by Natalie Morrison
LONDON, 13 Dec (APM) - "Smart" CAR-T cells armed to adapt themselves to sense their environment and to produce molecules that stimulate highly targeted anti-tumour activity, could potentially help development in solid tumours, Laurent Poirot, vice president of Cellectis' immunology division told APM.
Poirot was speaking via email this week following the publication of Cellectis' latest paper in Nature Communications, describing proof-of-concept on these smart CAR-T cells.
Its researchers are using gene-editing techniques to engineer "intelligent" CAR-T cells which can recognise cancerous tumours and cause a micro secretion of therapeutic proteins onto these tumours, which ultimately reshapes the tumour microenvironment and improves the T-cells ability to fight cancer, according to a statement from the French biopharma.
The scientists noted in the paper the engineering included repurposing T Cell receptor (TCR), CD25 and PD1 - "three major players of the T-cell activation pathway".
"We insert the CAR into the TCRα gene (TRAC-CAR) and IL-12P70 into either IL2Rα or PDCD1 genes. This process results in transient, antigen concentration-dependent IL-12P70 secretion, increases TRAC-CAR T-cell cytotoxicity and extends survival of tumour-bearing mice," they added.
"This gene network repurposing strategy can be extended to other cellular pathways, thus paving the way for generating smart CAR T cells able to integrate biological inputs and to translate them into therapeutic outputs in a highly regulated manner."
Limited CAR-T success
Poirot told APM that CAR-T cells have thus far shown high rates of complete responses in B-cell malignancies, but much more limited success in other cancers."It appears that CAR T-cells need to be boosted to enhance their potency and show efficacy in multiple cancer types. But attempts to increase activity of CAR-T cells can cause toxicity because of excessive inflammation throughout the body.
"The concept of smart CAR T cells lies in arming CAR-T cells with attributes that allows them to sense their environment and to produce molecules that stimulate antitumor activity only within the tumour."
The CAR-T field has generated a lot of attention since the approval of the first two therapies in 2017 - Novartis' Kymriah (tisagenlecleucel) (APMHE 54476) and Gilead's Yescarta (axicabtagene ciloleucel) (APMHE 55223) - believed to have potentially curative effects.
However, it the limits of CAR-T as treatments of liquid rather than solid tumours has been widely discussed, with many developers striving to find a way to utilise the technology for solid cancers, which tend to have bigger populations.
"Solid tumour is definitely an area where we think this technology could show benefit," Poirot said.
"Solid tumours and their microenvironment have evolved to survive immune surveillance in part by impairing normal functions of the patient’s own T-cells. Smart CAR T-cells are able to deliver within tumours molecules that could counteract the local immune-inhibitory mechanisms."
Finding ways to produce allogeneic CAR-T therapies which could be commercialised has also been a key goal of developers. The current versions approved are autologous, meaning they are made from the patients' own cells - a fact which adds a lot of complexity due to higher strain on the logistics of harvesting, transporting, engineering, re-transporting and re-administering the cells.
The smart CAR-T technology is "not limited to allogenic therapies as autologous cells could potentially improve their activity when armed with the possibility to react to the tumour environment", however, Poirot noted.
TCRs
Several experts have been touting the potential benefits of TCR therapies over CAR-T as a better way to target solid tumours, since they target intracellular antigens rather than the surface antigens targeted by CAR-T (APMHE 55438).Still, Poirot noted: "Although TCR therapies could in theory target more tumor antigens than CAR T-cells, including tumor-specific neoantigens, CAR T-cells can also be developed against some neoantigens.
"TCR therapies have actually shown little success in the clinic and the number of reachable targets does not determine the success of a technology."
He added that the concept of smart CAR-T cells is not directly related to the type of antigen targeted and can be applied to TCR technology.
"It's about how one uses T-cells' complex genetic circuitry, not just its ability to be activated by an antigen, to enhanced antitumor immunity in a controlled fashion," he said.
Future applications
Cellectis is now set on incorporating the smart CAR-T cell technology in future clinical applications, Poirot said.However, since the programmes are as yet "undisclosed", he was unable to give potential development indications, nor dates for incoming development.
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