CD19 CAR therapy has been shown to be effective against a range of B-cell cancers, including ALL, chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphomas (NHLs), but CR rates have varied.
“The frequency of complete responses is high in ALL (80%-90%), still rather high in NHL (50%-60%) and lowest in CLL (~20%),” Dr Sadelain told Cancer Therapy Advisor. “The durability of these responses is variable — lasting months to years. Thus, both frequency and durability of responses can still be improved.”
Most CAR-induced toxicities seen among patients with ALL are now managed successfully, but more needs to be understood about the molecular mechanisms of disease relapse while receiving CAR therapy, Dr Sadelain noted.
“The toxicities seen in some patients, especially ALL patients with high tumor burden, need to be better understood so they can be not only managed, but prevented,” he said.
Cytokine release syndrome (CRS) is one potentially very serious adverse response. Symptoms include fever with respiratory and hemodynamic insufficiencies, associated with the production of cytokines. Dr Sadelain and others are studying the cellular ecology and biology of CRS.
“CRS is usually controlled by the administration of an antibody blocking the IL6 receptor and corticosteroids,” Dr Sadelain said. “To prevent CRS would be preferable, but to that would require a deeper understanding of its mechanism. We recently succeeded in establishing animal models of this syndrome and discovered that the IL6 was not produced by the CAR T cells, but by host myeloid cells. This emerging knowledge will hopefully inform novel therapeutic interventions to prevent CRS.”
Cost is another challenge for CAR therapies.
“The high cost of the first-approved CAR therapies, which is potentially prohibitive, is a disappointment for the academics who spent a lifetime forging these ‘living drugs,’ as we called them a few years back,” said Dr Sadelain. “Pricing is not in our control — this is a matter for industry and regulators to settle — but we can help address this challenge by finding biological solutions that will lower the cost of production. Engineering allogeneic T cells or generating CAR T cells in vitro from pluripotent stem cells will hopefully enable the broader use of T-cell–based medicines.”
Dr Sadelain is optimistic about the future of CAR therapy. He anticipates advances in CAR design and “higher-quality” T cells thanks to genome-editing tools like clustered regularly interspaced short palindromic repeats (CRISPR) and the identification of additional targets in a wider range of malignancies, and “off-the-shelf” CAR-T products. CAR-based strategies will also be used to treat autoimmunity, severe infections, and graft rejection, he said.
“There is no reason CAR T cells would not work against solid tumors — it is well established that T cells can be effective against solid tumors, as demonstrated by the successes of checkpoint blockade,” he said. “It will, however, take some time to identify suitable targets and adapt CAR designs to address the different challenges posed by different types of cancers.”
- Enblad G, Karlsson H, Gammelgard G, et al. A phase I/IIb trial using CD19-targeted third-generation CAR T cells for lymphoma and leukemia [published online August 10, 2018]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-18-0426
- Sadelain M. CD19 CAR T cells. Cell. 2017;171(7):1471.