ASCO: Momentum gathers behind next wave of CAR-T therapies

This year’s virtual ASCO congress included dozens of presentations on CAR-T therapies, including an update from one of the two currently approved therapies – Gilead Sciences’ Yescarta – and new data on others coming through the pipeline.

Yescarta (axicabtagene ciloleucel) achieved a 93% overall response rate (ORR) in patients with relapsed or refractory indolent (slow growing) non-Hodgkin’s lymphoma (NHL), with 80% of them classed as having a complete response (CR) to the therapy.

Gilead’s Kite subsidiary said it plans to file for approval of the CD19-targeting CAR-T later this year on the new data from the ZUMA-5 trial, which included patients with two forms of NHL – follicular lymphoma (FL) and marginal zone lymphoma (MZL) – who had been treated with at least two prior lines of therapy

Yescarta is already used to treat large B-cell lymphoma and – if approved for the new indication - would give the CAR-T a niche free of competition from Novartis’ rival CD19 CAR-T Kymriah (tisagenlecleucel).

Yescarta was the approved in 2017 and since then has gown fairly slowly to reach $456m last year, while Kymriah – used to treat diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukaemia (ALL) but plagued with manufacturing issues affecting supply – brought in $278m.

BCMA battleground

A battle is also emerging among CAR-Ts targeting BCMA, an antigen that is found on multiple myeloma cells, and the takeaway message from ASCO seemed to be a big hit for Johnson & Johnson, whose CAR-T is trailing a Bristol-Myers Squibb therapy that is nevertheless closest to market.

BMS reported new data from the KarMMa trial of its ide-cel (idecabtagene vicleucel) candidate that backed up the durability of responses with its therapy, with an overall response rate (ORR) of 73% -including 33% complete responses – among heavily pre-treated myeloma patients.

The new data suggests a deepening response compared to an earlier readout last year, and comes as BMS is working on answering questions raised by the FDA when it rejected the company’s initial filing for ide-cel on the grounds that it lacked information on manufacturing.

BMS has said it intends to refile in July, but the delay could shorten the time before it faces competition from J&J’s upstart JNJ-4528, which is starting to steal its thunder with some impressive response rate numbers.

Updated results from the phase 1/2 CARTITUDE-1 study presented at ASCO showed that a 100% overall ORR in heavily pre-treated multiple myeloma patients reported last December had been maintained, with the CR rate rising from 66% to 86%, suggesting responses get better over time.

JNJ-4528 is in phase 3 testing, but J&J will be looking to file as early as possible to shorten BMS’ lead, and could potentially do so if the phase 2 stage of CARTITUDE-1 follows the same pattern.

BMS also presented results at ASCO with a follow-up to ide-cel, orva-cel (orvacabtagene autoleucel), revealing a 92% ORR and 35% CR rate among 62 myeloma patients.

Off-the-shelf CAR-T

While current CAR-Ts require cells to be harvested from patients, modified and grown in the lab, ASCO also saw updates from companies developing allogeneic or ‘off-the-shelf’ CAR-Ts based on standardised cells that proponents say could be administered more quickly and cheaply.

Among these, Allogene and Servier’s CD19-targeting ALLO-501, showed a 63% ORR rate out of 19 evaluable patients with relapsed or refractory non-Hodgkin’s lymphoma (NHL) in the phase 1 ALPHA trial. That included a CR in seven of the patients (36%), with PRs seen in another five (26%), with nine responders having no relapse over a four-month follow-up period.

In a subgroup of patients given a high dose of Allogene’s companion anti-CD52 antibody ALLO-647 – which is given to deplete patients’ own T cells to allow the CAR-Ts to take hold – the CR rate rose to 50%. Moreover, one patient who progressed after a PR was re-treated with the CAR-T and subsequently went on to go into remission.

Safety seemed to be pretty good, with only one case of cytokine-release syndrome and no evidence of graft-versus-host disease (GvHD) that can occur when the donated cells mount an immune response against the patient’s own tissues.

If approved, the off-the-shelf CAR-T would be a rival to marketed autologous therapies from Gilead and Novartis.

Meanwhile, Belgium’s Celyad gave a glimpse of the potential of CAR-T in solid tumours, a much tougher nut to crack than blood cancers, with its allogeneic CYAD-101 candidate in   relapsed/refractory metastatic colorectal cancer patients.

Two patients achieved a confirmed partial response and nine patients achieved stable disease, leading to a disease control rate of 73% with the therapy in the phase 1 alloSHRINK trial in 15 subjects, said Celyad.

The biotech now plans to expand the trial with additional patients later this year.