A curious tie-up between AstraZeneca and China’s AbelZeta has yielded what looks like a promising new Car-T project. C-CAR031 has shown a 50% confirmed response rate in its first-in-human study in the tough setting of heavily pretreated liver cancer, with no dose-limiting toxicities, its just unveiled ASCO abstract has shown.
C-CAR031 targets glypican-3 (GPC3), a protein said to be expressed in hepatocellular carcinoma, and is also “armoured” with TGFβRIIDN. It comprises the same construct as Astra’s own AZD5851, and both assets are cross-licensed under a deal struck last December, shortly after AbelZeta rebranded away from its former name of Cellular Biomedicine Group.
AZD5851 also features at ASCO, but only in a trials-in-progress poster, as does Sotio’s lead cell therapy candidate, the anti-GPC3 Car BOXR1030. Meanwhile, a poster on Takeda’s earlier attempt at this modality, TAK-102, paints a disappointing picture, likely explaining this project’s recent discontinuation.
Impressive
The C-CAR031 study comprises 24 patients with second to seventh-line hepatocellular carcinoma, 22 of whom were evaluable for efficacy at a 5 January data cutoff. The already impressive 50% ORR rises to 55% if an additional unconfirmed PR is included, and the authors highlight tumour shrinkage in lesions outside the liver.
The results comprise four dose levels, and only the lowest (one patient treated) hasn’t yielded a response. On safety there was no neurotoxicity, and grade 3 cytokine release was seen in only one patient. However, grade 3 or higher transaminase elevation occurred in 16.7%, one patient had grade 4 myelosuppression and another grade 3 interstitial pneumonitis.
Astra has China co-development rights to C-CAR031, while separately developing AZD5851 outside China; under December’s deal AbelZeta obtained a milestone and royalty interest in the latter. It seems likely that the two companies had been working on the same construct, and the cross-licensing arrangement was a means of agreeing how to proceed without one group encroaching on the other’s IP.
The C-CAR031 data will come as an additional boost for AbelZeta, whose rebranding drew a line under its past as Cellular Biomedicine Group (CBMG), an entity once listed on Nasdaq but later taken private. The Astra deal came seven months after a tie-up with Johnson & Johnson worth $245m up front for two other Car-T projects.
Takeda out
For its part, Takeda recently scaled back its cell therapy pipeline in a cull that saw TAK-102 discontinued. The project had been licensed from the Japanese group Noile-Immune Biotech in 2017, and Takeda put it into phase 1.
The abstract of an ASCO poster on TAK-102 details those phase 1 data, and while there are also no DLTs or neurotoxicity there aren’t any responses either, the best result among 11 solid tumour patients being stable disease. TAK-102, which after Takeda's discontinuation remains in Noile-Immune's pipeline as NIB102, is also “armoured”, but encodes IL-7 and CCL20 rather than TGFβRIIDN.
The ASCO data might also be of interest to Gilead, which in an April 2022 oncology deep dive presented the Car-T therapy KITE-509, which targets GPC3 and also blocks the TGFβ signal. However, despite Gilead promising clinical trials “in the near future” these have yet to materialise.
Cross-trial comparison in anti-GPC3 Car-T therapy
| Project | Co-expresses | Company | Trial | Efficacy | Safety |
|---|
| C-CAR031 | TGFβRIIDN | AbelZeta/ AstraZeneca | NCT05155189 | 11 cPR + 1 uPR in 22 pts | 16.7% gr3+ transaminase elevation, 4.2% gr4 myelosuppression |
| TAK-102/ NIB102 | IL-7 & CCL20 | Noile-Immune (discontinued by Takeda) | NCT04405778 | 0 responses in 11 pts | No DLTs or neurotoxicity |
| BOXR1030 | Glutamic-oxaloacetic transaminase 2 (GOT2) | Sotio | Duet-01 | None, ASCO TiP poster only |
| AZD5851 | TGFβRIIDN | AstraZeneca/ AbelZeta | Athena | None, ASCO TiP poster only |
The ASCO annual meeting takes place in Chicago on 31 May to 4 June.
