Article Text

Download PDFPDF

269 Preferential targeting of HER2-expressing cancer cells by FT825/ONO-8250, an off-the-shelf iPSC-derived CAR-T cell incorporating novel synthetic mechanisms for enhanced solid tumor activity
  1. Martin P Hosking1,
  2. Takao Arimori2,
  3. Soheila Shirinbak1,
  4. Kyla Omilusik1,
  5. Shilpi Chandra1,
  6. Cara Bickers1,
  7. Mika K Kaneko3,
  8. Angela Gentile1,
  9. Mohamed Elgendy1,
  10. Bertha Villa1,
  11. Zahid Bashir1,
  12. Rebecca Elstrom1,
  13. Susumu Yamamoto4,
  14. Takahiro Mizoguchi4,
  15. Tatsuya Ihara4,
  16. Daisuke Nakayama4,
  17. Lilly Wong1,
  18. Jode P Goodridge1,
  19. Tatsuo Maeda4,
  20. Junichi Takagi2,
  21. Yukinari Kato3 and
  22. Bahram Valamehr1
  1. 1Fate Therapeutics, Inc., San Diego, CA, USA
  2. 2Osaka University, Suita, Osaka, Japan
  3. 3Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
  4. 4Ono Pharmaceutical, Co., Ltd., Mishima-gun, Osaka, Japan
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.

Abstract

Background Although HER2-directed therapies have shown clinical benefit in solid tumors, on-target off-tumor toxicities and drug resistance mechanisms can limit their therapeutic application. Previously we have shown that the novel H2CasMab-2 HER2 binder preferentially recognizes HER2 expressed on tumors rather than normal cells as compared to trastuzumab, which readily binds to HER2 expressed on both tumor and normal cells. Binding sites for each have previously been identified in domain IV of HER2, with trastuzumab engaging a discontinuous epitope spanning nearly 50 amino acids and H2CasMab-2 binding to a short, continuous, and membrane-proximal region.

Methods FT825/ONO-8250 was generated from a clonally engineered iPSC line routinely differentiated and manufactured into CD8αβ+ T cells. Assay details will be outlined in the presentation.

Results Crystal structure analysis of H2CasMab-2 coupled with a short HER2 peptide containing its epitope were performed, revealing significant structural divergence from the consensus structure of HER2, and suggesting that H2CasMab-2, with its short and continual epitope, is uniquely capable of recognizing a local misfolding event in HER2. We experimentally confirmed this hypothesis with the reducing agent DTT to induce HER2 protein misfolding. Under these treatment conditions, HER2 engagement by H2CasMab-2 was significantly enhanced compared to trastuzumab (+2.6x vs -3.2x vs untreated; p=0.0002).

Additionally, we have verified that H2CasMab-2, unlike trastuzumab, uniquely recognizes carboxyl-terminal HER2 fragments (p95), where p95 detection has been observed in up to 30% of patients previously treated with trastuzumab and is considered a predictive marker of resistance to trastuzumab-based therapies.

Given the unique and differentiated HER2 binding characteristics of H2CasMab-2, we designed a H2CasMab-2 CAR construct and developed an off-the-shelf, iPSC-derived CAR-T cell therapy, termed FT825/ONO-8250. The product candidate also incorporates multiple synthetic features to overcome major barriers of solid tumor activity including antigen heterogeneity, suppressive microenvironment, poor effector cell trafficking, and limited product persistence.

FT825/ONO-8250 demonstrates preferential targeting of HER2 expressed by tumor cells in both in vitro and in vivo settings. Importantly, in these preclinical settings FT825/ONO-8250 displays limited cytolysis of HER2+ normal/non-tumorigenic cell lines, unlike trastuzumab-based primary CAR-T cells and ADCs such as trastuzumab-emtansine and trastuzumab-deruxtecan. Expression of high-affinity, non-cleavable CD16a by FT825/ONO-8250 also enables flexible complementation of CAR mediated tumor targeting when combined with therapeutic antibodies including EGFR (cetuximab), PDL1 (avelumab), and cMET (amivantamab) through antibody-dependent cellular cytotoxicity.

Conclusions FT825/ONO-8250 is currently undergoing Phase 1 testing for advanced HER2+ and/or EGFR+ solid tumors (NCT06241456). Available clinical and translational updates will also be shared.

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.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.