The Murky Waters of CAR-T
David Harris

The Murky Waters of CAR-T

New approaches to treating cancer have shown great promise, but they also come with serious risks that give us cause for concern. 

There is an urgent need to develop new therapies for the treatment of cancer. Leading the charge are those that harness the immune system’s unique ability to identify and destroy tumor cells. One such immunotherapy is chimeric antigen receptor (CAR) T cells, which involves infusing patients with genetically modified T cells. CAR T cells are produced in GMP specialized facilities and possess an enhanced ability to recognize and kill tumor cells. CAR T therapies have proven to be highly effective in certain hematological cancers and the first FDA-approved treatments are anticipated in 2017, with companies including KITE pharmaceuticals and Novartis leading the way. However, there is a delicate balance required to achieve optimal CAR T cell activation without producing excessive toxicity. Recently Juno therapeutics announced it would discontinue its JCAR015 CAR T cell program (known as Rocket) after the death of 5 patients treated with a combination of chemotherapy and CD19-directed CAR T. The patients, all of whom had an advanced form of B cell acute lymphocytic leukemia (ALL), died after developing cerebral edema, a condition which causes swelling of the brain. While it is still not clear whether the CAR T cells caused the deaths in any of these cases, the FDA recently announced plans to establish a database to evaluate CAR T-cell safety and identified specific safety-related factors associated with the conduct of clinical trials.

The most serious side effect associated with CAR T cell therapy is cytokine release syndrome (CRS), a reversible yet potentially life-threatening condition mediated by the release of inflammatory cytokines following immune cell activation and tumor cell lysis. CRS appears to be exacerbated in patients with a high tumor load and impacted by the dose and timing of CAR T infusions. Fortunately, the effects of CRS can be alleviated by the use of tocilizumab (anti-IL-6R Ab) and steroids. Another side effect associated with CAR T-cell therapies that specifically target the B cell-specific marker CD19 for the treatment of blood cancers—the most popular approach so far—is B-cell aplasia, or loss of B cells, rendering patients susceptible to infection. Innovative approaches to CAR T cell design are being developed to reduce the possibility of undesirable side effects and improve temporal control of CAR T-cell activation in vivo.  A number of different suicide genes or safety switches have been incorporated into CAR design and are being evaluated in clinical trials.

While CAR T therapy has been highly successful for treating patients with blood cancers, treatment options for solid tumors are limited. The lack of tumor cell specific targets, the requirement for homing of CAR T-cells to specific disease sites, the dense matrix of stromal tissue that limits immune cell infiltration and the immunosuppressive tumor microenvironment (TME) remain significant obstacles. Meanwhile, a variety of strategies are being developed to enhance the potency of CAR T cells. These include engineering CARs to co-express immunomodulatory cytokines, and chemokine receptors, which are required for efficient homing of cells to the tumor site. The use of CRISPR/Cas9 gene editing techniques to selectively delete negatively regulating genes, such as PD-1 is also being evaluated. This approach is also being utilized to create CAR T-cells lacking an endogenous T-cell receptor, reducing the likelihood of graft-versus-host-disease, and, offering the potential for “off-the-shelf” universal CAR therapies.

The culmination of many years of research has seen the development of the first wave of CAR T-cell therapies. The next decade is likely to see major advances in CAR T-cell design, manufacturing processes and ultimately it is hoped, improved safety and clinical outcomes for increased numbers of patients in a broader spectrum of cancers. Pre-clinical efficacy and safety testing will be at the forefront of this effort.

(This blog was adapted from an earlier article David wrote for The Scientist.)