Endogenous bystander killing mechanisms enhance the activity of novel FAP‐specific CAR‐T cells against glioblastoma

Author:

Yu Wenbo12,Truong Nga TH12,Polara Ruhi1,Gargett Tessa123,Tea Melinda N1,Pitson Stuart M13,Cockshell Michaelia P1,Bonder Claudine S13,Ebert Lisa M123ORCID,Brown Michael P123

Affiliation:

1. Centre for Cancer Biology SA Pathology and University of South Australia Adelaide SA Australia

2. Cancer Clinical Trials Unit Royal Adelaide Hospital Adelaide SA Australia

3. Adelaide Medical School The University of Adelaide Adelaide SA Australia

Abstract

AbstractObjectivesCAR‐T cells are being investigated as a novel immunotherapy for glioblastoma, but clinical success has been limited. We recently described fibroblast activation protein (FAP) as an ideal target antigen for glioblastoma immunotherapy, with expression on both tumor cells and tumor blood vessels. However, CAR‐T cells targeting FAP have never been investigated as a therapy for glioblastoma.MethodsWe generated a novel FAP targeting CAR with CD3ζ and CD28 signalling domains and tested the resulting CAR‐T cells for their lytic activity and cytokine secretion function in vitro (using real‐time impedance, flow cytometry, imaging and bead‐based cytokine assays), and in vivo (using a xenograft mimicking the natural heterogeneity of human glioblastoma).ResultsFAP‐CAR‐T cells exhibited target specificity against model cell lines and potent cytotoxicity against patient‐derived glioma neural stem cells, even when only a subpopulation expressed FAP, indicating a bystander killing mechanism. Using co‐culture assays, we confirmed FAP‐CAR‐T cells mediate bystander killing of antigen‐negative tumor cells, but only after activation by FAP‐positive target cells. This bystander killing was at least partially mediated by soluble factors and amplified by IL‐2 which activated the non‐transduced fraction of the CAR‐T product. Finally, a low dose of intravenously administered FAP‐CAR‐T cells controlled, without overt toxicity, the growth of subcutaneous tumors created using a mixture of antigen‐negative and antigen‐positive glioblastoma cells.ConclusionsOur findings advance FAP as a leading candidate for clinical CAR‐T therapy of glioblastoma and highlight under‐recognised antigen nonspecific mechanisms that may contribute meaningfully to the antitumor activity of CAR‐T cells.

Funder

National Health and Medical Research Council

Tour de Cure

Cancer Council South Australia

Mark Hughes Foundation

Neurosurgical Research Foundation

Publisher

Wiley

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