Ash 2020 cell therapy preview – the battle for recognition

With many of the usual targets on display Fate, Celyad, Allovir and others look to maintain momentum.

Conferences

The Ash conference is usually a mecca for cell therapy followers. Its 2020 instalment features plenty of Car-T and Car-NK presentations, though investors might rue the fact that these risk being overshadowed by antibody modalities.

Clinical data to watch on adoptive cell therapies include those on Fate’s allogeneic Car-NK project FT596 and Celyad’s Cyad-02, a Car using short hairpin RNA technology. Meanwhile, Allovir will want to justify enthusiasm for its recent flotation, while BCMA-targeted multiple myeloma assets fight to stand out from the crowd.

The most advanced anti-BCMA Car-T therapy is Bristol Myers Squibb/Bluebird’s ide-cel, which faces a March 27, 2021 US FDA action date despite an earlier refuse-to-file letter. The asset to watch, however, is Johnson & Johnson/Legend Biotech’s cilta-cel, whose Cartitude-1 study is showing a remarkable 95% remission rate, according to the Ash abstract.

Not only that, but Bristol/Bluebird’s follow-up, bb21217, looks disappointing, Ash data suggest. A US NCI group including Dr James Kochenderfer, who has also worked on ide-cel, is separately presenting clinical results on a new approach, FHVH-BCMA-T, which uses a heavy chain antibody fragment rather than the normal scFv.

With most abstracts citing relatively early data cut-offs, updates at Ash itself will be keenly awaited. Among these Poseida will no doubt field questions if responses to P-BCMA-101 continue to look better at low than at high doses.

Long time coming

First clinical data on FT596, Fate’s first Car-modified NK cell approach, have been a long time coming: the FDA signed off the IND in September 2019, but the trial did not start until April this year.

Even so there might be disappointment as the Ash abstract details only a single case study, in a lymphoma subject who went into partial response after a single dose. Expectations for FT596 are high given the 73% response rate cited for an unrelated anti-CD19 Car-NK project run by MD Anderson’s Dr Katy Rezvani.

There might be more on FT596 at Ash, but some analysts are reining in expectations of meaningful data before next year. In the unmodified NK cell sphere, meanwhile, FC21-NK data could support Sanofi’s decision to buy Kiadis for $358m this month.

Selected Ash 2020 cell therapy presentations
Project Type Company Abstract detail Abstract
Leukaemia/lymphoma
Auto1 Anti-CD19 Car-T Autolus Adult ALL, 13 May 2020 cut: 16/19 MRD-ve CR, 4 relapses 160
Auto3 Anti-CD19/CD22 Car-T Autolus Alexander study, Keytruda combo in lymphoma, 13 Jul 2020 cut 600
GC022C Anti-CD19/CD22 Car-T Gracell 24-hr manufacturing process 159
MB-CART2019.1 Anti-CD19/CD20 Car-T Miltenyi Biotec Lymphoma, ORR 75%, 5/12 CR 404
UCART22 Anti-CD22 Car-T* Cellectis Adult ALL, 1 Jul 2020 cut: 2/5 CR 163
Multiple myeloma
Ciltacabtagene autoleucel Anti-BCMA Car-T J&J (ex Legend) Cartitude-1 study, 20 May cut: 95% ORR, mDoR not reached 177
bb21217 Anti-BCMA Car-T Bluebird/BMS 1 Mar 2020 cut: 55% ORR, 8/44 CR 130
CT053 Anti-BCMA Car-T Carsgen 30 Jun 2020 cut: 88% ORR, 19/24 CR 132
P-BCMA-101 Anti-BCMA Car-T Poseida 30 Jun 2020 cut: 57% ORR (n=34) 134
FHVH-BCMA-T Anti-BCMA Car-T (heavy chain) NCI 90% ORR (n=20) 498
ALLO-715 Anti-BCMA Car-T* Allogene 8 Jul 2020 cut: 33% ORR (n=15), one death due to infection 129
NK cells
FC21-NK NK cells* Kiadis (Sanofi) AML, 14 Apr 2020 cut: 8/12 CR, mOS 17.6mth 68
GDA-201 NK cells* Gamida Cell Lymphoma, 73% ORR, 10/15 CR 63
FT596 Anti-CD19 Car-NK* Fate Case report only 2356
NKX101 NKG2D Car-NK* Nkarta No clinical data 1040
Others
Cyad-02 NKG2D Car-T (shRNA) Celyad Aug 2020 cut: 6 AML/MDS pts, no efficacy data 990
UCART123 Anti-CD123 Car-T* Cellectis Ameli-01 AML study, no clinical data 1039
ALVR109 Anti-Covid-19 T cells* Allovir No clinical data 612
*Allogeneic project; remainder autologous.

Celyad has been working on Car-T cells targeting NKG2D ligands for some time, but Ash will feature the first clinical data on Cyad-02, a construct that aims to improve on an earlier iteration, Cyad-01.

One problem with Cyad-01 is Car-T fratricide, caused by T cells' own transient expression of NKG2D ligands; Cyad-02 aims to silence these ligands using shRNA technology. The Ash abstract says Cyad-02 showed threefold better expansion than Cyad-01, and promises to deliver “preliminary clinical activity data”.

While Cyad-02 is an autologous therapy, Celyad is separately developing allogeneic Cars. One of its allogeneic approaches also uses shRNA for gene silencing, so the Cyad-02 data could provide proof of concept beyond the use in the abstract.

Allogeneic therapies will of course be aired extensively at Ash, and a presidential symposium on 8 December will see UCLA’s Dr Gay Crooks discussing universal cell sources. Dr Crooks’s pluripotent stem cell generation technology was licensed to Kite before that company was bought by Gilead.

Other presentations of general interest include a paper suggesting that CD5 knock-out enhances Car-T cell activity, and another claiming that aberrations in CD58 curtail the efficacy of Yescarta. The latter is also being highlighted at a December 5 press briefing, along with preclinical data on Allovir’s anti-Covid-19 T-cell therapy ALVR109.

Investors in Allovir, whose stock has doubled since the group raised $318m in a July IPO, will pay close attention.

Ash 2020 will take place in virtual format on December 5-8.

Vantage analysis previously summarised upcoming Ash presentations that resulted in early share price moves, cancer-focused abstracts outside cell therapy, and those in non-oncology indications.

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