As immunotherapy gains popularity, CAR-Ts forge a path of their own

The CAR-T (chimeric antigen receptor-T cell) development race has been closely followed over the past few years with key industry players achieving orphan drug or breakthrough therapy statuses for treating certain cancers. These facilitate expedited review and quicker potential FDA approval. Clinical trials reveal promising findings for patients previously unresponsive to conventional treatments. Future efforts proposed address concerns found during these trials, adding features to CAR-Ts that should increase therapeutic efficacy. In this article, IDTechEx outlines this technology and highlights ideas expected to enhance its adoption.

CAR-T production first requires T cells are collected from a patient. These are transfected, where viruses incorporate engineered genetic information (a 'construct') into the cell to produce a chimeric antigen receptor (CAR) against a specific cancer antigen. In a given construct, an antigen binding region faces the extracellular environment and is connected via transmembrane domain to an intracellular signaling domain facing the intracellular environment. Binding of the extracellular region activates the intracellular domain causing anti-cancer T cell 'effector functions'.

CAR-T therapy shows promising results in certain trials where 70-90% of leukemic patients achieved complete responses. Recently, remission was observed using CAR-Ts to treat multifocal glioblastoma in a phase I trial at City of Hope. One concern highlighted by these trials is possible 'cytokine release syndrome' (CRS), a potentially lethal side effect stemming from immune system over-activation. While little is known on its exact causes, other limitations regarding specificity and control are addressed by new construct designs.

The future of CAR-Ts may see the addition of new mechanisms to increase the therapy's efficacy, specificity, and control. For example, constructs can be engineered to work with nuclear factors to induce localized release of cytokines that enhance immune cell recruitment. These 'T cells redirected for universal cytokine killing' (TRUCKs) may have improved anticancer activity.

 

 

To enhance specificity, tandem, dual, or safety CAR constructs can be made containing binding regions against two different targets. For 'tandem' or 'dual CARs', both cancer-specific antigen binding regions must bind to activate the CAR-T. For a 'safety CAR', one construct contains an antigen binding region against cancer activating the CAR-T, and a separate construct contains a binding region for normal tissue inhibiting the CAR-T. This feature protects normal tissue from being destroyed even if it expresses low levels of a characteristically cancer-type antigen.

 

Control of CAR-Ts has been one concern, as it is desirable to end treatment if side effects are too severe. The use of a 'conditional CAR' construct has been proposed whereby CAR-Ts are only activated upon administration of another agent bringing the activating region together with the co-stimulatory region. Similarly, because CAR-Ts are "living therapies", CAR-T elimination has also been examined. Here, a 'marked CAR' constructs where CAR-Ts also express selection markers allow physicians to cease treatment by administering an antibody against the marker, targeting the CAR-Ts for degradation.

Despite an estimated 14 million new cancer cases worldwide, CAR-Ts may face obstacles for widespread implementation due to side effects with unclear etiologies like CRS. However, initial studies appear promising, particularly for patients unresponsive to traditional treatments. Indeed, chemotherapy resistance as high as 25% is reported for ovarian cancer, the 5th leading cause of cancer death in women with over 200,000 new cases per year. Proposed CAR-T designs increasing specificity and safety can be expected to address previously reported concerns, enhancing adoption of this exciting therapy.