Combinational targeting offsets antigen escape and enhances effector functions of adoptively transferred T cells in glioblastoma.
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.
1] Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA [2] Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA [3] Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
Meenakshi
M
Hegde
Amanda
A
Corder
Kevin K H
KK
Chow
Malini
M
Mukherjee
Aidin
A
Ashoori
Yvonne
Y
Kew
Yi Jonathan
YJ
Zhang
David S
DS
Baskin
Fatima A
FA
Merchant
Vita S
VS
Brawley
Tiara T
TT
Byrd
Simone
S
Krebs
Meng Fen
MF
Wu
Hao
H
Liu
Helen E
HE
Heslop
Stephen
S
Gottschalk
Stephen
S
Gottachalk
Eric
E
Yvon
Nabil
N
Ahmed
D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005909:Glioblastoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D057809:HEK293 Cells; D006801:Humans; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured; D019139:Tumor Escape; D023041:Xenograft Model Antitumor Assays
D000951:Antigens, Neoplasm; D053663:Interleukin-13 Receptor alpha2 Subunit; D018719:Erb-b2 Receptor Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins