Multi-antigen recognition circuits overcome challenges of specificity, heterogeneity, and durability in T cell therapy for glioblastoma

Choe et al. (BioRxiv) DOI: 10.1101/2021.01.07.425632

 

Keywords

  • CAR T cells

  • synNotch receptors

  • Glioblastoma

 

Main Findings

  • In this preprint, Choe et al engineered novel CAR T cells with prime-and-kill circuits that allow for specific and homogenous killing of glioblastoma cells

  • Prime-and-kill CAR T cells consist of (1) a priming synNotch receptor whose intracellular domain is cleaved upon recognition of either the glioblastoma-specific antigen EGFRvIII, or the brain-specific antigen MOG. This induces transcription of (2) a chimeric antigen receptor with binding sites for EphA2 and IL13Ra2 which lead to T cell activation and cell killing

  • These cells can act in cis – killing glioblastoma cells expressing both antigens – and in trans, killing glioblastoma cells lacking the priming antigen

  • Effective killing occurs in vitro with as little of 10% of tumor cells expressing the priming antigen

  • In vivo, prime-and-kill CAR T cells durably suppress growth of patient-derived xenograft tumors with heterogenous EFGRvIII expression as compared to conventional CARs

  • Conditional expression of the CAR in prime-and-kill CAR T cells prevent tonic signalling and exhaustion, allowing the cells to persist in the tumor in a naïve, memory-like state

  • These specialized CAR T cells elicit tumor regression in vivo with tissue-specific priming antigen (MOG)

Limitations

  • Tissue targeting of T cells is a potent method to reach cancers that lack an antigen that is exclusive to tumor cells. However, their effect was not monitored as long as with the EGFRvIII-primed cells so longer analysis will be necessary to conclude complete remission.

  • Additionally, when the priming antigen was the tumor-specific EGFRvIII, no prime-and-kill T cells were found in the spleen, but when primed with the tissue-specific MOG antigen, a small number of primed cells were found in the spleen. Although the percentage was low, this could indicate that primed cells may still traffic to distant sites and can mediate killing of the small portion of healthy cells that express this killing antigen. Studying the kinetics of CAR turnover in vitro as well as studying the killing of EphA2/IL13Ra2 expressing cells in other tissues would be helpful in analysing this off-tumor effect.

  • Engineering and manufacturing of sophisticated T cell receptors requires complex regulatory procedures and high costs, which may slow its clinical translatability and limit the number of patients it can reach. However, established practices for conventional CARs and their recent FDA approval holds promise for other therapeutic T cell designs.

Significance/Novelty

  • They had previously demonstrated the prime-and-kill approach, but in this preprint they showed that it can kill not only tumor cells expressing both the priming antigen and the killing antigen, but also tumor cells expressing only the killing antigen.

  • Their approach can be broadly applied to other solid tumor types which share the same challenges.

  • Additionally, by testing the efficacy with different priming antigens they showed the modularity of their approach and the ability to tailor it to meet the various challenges of different cancer types.

Credit 

Reviewed by Miriam Saffern as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford. Follow her on Twitter.