04 April 2019

CAR-T therapy in the personalised medicine sector

Chimeric antigen receptors (CARs) are artificial proteins that are used to redirect immune system cells to attack targets that are normally invisible to them, such as cancer cells. CARs are typically made by fusing the antigen binding domain of an antibody specific to a target of interest to the transmembrane and intracellular signalling domains of receptors normally found on the surface of immune cells. When a T-cell or other immune cell expressing the CAR encounters the target, the CAR binds it and stimulates the cell to attack.

Interest in CARs has rocketed following reports a few years ago that patients with refractory blood cancers were achieving complete remission after CAR cell therapy. Even a single dose of CAR cells can be highly effective, and for a very long period of time, because unlike conventional drugs, CAR cells are able to live on and patrol inside the body, much like normal immune cells. Due to its impressive effects in treating blood cancers, an anti-CD19 CAR-T therapy called Kymriah (tisagenlecleucel) became, in 2017, the first genetically modified cell therapy approved by the FDA. The Kymriah approval was shortly followed by FDA approval of a second anti-CD19 CAR-T therapy called Yescarta (axicabtagene ciloleucel). Both drugs gained approval in Europe in 2018, and it is likely that more CAR cell therapies will be approved, particularly in relation to blood cancers.

Current Challenges
One of the main challenges of CAR cell therapy is manufacture. ‘Foreign’ cells are normally rejected by the host immune system, so it is important to manufacture CAR cells that are a suitable match to the recipient. In the case of Kymriah and Yescarta, this is achieved by using the patient’s own T-cells to engineer the CAR cell therapy they are going to receive. Both drugs are thus a form of ‘personalised medicine’, the manufacture of which for patients in different countries presents a logistical challenge that increases the cost of therapy. In the US, for example, the list price of Yescarta is reported to be $373,000.

Patent Landscape
The growing interest in CAR-T therapy has been accompanied by massive growth in the number of CAR-related patent filings, see figure 1.

The biggest PCT filers by applicant name include Cellectis, Juno Therapeutics, Novartis, the University of Pennsylvania, and the US Department of Health and Human Services. Juno, which has been acquired by Celgene, has a candidate anti-CD19 CAR-T therapy called JCAR017, and Celgene has a candidate anti-BCMA CAR-T therapy called bb2121 (developed in collaboration with Bluebird Bio), both of which are in clinical testing against blood cancers. Novartis owns the Kymriah product, which it developed in collaboration with The University of Pennsylvania. Other significant players include Kite Pharma, now part of Gilead, which owns the Yescarta product. Both Kite and Novartis also have candidate anti-BCMA CAR-T therapies that are undergoing clinical evaluation.

The patentability of CAR cases is often based on aspects of CAR design. The choice of target antigen or binding domain may give rise to patentability, much like in conventional antibody cases. Other design aspects include the choice or combination of transmembrane and intracellular signalling domains, and the format of the CAR, which may be presented e.g, as a single molecule or as a split structure in which the target binding and intracellular signalling functions are partitioned into separate molecules that can associate.

Patent protection can also be sought for aspects of CAR cell manufacture. For example, Gilead highlights Kite’s European and US manufacturing patent applications as relevant to its Yescarta product. Particular medical applications of CAR cells may also form the basis of patentability.

With an increasingly crowded patent landscape comes litigation. Kite has already tried – unsuccessfully – to invalidate a US patent relating to Sloan-Kettering’s CAR technology, and further disputes seem inevitable.

The Future
It is likely that approval will soon be given for the treatment of further forms of blood cancer using CAR cell therapy, and it is hoped that this new class of drugs will also prove effective at treating solid tumours. Much research effort is also going into the development of ‘universal’ CAR cells – an off-the-shelf product that does not require personalised manufacturing. Cellectis and Celyad both have universal CAR-T therapy candidates in clinical testing.

This article was first published in the March 2019 edition of Intellectual Property Magazine.