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116 Multi-antigen targeting of heterogenous solid tumors using CAR T cells secreting bi-specific T-cell engagers
  1. Martin Hosking,
  2. Bishwas Shrestha,
  3. Megan Boyett,
  4. Soheila Shirinbak,
  5. Angela Gentile,
  6. Eric Sung,
  7. Yijia Pan,
  8. Tom Lee,
  9. Jason ORourke,
  10. Dan Shoemaker,
  11. Cokey Nguyen and
  12. Bahram Valamehr
  1. Fate Therapeutics, Inc., San Diego, CA, USA


Background Although CAR T cells have been shown to be effective and potent in treating several hematologic malignancies, engineered T-cell therapies have had limited success in addressing solid tumors. Unlike liquid tumors where uniformly expressed antigens are accessible and can be effectively targeted, tumor access and antigen heterogeneity are a significant barrier to the successful development of CAR-T cells in solid tumors.

Methods Here we demonstrate that the combination of a bi-specific T-cell engager (BiTE) targeting EpCAM with a CAR T cell targeting HER2 enhances the in vitro and in vivo anti-tumor activity against heterogenous solid tumors.

Results We observed a dose-dependent enhancement of cytolytic activity when EpCAM-specific BiTEs were titrated alongside 4D5-based HER2-specific CAR T cells against HER2low tumors, enhancing maximal cytolysis by two-fold compared to CAR T cells alone (figure 1). Moreover, the escape of HER2low tumor cells in mixed heterogenous culture systems was circumvented by the combination of HER2-specific CAR T cells and EpCAM-specific BiTEs. The enhancement of efficacy was further demonstrated in an established HER2low MDA-MB-231 xenografts. HER2-specific CAR T cells were unable to contain Her2low tumors, whereas tumor growth was effectively controlled in mice receiving both EpCAM-specific BiTEs and HER2-specific CAR T cells.

Abstract 116 Figure 1

EpCAM specific BiTEs supplement CAR-T efficacy in vitro (A) HER2 and EpCAM expression of SKOV3, MDA-MB-231, and K562 tumor cells was assessed by flow cytometry. (B) HER2 specific CAR-T rapidly targeted and lysed HER2High SKOV3 tumor cells as measured via xCelligence RTCA assay. (C) SKOV3 were co-cultured with untransduced CD8+ T cells and the indicated concentrations of EpCAM BiTE and specific cytolysis was assessed. (D) MDA-MB-231 (HER2low) tumor cells were co-cultured with HER2 CAR-T ± EpCAM BiTE and specific cytolysis was determined

Conclusions Collectively, these data demonstrate that multi-antigen targeting mediated by BiTEs and CARs extends overall anti-tumor efficacy in preclinical models of heterogenous solid tumors. Fate Therapeutics is currently using its proprietary induced pluripotent stem cell (iPSC) product platform to generate iPSC-derived CAR T cells and iPSC-derived CAR NK cells that secrete BiTEs for the treatment of solid tumors.

Ethics Approval These studies were approved by Fate Therapeutics Institutional Animal Care and Use Committee and were carried out in accordance with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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