CARs on a highway with roadblocks

On August 30^th 2017, the US Food and Drug Administration (FDA) approved KYMRIAH™ (tisagenlecleucel, CTL019) for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse (source https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm).^1–3 KYMRIAH™ consists of autologous cytotoxic T lymphocytes (CTLs) genetically engineered to express a CD19-specific chimeric antigen receptor (CAR), which are commonly referred to as CAR-T cells.^4–6 CARs are fusion proteins that comprise (1) an extracellular single-chain variable fragment (scFV), which is responsible for antigen specificity; (2) a transmembrane domain; and (3) one or more intracellular domains with co-stimulatory functions, which are derived from CD247 (best known as CD3ζ) and - potentially - other receptors involved in T cell activation.^5–7 Specifically, KYMRIAH™ harnesses the co-stimulatory domains of CD3ζ and TNF receptor superfamily member 9 (TNFRSF9, best known as 4-1BB or CD137).^5,6,8 CAR expression endows CTLs with the ability to recognize and kill cells expressing a specific antigen independent of MHC Class I presentation.^9,10

The safety and efficacy of KYMRIAH™ were demonstrated by the ELIANA study, a multicenter clinical trial involving 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL (NCT02435849).^11,12 Three months after a single dose of KYMRIAH™, 83% of the patients achieved complete remission. Grade 3 neurological events were documented in 15% of the patients, while 47% of them experienced grade 3 or 4 cytokine release syndrome (CRS). At odds with other clinical trials testing CAR T-cells in cancer patients,^13,14 no deaths and no incidents of cerebral edema were recorded (source https://www.novartis.com/news/media-releases/novartis-pivotal-ctl019-6-month-follow-data-show-durable-remission-rates). In consideration of the risk for CRS and neurological events, KYMRIAH™ is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). This involves the prescription and delivery of KYMRIAH™ by staff trained to recognize and manage CRS and neurological events, in the context of certified health care centers with verified availability of tocilizumab (an antagonist of the receptor for interleukin-6 commonly used to manage CRS) (source https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm). Importantly, KYMRIAH™ is not a cancer-specific agent sensu stricto. Indeed, KYMRIAH™ targets all CD19 cells, including healthy plasmocytes and other components of the B-cell lineage, which results in profound and protracted B-cell aplasia.^15,16 Intravenous immunoglobulin replacement is commonly used to prevent infection in patients receiving KYMRIAH™.^15,16

The decision of the US FDA to license KYMRIAH™ is historical, as KYMRIAH™ represents the first form of gene therapy approved for use in humans in the US.^1–3 In China, another form of gene therapy, namely, a recombinant oncolytic adenovirus delivering tumor protein p53 (TP53, best known as p53) has been approved for the treatment of head and neck cancer as early as in 2006.^17–19 Several other regulatory agencies are expected to follow up on the FDA decision and license KYMRIAH™ in the respective areas of competence. That said, the approval of KYMRIAH™ - which will be provided at the cost of 475,000 USD - has sparked an intense ethical debate in the field. The National Cancer Institute estimates that approximately 3,350 patients aged 20 and younger are diagnosed with ALL each year, 80–85% of which suffer from the B-cell variant (source http://seer.cancer.gov/statfacts/html/alyl.html). A considerable proportion of these pediatric patients (40-50%), however, gets completely cured by conventional treatments. Moreover, a majority of patients who relapse do so only several years later as they potentially become older than 25 (and hence ineligible to KYMRIAH™).^20,21 Thus, the predicted number of individuals potentially benefiting from KYMRIAH™ treatment (at an 85% overall response rate) seems remarkably low. It is tempting to compare KYMRIAH™ to an expensive CAR running on a highway with several roadblocks. It will be important to remove these obstacles to maximize the benefits of KYMRIAH™ for cancer patients. Beyond any doubt, CAR-T cells represent an extraordinary scientific achievement, and it will be interesting to see where they will drive modern tumor immunotherapy over the next few years.

Acknowledgments

LG is supported by an intramural startup from the Department of Radiation Oncology of Weill Cornell Medical College (New York, US), and by Sotio a.c. (Prague, Czech Republic).