As Kite ploughs on with its mission to submit the first ever CAR-T project to the US FDA it is keeping its foot firmly on the early development pedal, yesterday unveiling a three-pronged strategy that blatantly challenges its key competitors.
These efforts, including design of allogeneic cells and therapies with on/off switches, are the result of work that has quietly gone on in the background over the past year or so (see table below). Kite yesterday also revealed the first fruits of its collaboration with Amgen, though for now investors will undoubtedly focus on its filing plans for KTE-C19.
Despite the short duration of follow-up in the interim data from the pivotal Zuma-1 trial, at Kite’s analyst day yesterday the group repeated its plan to file KTE-C19 before the end of this year (Kite flies, but durability remains the key unknown, September 27, 2016).
This, it hinted, might come as a rolling submission, capable of incorporating additional Zuma-1 data as these emerge. Many pricing comparators were presented, from $180,000 for two cycles of Blincyto to $930,000 for an allogeneic stem cell transplant, but ultimately the cost of KTE-C19 would be revealed at launch, said Shawn Tomasello, Kite’s chief commercial officer.
In the meantime the company shed light on early-stage projects that it had until now kept under wraps, including the first asset arising from its 2015 deal with Amgen – KITE-796, a CAR against the CLL-1 antigen present on myeloid cells in AML.
This incorporates an on/off switch based on Kite’s collaboration with Cell Design Labs and Dr Wendell Lim's lab at the University of California, San Francisco. Thus it is a clear challenge to Bellicum, and in fact the switch bears some similarity to Bellicum’s GoCAR-T technology, except it uses gibberelic acid rather than rimiducid for activation.
Ability to switch this CAR on and off is particularly important, said Kite’s R&D head, David Chang, as the long-term absence of myeloid cells that KITE-796 would produce would be unacceptable – in contract to B-cell aplasia, which anti-CD19 CARs cause, but which can be overcome by administration of intravenous immunoglobulin.
A second addition to the pipeline was KITE-585, targeting BCMA, which Mr Chang accepted was a busy space – Novartis, Juno and Bluebird/Celgene are all working on anti-BCMA CARs (Juno throws down the multiple myeloma gauntlet to Bluebird, August 8, 2016). Kite and Bluebird have CRADAs with the NCI’s Dr James Kochenderfer, but KITE-585 is unrelated to either.
Both KITE-796 and KITE-585 use fully human binding regions – a fast-emerging strategy to avoid T-cell rejection by the host immune system. Kite said phase I data on a fully human anti-CD19 CAR, the subject of another NCI licence, would be presented this year, and the ASH meeting looks like a possible venue.
|Selection of Kite's early-stage projects revealed at Oct 18 analyst day|
|huCD19||CAR-T vs CD19||Phase I (NCT02659943) data possible 2016||Fully human ScFv; licence from NCI/Dr James Kochenderfer Jul 2016|
|KITE-718||TCR vs MAGE A3/A6||IND for NSCLC & bladder cancer in 2016||Class II TCR, but will use CD4+ & CD8+ T cells; licence from NCI Oct 2015|
|KITE-585||CAR-T vs BCMA||IND for multiple myeloma in 2017||Fully human ScFv; internal Kite project via Jun 2015 Adimab deal|
|KITE-796||CAR-T vs CLL-1||IND for AML in 2018||First target from Amgen deal; fully human; on/off switch from Cell Design Labs|
|KITE-439||TCR vs HPV-16 E7||IND for cervical & H&N cancer in 2018||Kite has separate NCI CRADA for HPV-16 E7 antigen as of Jun 2016|
Meanwhile, Juno and Cellectis were directly challenged in solid tumours and allogeneic, or off-the-shelf, CARs respectively, though for now Kite trails these rivals and has revealed no specific assets yet.
Kite aims to target solid tumours with enhanced T cells – Juno calls these “armored” CARs – and Kite’s take involves additional expression of transmembrane immunomodulatory proteins.
The basis of its allogeneic work is technology licensed from UCLA earlier this year to gain access to a single, renewable cell source that is highly susceptible to gene engineering. These pluripotent cells will undergo multiple gene-editing steps to eliminate the risk of graft-versus-host disease and graft rejection, as well as introducing an invariable MHC region to overcome rejection by natural killer cells.
And Kite revealed a big push into engineered T-cell receptor (TCR) therapeutics, with a focus on KITE-718 and KITE-439, its first two projects in this area.
A major drawback of developing TCRs is that they must be matched to a person’s HLA haplotype, and most groups are focusing on the HLA-A2 type, present in 40% of Caucasians. Kite yesterday said it was working additionally to cover A1, A3, A11 and A24 haplotypes, accounting for up to 81% of the US population.
However, it remains wedded to naturally occurring TCRs – in stark contrast to Adaptimmune, the leading TCR player, which insists that only affinity-optimised TCRs are capable of recognising and/or eliminating tumour antigens.
Like with allogeneic CARs, on/off switches and next-generation constructs, it will take real clinical data to determine which approach is best here, and given the amount of academic data sharing that has gone on it might be impossible to avoid more litigation. For now, however, Kite has made it clear that it is not resting on its laurels.
EP Vantage has previously published a broad overview of the current opportunities and risks in the CAR-T space. A free copy of the report is available by download.