B7-H3 Specific CAR T Cells for the Naturally Occurring, Spontaneous Canine Sarcoma Model

Shihong Zhang, R. Graeme Black, Karan Kohli, Brian J. Hayes, Cassandra Miller, Amanda Koehne, Brett A. Schroeder, Kraig Abrams, Brian C. Schulte, Borislav A. Alexiev, Amy B. Heimberger, Ali Zhang, Weiqing Jing, Juliana Chi Kei Ng, Himaly Shinglot, Bernard Seguin, Alexander I. Salter, Stanley R. Riddell, Michael C. Jensen, Stephen GottschalkPeter F. Moore, Beverly Torok-Storb, Seth Michaels Pollack*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant animal models. In this study, we sought to establish a chimeric antigen receptor (CAR) T-cell treatment model for naturally occurring canine sarcomas as a model for human CAR T-cell therapy. Canine CARs specific for B7-H3 were constructed using a single-chain variable fragment derived from the human B7-H3–specific antibody MGA271, which we confirmed to be cross-reactive with canine B7-H3. After refining activation, transduction, and expansion methods, we confirmed target killing in a tumor spheroid three-dimensional assay. We designed a B7-H3 canine CAR T-cell and achieved consistently high levels of transduction efficacy, expansion, and in vitro tumor killing. Safety of the CAR T cells were confirmed in two purposely bred healthy canine subjects following lymphodepletion by cyclophosphamide and fludarabine. Immune response, clinical parameters, and manifestation were closely monitored after treatments and were shown to resemble that of humans. No severe adverse events were observed. In summary, we demonstrated that similar to human cancers, B7-H3 can serve as a target for canine solid tumors. We successfully generated highly functional canine B7-H3–specific CAR T-cell products using a production protocol that closely models human CAR T-cell production procedure. The treatment regimen that we designed was confirmed to be safe in vivo. Our research provides a promising direction to establish in vitro and in vivo models for immunotherapy for canine and human solid tumor treatment.

Original languageEnglish (US)
Pages (from-to)999-1009
Number of pages11
JournalMolecular cancer therapeutics
Volume21
Issue number6
DOIs
StatePublished - Jun 2022

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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