‘Smart CAR-T’ immunotherapy safer and more effective in mice

Written by Alexander Marshall

A new ‘smart CAR-T’ immunotherapy, produced by Cellectis, could be a safer and more effective treatment according to a new publication.

Research in Nature Communications describes a novel product from Cellectis (NY, USA) that is set to further immunotherapy and CAR-T treatments. The new ‘smart CAR-T cells’ are a genetically engineered variant of the popular CAR-T therapy, which have been designed to be safer and more effective in their treatment of cancer. Researchers have modified three key genes within the cells, which they claim allows an antigen-concentration dependent response to remodel the microenvironment and increase the effectiveness of the CAR-T treatment.

The product, tested in tumor-bearing mice, was shown to extend their survival by integrating the biological T-cell pathways into the CAR-T mechanism. The team from Cellectis did this by utilizing the gene editing tool, TALONS, to insert the chimeric T-cell receptor gene into the TCRα locus, as well as inserting the IL-12P70 gene into either the PDCD1 or IL2Rα loci. By inserting the IL-12P70 genes into these loci, the researchers were able to link the expression of IL-12P70 to the antigen concentration in a highly regulated manner.

By integrating the pro-inflammatory IL-12P70 gene into the CAR-T response, the researchers believe they were able to then cause a strongly controlled, local release of the cytokine, allowing an alteration of the microenvironment and increasing the efficiency of the CAR-T cells, while avoiding issues that are prevalent in normal administration of the cytokine.

 “Discussion around the tumor microenvironment has become a popular topic in the CAR T-cell space, and with recent advancements in gene editing technologies, especially TALEN®, it is now possible to manipulate the way a T-cell regulates itself to adapt to its environment,” explained Dr. Philippe Duchateau (Cellectis). “With seamless modification of multiple genes, and subsequently rewiring their natural regulatory processes, this approach causes the T-cells to secrete therapeutic proteins of interest in a tightly controlled and localized manner. We have essentially transformed the current T-cells used today into precise and powerful micro-robots that can spray IL-12 specifically onto cancer cells — potentially avoiding the toxicity of a systemic injection of IL-12, while enhancing CAR-T activity.”

Cellectis plans to further their research into gene editing and immunotherapy, with the aim to treat multiple cancer types, so they will find this innovation an exciting step towards bringing their off-the-shelf CAR-T therapies to market.

Sources: Sachdeva M, Busser B, Temburni S, et al. Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality. Nat Comms. 10, 5100 (2019); www.cellectis.com/en/press/cellectis-publishes-creation-of-smart-car-t-cells-for-potentially-safer-more-effective-treatments-for-cancer-in-nature-communications/

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