CAR-T keeps driving forward: a round-up of recent scientific and commercial developments


The pace of development in the CAR-T world, both scientific and commercial, is showing no sign of letting up. We have selected some highlights since our last review in May below.

Beginning the month with the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, June was another active month for CAR-T with several companies timing significant announcements to coincide with the meeting.

On 30 May, researchers at the University of Pennsylvania published details of a case study in which a patient treated for chronic lymphocytic leukaemia (CLL) in 2013 went into remission because of a single CAR-T cell and the cells it produced as it multiplied. Calling the case “a series of fortunate events” researchers reported that the patient has stayed cancer free for five years and still has CAR-T cells in his immune system. The treatment involved engineering the patient’s T cells to recognise a protein (CD19) present on leukaemia cells by inserting the genetic code for a CAR that recognises the protein randomly into the patient’s DNA. This approach is often limited by the extent of expansion and persistence of the CAR-T cells, however in this case researchers discovered that the sequence had inserted itself into a gene called TET2 which is a master regulator of blood cell formation and a tumour suppressor gene. The researchers think that disruption of the TET2 gene in this manner enabled the CAR-T cells to effectively expand and eradicate the patient’s leukaemia. These findings are exciting as they suggest that if the location of insertion of the CAR genetic code could be optimised, the minimum dose necessary for successful CAR-T therapy for treating CLL may be just a single cell.

The number of CAR-T clinical trials underway is rapidly growing as interest in the area increases, and the ASCO annual meeting was an opportunity for both Kite Pharma and Legend Biotech to announce commencement of new CAR-T clinical trials. Kite Pharma announced it has opened a new Phase 3 clinical trial to investigate the effectiveness of Yescarta as a second line therapy for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have failed prior chemotherapy. Yescarta is already approved for treatment of patients with relapsed or refractory aggressive B-cell non-Hodgkins lymphoma who have failed at least two prior therapeutic approaches. Separately, and at an earlier stage of clinical development, Legend Biotech announced that the FDA had authorised its development partner Janssen Biotech to commence a Phase 1b/2 clinical trial in patients with relapsed or refractory multiple myeloma to investigate safety and efficacy of LCAR-B38M, a CAR-T therapy which is part of a collaboration between Legend and Janssen to develop CAR-T therapy for multiple myeloma globally.

On June 12, French biotech Cellectis published details of its development of CubiCAR, an all-in-one CAR architecture with an embedded multifunctional tag for purification, detection and elimination of CAR-T cells. The approach was developed in collaboration with Allogene and combines the therapeutic effects of CAR-T with a safeguard. The CubiCAR CAR-T cells were effectively destroyed by using the antibody rituximab (a medication which is usually used to treat certain autoimmune diseases and types of cancer). This “safety switch” could enable doctors to eliminate the CAR-T cells if the treatment triggers dangerous immune reactions (a common side effect with CAR-T therapy). Adding a safety switch is not a new development but other CAR-T safety switches have been separate from the CAR itself which, according to the Cellectis researchers, can result in a mismatch between the two. Cellectis and Allogene will now evaluate the approach across Allogene’s extensive allogenic CAR-T pipeline. Allogenic CAR-T cells are made from T-cells from healthy donors and it’s hoped that this “off the shelf” approach could address the manufacturing challenges presented by autologous therapies and therefore result in lower manufacturing complexity and costs.

Also focussing on CAR-T switches is AbbVie. On June 25, AbbVie announced a new collaboration with Calibr (a San Diego based non-profit translational research institute) under which AbbVie will gain exclusive access to Calibr’s switchable CAR-T platform for up to four years with the option to acquire an exclusive licence to the platform. Calibr’s platform is designed to enhance safety, versatility and efficacy through a modular “switchable” CAR-T cell that uses antibody-based switch molecules to control the activation and antigen specificity of CAR-T cells. The two organisations will work together to develop T-cell therapies directed to solid tumour targets identified by AbbVie. Solid tumours have historically proved challenging to treat with CAR-T cell therapy so the new collaboration is a positive development.

From a commercial perspective, perhaps the biggest CAR-T news came at the end of the month when, on 29 June, the EMA’s Committee for Medicinal Products for Human Use (CHMP) recommended the first two marketing authorisations for CAR-T therapies in the EU. Novartis’ Kymriah and Kite Pharma’s Yescarta are both already authorised in the US and the EMA’s recommendation is a major step towards approval in the EU. CHMP recommended Kymriah for the treatment of refractory or relapsed B-cell acute lymphoblastic leukaemia (ALL) and for relapsed or refractory DLBCL and recommended Yescarta for the treatment of relapsed or refractory DLBCL and primary mediastinal large B-cell lymphoma (PMBCL). The positive CHMP opinions will now be sent to the European Commission which will take the decision on granting EU-wide marketing authorisations. Assuming the marketing authorisations are granted, individual member states will then need to wrestle with difficult decisions on pricing and reimbursement models. As we reported previously, in the UK Kymriah and Yescarta have already been referred to NICE for an assessment of their clinical and cost effectiveness. Considering the high list prices in the US ($475,000 and $373,000 respectively) and pressures on the NHS from rising drug prices, it will be interesting to see how pricing issues for these big ticket therapies will be resolved and whether they will be made available to NHS patients in the UK.

May and June were also busy months for biotech fundraising with favourable market conditions resulting in a boom in biotech IPOs. CAR-T companies took advantage with a NASDAQ IPO for Autolus and Celyad also raising additional funds through a global offering, each to support the continued clinical development of their lead assets.

In June, Autolus was listed on NASDAQ raising approximately $150 million. Autolus, based in London, is developing next-generation programmed T cell therapies and leads the UK CAR-T market. Bristows advised UCL Business on Autolus’ spin-out from University College London and initial £30 million equity financing in 2015 and since then Autolus has undergone rapid growth. Autolus plans to use the bulk of the funds raised to complete proof-of-concept phases of four of its Phase 1/2 clinical trials in hematological cancer indications and to advance three of these product candidates through later phases of clinical development and, potentially, registration. The funds will also be used for manufacturing activities and to support non-clinical development to IND filing of its earlier stage hematological programs and its product candidates targeting solid tumour indications.

In May, Celyad, which currently has a dual listing on the Euronext and NASDAQ, raised approximately $54.4 million through a global offering. Celyad intends to use the funds to advance the development of its lead drug product candidate CYAD-01 (which contains autologous T cells transduced with a CAR based on the NKG2D receptor) through Phase 1 and potentially Phase 2 clinical development as a treatment for refractory cancers. Celyad will also use some of the funds to advance additional CAR-T cell therapy drug product candidates for the treatment of hematologic and solid tumours.