title: Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape.
abstract: In preclinical models of glioblastoma, antigen escape variants can lead to tumor recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the heterogeneous expression of antigens on glioblastomas, we hypothesized that a bispecific CAR molecule would mitigate antigen escape and improve the antitumor activity of T cells. Here, we created a CAR that joins a HER2-binding scFv and an IL13Rα2-binding IL-13 mutein to make a tandem CAR exodomain (TanCAR) and a CD28.ζ endodomain. We determined that patient TanCAR T cells showed distinct binding to HER2 or IL13Rα2 and had the capability to lyse autologous glioblastoma. TanCAR T cells exhibited activation dynamics that were comparable to those of single CAR T cells upon encounter of HER2 or IL13Rα2. We observed that TanCARs engaged HER2 and IL13Rα2 simultaneously by inducing HER2-IL13Rα2 heterodimers, which promoted superadditive T cell activation when both antigens were encountered concurrently. TanCAR T cell activity was more sustained but not more exhaustible than that of T cells that coexpressed a HER2 CAR and an IL13Rα2 CAR, T cells with a unispecific CAR, or a pooled product. In a murine glioblastoma model, TanCAR T cells mitigated antigen escape, displayed enhanced antitumor efficacy, and improved animal survival. Thus, TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Hegde
authors.forename: Malini
authors.initials: M
authors.lastname: Mukherjee
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Grada
authors.forename: Antonella
authors.initials: A
authors.lastname: Pignata
authors.forename: Daniel
authors.initials: D
authors.lastname: Landi
authors.forename: Shoba A
authors.initials: SA
authors.lastname: Navai
authors.forename: Amanda
authors.initials: A
authors.lastname: Wakefield
authors.forename: Kristen
authors.initials: K
authors.lastname: Fousek
authors.forename: Kevin
authors.initials: K
authors.lastname: Bielamowicz
authors.forename: Kevin K H
authors.initials: KK
authors.lastname: Chow
authors.forename: Vita S
authors.initials: VS
authors.lastname: Brawley
authors.forename: Tiara T
authors.initials: TT
authors.lastname: Byrd
authors.forename: Simone
authors.initials: S
authors.lastname: Krebs
authors.forename: Stephen
authors.initials: S
authors.lastname: Gottschalk
authors.forename: Winfried S
authors.initials: WS
authors.lastname: Wels
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Baker
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
authors.forename: Maksim
authors.initials: M
authors.lastname: Mamonkin
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.forename: Nabil
authors.initials: N
authors.lastname: Ahmed
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D016219:Immunotherapy, Adoptive; D018793:Interleukin-13 / Q000378:metabolism; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D016513:Mice, SCID; D009364:Neoplasm Recurrence, Local; D009368:Neoplasm Transplantation; D011485:Protein Binding; D055503:Protein Multimerization; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D019076:Transgenes; D019139:Tumor Escape
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D018719:Erb-b2 Receptor Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; C524056:Erbb2 protein, mouse