispecific antibodies (BsAb) are two powerful immunotherapy approaches for retargeting lymphocytes toward cancer cells. Despite their success in lymphoblastic leukemia, solid tumors have been more recalcitrant. Identifying therapeutic barriers facing CAR-modified (CART) or BsAb-redirected T (BsAb-T) cells should facilitate their clinical translation to solid tumors. Novel lentiviral vectors containing low-affinity or high-affinity 4-1BB second-generation anti-GD2 (disialoganglioside) CARs were built to achieve efficient T cell transduction. The humanized anti-GD2 × CD3 BsAb using the IgG-scFv platform was described previously. CART and BsAb-engaged T cells were tested for viability, proliferation, and activation/exhaustion marker expression, and in vitro cytotoxicity against GD2(+) tumor cells. The antitumor effect of CAR-grafted and BsAb-T cells was compared in a human melanoma xenograft model. The majority of high CAR density T cells were depleted upon exposure to GD2(+) target cells while the BsAb-T cells survived. The in vitro cytotoxicity of the surviving CART cells was inferior to that of the BsAb-T cells. Using low-affinity CARs, inclusion of the 4-1BB co-stimulatory domain or exclusion of a co-stimulatory domain, or blocking PD1 did not prevent CART cell depletion. Both CART cells and BsAb-T cells penetrated established subcutaneous human melanoma xenografts; while both induced tumor regression, BsAb was more efficient. The fate of T cells activated by BsAb differs substantially from that by CAR, translating into a more robust antitumor effect both in vitro and in vivo. © 2017 The Author(s). Published with license by Taylor & Francis Group, LLC © 2017, © Sayed Shahabuddin Hoseini, Konstantin Dobrenkov, Dmitry Pankov, Xiaoliang L. Xu, and Nai-Kong V. Cheung.
Keywords: immunotherapy; chimeric antigen receptor; disialoganglioside; bispecific antibody; t cell exhaustion
Journal Title: OncoImmunology
Volume: 6
Issue: 6
ISSN: 2162-4011
Publisher: Landes Bioscience  
Date Published: 2017-01-01
Start Page: e1320625
Language: English
DOI: 10.1080/2162402x.2017.1320625
PROVIDER: scopus
PMCID: PMC5486173
PUBMED: 28680755
Notes: Article -- Export Date: 1 August 2017 -- Source: Scopus
Citation Impact
MSK Authors
  1. Nai-Kong Cheung
    573 Cheung
  2. Xiaoliang Xu
    16 Xu
  3. Dmitry D. Pankov
    21 Pankov
  4. Sayed Shahabuddin Hoseini
    12 Hoseini