Combinational Targeting offsets antigen escape and enhances effector functions of adoptively transferred T cells in glioblastoma

Meenakshi Hegde, Amanda Corder, Kevin Kh Chow, Malini Mukherjee, Aidin Ashoori, Yvonne Kew, Yi Jonathan Zhang, David S. Baskin, Fatima A. Merchant, Vita S. Brawley, Tiara T. Byrd, Simone Krebs, Meng Fen Wu, Hao Liu, Helen E. Heslop, Stephen Gottachalk, Eric Yvon, Nabil Ahmed

Research output: Contribution to journalArticle

127 Citations (Scopus)

Abstract

Preclinical and early clinical studies have demonstrated that chimeric antigen receptor (CAR)-redirected T cells are highly promising in cancer therapy. We observed that targeting HER2 in a glioblastoma (GBM) cell line results in the emergence of HER2-null tumor cells that maintain the expression of nontargeted tumor-associated antigens. Combinational targeting of these tumor-associated antigens could therefore offset this escape mechanism. We studied the single-cell coexpression patterns of HER2, IL-13Rα2, and EphA2 in primary GBM samples using multicolor flow cytometry and immunofluorescence, and applied a binomial routine to the permutations of antigen expression and the related odds of complete tumor elimination. This mathematical model demonstrated that cotargeting HER2 and IL-13Rα2 could maximally expand the therapeutic reach of the T cell product in all primary tumors studied. Targeting a third antigen did not predict an added advantage in the tumor cohort studied. We therefore generated bispecific T cell products from healthy donors and from GBM patients by pooling T cells individually expressing HER2 and IL-13Rα2-specific CARs and by making individual T cells to coexpress both molecules. Both HER2/IL-13Rα2-bispecific T cell products offset antigen escape, producing enhanced effector activity in vitro immunoassays (against autologous glioma cells in the case of GBM patient products) and in an orthotopic xenogeneic murine model. Further, T cells coexpressing HER2 and IL-13Rα2-CARs exhibited accentuated yet antigen-dependent downstream signaling and a particularly enhanced antitumor activity.

Original languageEnglish (US)
Pages (from-to)2087-2101
Number of pages15
JournalMolecular Therapy
Volume21
Issue number11
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

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Glioblastoma
T-Lymphocytes
Antigens
Neoplasm Antigens
Neoplasms
Null Lymphocytes
T-Cell Antigen Receptor
Immunoassay
Glioma
Fluorescent Antibody Technique
Flow Cytometry
Theoretical Models
Tissue Donors
Cell Line
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Combinational Targeting offsets antigen escape and enhances effector functions of adoptively transferred T cells in glioblastoma. / Hegde, Meenakshi; Corder, Amanda; Chow, Kevin Kh; Mukherjee, Malini; Ashoori, Aidin; Kew, Yvonne; Zhang, Yi Jonathan; Baskin, David S.; Merchant, Fatima A.; Brawley, Vita S.; Byrd, Tiara T.; Krebs, Simone; Wu, Meng Fen; Liu, Hao; Heslop, Helen E.; Gottachalk, Stephen; Yvon, Eric; Ahmed, Nabil.

In: Molecular Therapy, Vol. 21, No. 11, 01.01.2013, p. 2087-2101.

Research output: Contribution to journalArticle

Hegde, M, Corder, A, Chow, KK, Mukherjee, M, Ashoori, A, Kew, Y, Zhang, YJ, Baskin, DS, Merchant, FA, Brawley, VS, Byrd, TT, Krebs, S, Wu, MF, Liu, H, Heslop, HE, Gottachalk, S, Yvon, E & Ahmed, N 2013, 'Combinational Targeting offsets antigen escape and enhances effector functions of adoptively transferred T cells in glioblastoma', Molecular Therapy, vol. 21, no. 11, pp. 2087-2101. https://doi.org/10.1038/mt.2013.185
Hegde, Meenakshi ; Corder, Amanda ; Chow, Kevin Kh ; Mukherjee, Malini ; Ashoori, Aidin ; Kew, Yvonne ; Zhang, Yi Jonathan ; Baskin, David S. ; Merchant, Fatima A. ; Brawley, Vita S. ; Byrd, Tiara T. ; Krebs, Simone ; Wu, Meng Fen ; Liu, Hao ; Heslop, Helen E. ; Gottachalk, Stephen ; Yvon, Eric ; Ahmed, Nabil. / Combinational Targeting offsets antigen escape and enhances effector functions of adoptively transferred T cells in glioblastoma. In: Molecular Therapy. 2013 ; Vol. 21, No. 11. pp. 2087-2101.
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AU - Wu, Meng Fen

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