In the same week that Kite Pharma announced positive data from a pivotal study of its lead CAR-T candidate, KTE-C19 (easier to remember- and to spell- than the non-proprietary designation axicabtagene ciloleucel) in patients with B-cell non-Hodgkin lymphoma (NHL) refractory to other treatments, a one-time leader in the CAR-T race, Juno Therapeutics, pulled the plug on its lead candidate, JCAR015.
CAR-T (chimeric antigen receptor – the “T” is for T cell) is a form of adoptive cell transfer therapy which involves collection of T-cells from the patient and genetically engineering them to express receptors specific for a protein expressed on the tumour surface. After expansion in the laboratory, the transformed cells are infused back into the patient to seek and destroy tumour cells.
CAR-T therapy first made headlines by achieving unprecedented remission rates in patients with acute lymphoblastic leukaemia (ALL), chronic lymphocytic leukaemia (CLL) and NHL where all available treatments had failed to slow disease progression. The other side of the coin was the accompanying high incidence of life-threatening adverse events arising from the massive release of cytokines (part and parcel of the anti-tumour response) and from immune-related neurotoxicity.
Juno’s JCAR015 was placed on clinical hold early in development following a death attributed to cytokine release syndrome and again twice in 2016 following five deaths from cerebral oedema during a Phase II study in ALL patients. The company initially speculated that the deaths might be related to changes in a pre-treatment regimen involving two chemotherapy drugs but the decision to halt further development suggests that JCAR015 itself is now thought be the culprit.
CAR-T candidates from Kite Pharma and Novartis have also resulted in high rates of cytokine release and neurotoxicity-related adverse events, but, so far, these have proved to be more manageable or of lesser severity than those occurring during the JCAR015 studies. No cerebral oedema occurred in the Kite Pharma pivotal study, with two treatment-related deaths probably arising from cytokine release.
Juno hope to stay in the game with an earlier stage CAR-T candidate, JCAR017, which showed a relatively low incidence of severe adverse events in a small study conducted in NHL patients, but the abandonment of JCAR015 puts Juno a long way behind Kite Pharma and Novartis, with both shooting for regulatory approval in 2017.
CAR-T treatment will probably never be a “safe” option, although adverse event management would be expected to improve with experience. If regulators can be convinced that the benefits of CAR-T therapy outweigh risk, safety is likely to be a secondary concern for individuals cursed with otherwise untreatable B-cell malignancies.
An arguably bigger challenge facing Kite Pharma, Novartis and other CAR-T contenders is whether individualised adoptive cell transfer therapies can be reliably scaled up and delivered at a cost that healthcare systems are able and willing to meet.
An arguably bigger challenge facing Kite Pharma, Novartis and other CAR-T contenders is whether individualised adoptive cell transfer therapies can be reliably scaled up and delivered at a cost that healthcare systems are able and willing to meet.
Kite Announces Positive Topline Primary Results of Axicabtagene Ciloleucel from First Pivotal CAR-T Trial in Patients with Aggressive Non-Hodgkin Lymphoma. Company press release online 28th February 2017. http://tinyurl.com/js7293j
Juno Therapeutics Reports Fourth Quarter and 2016 Financial Results. Company press release online 1st March 2017. http://tinyurl.com/hunp9uh
