CAR-T round-up: off-the-shelf challengers and avoiding the (cytokine) storm


It has been another busy period for CAR-T therapies.

As we reported in September, the first two CAR-T therapies, Novartis’ Kymriah® and Kite Pharma’s Yescarta®, were authorised for use in the European Union on 27 August 2018.  These are both autologous therapies.  Meanwhile, there is also significant market excitement surrounding the allogeneic CAR-T treatments in development (as we noted in August, some of the advantages of “off-the-shelf” allogeneic treatments, if successful, are that the significant cost and time required for individual cell manufacturing for each patient is cut and greater reproducibility should be possible).

A notable example is Allogene Therapeutics, co-founded last year by the former executives of Kite Pharma to focus on allogeneic CAR-T therapies, which achieved a record-breaking IPO last month with a $324m launch on Nasdaq. Allogene acquired a portfolio from Pfizer earlier this year of 16 pre-clinical CAR-T cell therapy agents licensed from Cellectis and Servier and the US rights to UCART19, an allogeneic CAR-T therapy candidate being developed for the treatment of CD19-expressing haematological malignancies.  UCART19 is already in phase 1 development for the treatment of relapsed/refractory ALL, and could be a competitor for Novartis’ Kymriah. Allogene also plans to take a second anti-CD19 CAR-T therapy, ALLO-501, into a clinical trial for non-Hodgkin lymphoma in the first half of next year. Allogene believes its platform will have the ability to scale production to reduce cost, with a single manufacturing run having the potential to create therapies for approximately 100 patients.

There is also an increased focus on technologies to address patient safety and reduce the risks of side effects such as cytokine release syndrome that are associated with classical CAR-Ts. Xiphos Biosciences has developed convertible CAR-Ts expressing a mutated NKG2D receptor that is inactive until it is switched on by their engineered bispecific antibody. One end of the bispecific antibody binds to the mutated NKG2D receptors on the convertible CAR-T, whilst the other end binds to the tumour-associated antigens on the target cell. This bridging causes activation of the T cell and destruction of the target cancer cell. The approach could enable Xyphos’ convertible CAR-T cells to target multiple antigens through the use of bispecific antibodies with different targets, allowing target switching and multiplexing. At the same time, there is an inbuilt safety function – the theory is that the activity of the convertible CAR-Ts can be controlled by dose titration of the bispecific antibodies, providing a means of preventing or managing adverse events such as “cytokine storms” by switching off the convertible CAR-Ts as necessary. Xyphos’ products are still in the discovery and preclinical stages, but a collaboration with the Parker Institute for Cancer Immunotherapy was announced in October, with Parker’s investment intended to move Xyphos’ products towards the clinic.

Cabaletta Bio has also developed a next-generation CAR-T product (CAAR-T) with a similar focus on reducing side effects. Cabaletta’s T cell products, which incorporate CAARs (Chimeric Auto Antibody Receptors), are designed to bind and destroy only the specific B cells that produce autoantibodies, while sparing normal B cells. Since these CAAR-Ts detect only the disease-causing B cells, they are hoped to have a substantially lower risk of serious side effects than traditional CAR-Ts, which also destroy normal B cells. Cabaletta’s foundational platform and lead asset DSG3-CAART, which targets the skin blistering B cell-mediated autoimmune disease mucosal pemphigus vulgaris, are based on early work conducted at the University of Pennsylvania (Penn) by two of the company’s co-founders. Cabaletta announced in November 2018 that it had signed an exclusive licence agreement and executed sponsored research agreements with Penn for the discovery and development of engineered T cell therapy products for B cell-mediated autoimmune disease. Cabaletta has also entered into a master services agreement with Penn that will allow it to enter into agreements to develop a first CAAR product for mucosal pemphigus vulgaris.

It will be interesting to follow the progress of these next stage technologies.