Chimeric Antigen Receptor (CAR) T cells are the protagonist in the evolving story of adoptive immunotherapy research. The villain in the story is almost always cancer, but the ability of CAR T cells to eliminate specific cell populations means they may hold broader therapeutic promise. Genetically modifying T cells to express effective, specific chimeric receptors enables them to recognize and destroy disease-causing cells. Where CAR designers are able to identify reliable molecular targets, CAR T cells may be a powerful tool with which to go after those markers.

Despite the potential, picking suitable antigens for complex or partly-understood diseases is challenging. Nevertheless, clinical efficacy has been observed in autoimmune diseases such as systemic lupus erythematosus (SLE) and idiopathic inflammatory myopathy (IIM). Trials exploring applying CAR T cells for diseases like SLE and IIM have shown signs of clinical efficacy1,2, opening new avenues for treatment possibilities.

Beyond autoimmune diseases, CAR T cells exhibit promise in addressing some non-cancerous conditions like severe asthma, type 1 diabetes, and cardiac fibrosis. One commonality among these conditions is the accumulation of excessive connective tissue, also known as fibrosis. This connective tissue build-up is a pathological process observed in various medical conditions. Targeting fibrosis holds implications not only for cardiac conditions but also for diseases like liver disease, chronic kidney disease, and various lung conditions.

Senescence, a hallmark of aging, is implicated in various chronic diseases. CAR T cells targeting senescent cells offer a potential therapeutic strategy, but these target cells may not share any single molecular marker. This may not be entirely bad, as working with target molecules which only some senescent cells share might lend hypothetical therapies greater specificity.

As with any new therapy, safety considerations must come first. Cytokine release syndrome (CRS), in which the infused CAR T cells become activated and rapidly release a large amount of cytokines, is a known CAR-T therapy risk. Symptoms can be severe, including fever, fatigue, nausea, difficulty breathing, and low blood pressure. CRS and other serious side-effects are why CAR-T cells that remain in a patient’s body only temporarily are appealing, lest negative health impacts become a long-term danger.

Critical questions surrounding therapeutic index, optimal dosing, transient therapeutic activity, and the impact of CAR T cells on regenerative processes in tissues will influence the trajectory of the technology. Though the path from theory to practice must be treaded carefully, the potential of CAR T cell therapies to impact the treatment and prognosis for myriad diseases is broad. Numerous emerging technologies, such as new gene editing approaches and artificial intelligence systems may influence the viability of these therapies, unlocking heretofore unseen treatment options.

 

References

  1. Mougiakakos, D., et al. (2021). CD19-targeted CAR T cells in refractory systemic lupus erythematosus. New England Journal of Medicine, 385(6), 567–569.
  2. Müller, F., et al. (2023). CD19-targeted CAR T cells in refractory antisynthetase syndrome. The Lancet, 401(9876), 815–818.
  3. Baker, D. J., Arany, Z., Baur, J. A., Epstein, J. A., & June, C. H. (2023). CAR T therapy beyond cancer: the evolution of a living drug. Nature, 619, doi.org/10.1038/s41586-023-06243-w