Checkpoints and CAR-Ts

Checkpoint inhibitors inhibit the mechanisms by which tumour cells inhibit T-cell activity (a key component of the normal cellular immune response) and overcome the immune system. The success of monoclonal antibodies targeting these checkpoints, including PD-1 (for example, nivolumab and pembrolizumab), PD-L1 (for example, atezolumab) and CTLA-4 (for example, ipilimumab) in a range of cancers is obvious.

The past five years have also seen great progress in the development and application of cell engineering in an effort to personalise cancer treatment. Say hello to chimeric antigen receptor T cell (CAR-T) therapy – a combination of immuno-, cell- and gene therapy, and the next big thing in oncology.

The basis of CAR-T is the use of engineered T-cells that express a chimeric antigen receptor on their cell membrane. This receptor acts with an external target-binding domain that is designed to recognise a specific tumour antigen, and an internal activation domain, which is responsible for activating the T-cell when the CAR-T binds its target. T-cells are extracted from the patient and genetically modified and expanded in vitro before reinfusion.

There has been rapid and extensive development in CAR-T therapy, and clinical trials have demonstrated impressive remission rates. The race to bring the first CAR-T drug to market has intensified recently. In March 2017, a US biologics licence was filed for tisagenlecleucel-T (CTL019) for the treatment of relapsed and refractory paediatric and young adult patients with B-cell acute lymphoblastic leukaemia. An EMA filing is expected later in 2017. Phase II results presented at the 2016 American Society of Haematology meeting showed that 82% (41 of 50) of patients infused with CTL019 achieved complete remission or complete remission with incomplete blood count recovery at three months post-infusion.¹

Targeting solid tumours is a big challenge in the field of immuno-oncology. Low T-cell infiltration and an immunosuppressive environment prevent the immune system from effectively attacking these tumours and some think that the way to go for CAR-T is combination therapies combining checkpoint inhibitors with CAR-T cells. Data presented at the AACR 2017 from a Phase I dose escalation trial of T4 CAR-T therapy in head and neck squamous cell carcinoma showed a disease control rate of 44%, and that all patients in one cohort achieved stable disease. Treatment-related adverse events were found to be grade 2 or lower, with no dose-limiting toxicities observed.²

Whether or not CAR-T will represent future standard of care for previously unresponsive haematological cancers is to be revealed, but there is plenty going on in the CAR-T space in the meantime. To this end, the Summer issue of Hospital Pharmacy Europe will include an article by Dr Tiene Bauters, HPE editorial board member, on this hot topic.

References
1. Grupp S et al. Analysis of a global registration trial of the efficacy and safety of CTL019 in pediatric and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL). https://ash.confex.com/ash/2016/webprogram/Paper90831.html (accessed May 2017).
2. Papa S et al. T4 immunotherapy of head and neck squamous cell carcinoma using pan-ErbB targeted CAR T-cells. In: Proceedings from the 2017 AACR Annual Meeting; 1–5 April 2017; Washington, DC: Abstract CT118.