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Arming CAR-T cells to fight solid tumours

Written by Charlotte Harrison, Science Writer 

Immunotherapy with chimeric antigen receptor T cells (CAR-T cells) has yielded impressive anticancer responses in several types of blood cancer. But CAR-T cells aren’t very good at combatting solid tumours, in part due to the immunosuppressive microenvironment found in these tumours.   

Now, a paper published in Nature Biomedical Engineering shows that manipulating CAR-T cells so they express a bacterial virulence factor enables the CAR-T cells to trigger a potent immune response and inhibit the growth of solid cancers in mice.  

A call to arms 

The authors armed CAR-T cells with a protein called neutrophil-activating protein (NAP) from the bacterium Helicobacter pylori. This protein was chosen because it has strong immunomodulatory properties; it attracts innate immune cells, activates dendritic cells and creates a local pro-inflammatory milieu.  

The CAR(NAP)-T cells were tested in mouse models of several tumour types, including subcutaneous murine pancreatic ductal adenocarcinoma, neuroblastomas and colon carcinomas. Treatment of mice with CAR(NAP)-T cells led to slower tumour growth and higher survival rates than therapy with conventional CAR-T cells. 

The researchers also tested the applicability of human CAR(NAP)-T cells. In an in-vitro assay, human CAR(NAP) T cells killed human cancer cells. 

Immune-mediated fighting 

The authors next investigated the mechanism by which CAR(NAP) T cells have improved therapeutic effects. They propose that NAP turns the tumour microenvironment into one that can trigger a strong immune response. Secreted NAP  

activates dendritic cells to facilitate the activation of endogenous CD8+ T cells directed against antigens other than the CAR target. The activated CD8+ T cells then mediate an immune response — known as a bystander response — against the tumour.   

The fact that the immune response mediated by CAR(NAP) T cells is not dependent on the antigen of the CAR target is particularly important; a particular tumour-associated antigen that CAR T cells could target is often heterogeneously expressed in solid tumours. It also means that the NAP approach may be used to engineer CAR T cells regardless of the CAR target antigen and tumour types. 

“We believe that this new technology to arm CAR-T cells has the potential to completely change CAR-T cell treatment,” said study author Di Yu in a press release

Based on the results of the current study, the authors and Elicera Therapeutics are planning a clinical trial with CAR(NAP)-T cells and hope to recruit the first patient by the end of this year.

Image Credit: Canva