Physicians want CAR-T cells to proliferate in the body, growing in number to mount a strong attack on tumors. However, they have little control over this process after administering the cells. In some cases, CAR-T cells expand rapidly and dangerously, causing potentially-fatal cytokine storms.
Cellectis’ response is to bake a molecular safeguard into the CAR-T itself. Roche’s approved antibody rituximab binds to the safety feature, leading to the elimination of the CAR-T cells.
Such mechanisms, dubbed “suicide switches,” have been discussed since the potential for CAR-T cells to drive runaway responses became clear in the early days of the development of the new class of medicines.
That led to the proliferation of ideas for safety mechanisms. Ideally, such a mechanism would be nonimmunogenic and facilitate rapid cell elimination when exposed to an approved drug.
Cells that express CD20, a protein of human origin that binds to rituximab, meet these criteria but, as Cellectis sees it, this and other comparable proposals all suffer from the same flaw: the safety switch is separate from the CAR and presented on the cell surface.
This creates the risk that cells with CAR architecture but without safety switches will emerge. These cells would be immune to rituximab, rendering the safety mechanisms ineffective.
By building its switch into the CAR architecture, Cellectis thinks its CubiCAR approach can prevent the emergence of cells that lack the safeguard. That belief is backed up by research published in Scientific Reports.
The experimental CubiCAR T cells proliferated and attacked tumors, suggesting efficacy is unaffected by the safety features. Cellectis saw the population of the cells rebound following depletion in mice with tumors, demonstrating their propensity to proliferate in the presence of disease.
One possible weakness of the approach is its use of a biologic to activate the switch. The superior biodistribution of small molecules has led some research groups to conclude they are preferable to biologics in the context of CAR-T safety switches.
The market
The CubiCAR technology is yet to make its way into Cellectis’ clinical-phase candidates, which it is developing internally and through an outlicensing deal with Arie Belldegrun’s Allogene Therapeutics.
These therapies are allogeneic, making them simpler to produce than first-generation CAR-Ts that use a patient’s own cells. Other next-generation CAR-Ts are differentiating themselves with safety and control features, although these are yet to come to market.
For now, patients are reliant on a protocol involving corticosteroids and Roche’s immunosuppressive drug tocilizumab. The protocol has improved outcomes in patients who suffer CAR-T-related immune flare ups but there remains a need for better ways to manage the strongest reactions.