Optimizing CAR structures to enhance efficacy in solid tumours; moving from linear to lateral architectures.

Second generation Chimeric Antigen Receptor (CAR) T-cells have revolutionised the treatment of B-cell and plasma cell malignancies, achieving potent and durable responses across a number of indications. Unfortunately, efficacy of CAR T-cell therapy against the vast majority of solid tumours has been underwhelming. This disparity is due to the increased number of hurdles associated with targeting solid tumours, including antigen heterogeneity, poor infiltration of the CAR T-cells into the tumour deposits and the highly immunosuppressive microenvironment that typifies many solid tumours. Whilst multiple strategies aimed at overcoming these hurdles are under investigation, enhancing T-cell responses through optimising the function of the CAR itself represents a key, yet understudied, area.

 

In this webinar, I will outline how the optimisation of CAR structure can be used to enhance T-cell efficacy. The move from a traditional ‘linear’ configuration, in which signalling domains are placed in cis (and thus progressively further from the plasma membrane) to a ‘lateral’ structure, in which the signalling domains are placed across the plasma membrane (and thus at their endogenous membrane-proximal locations) enhances the proliferation, survival and anti-tumour activity of the CAR T-cells, resulting in substantial efficacy across multiple in vivo models of solid tumours. These lateral CAR T-cells can then be combined with appropriate armouring technologies to further enhance anti-tumour efficacy.

 

Learning Objectives