Cytospire raises £61M to take gamma-delta T-cell engager into the clinic

Conventional TCEs bind CD3 on T cells to drive destruction of tumor cells. The modality has improved outcomes in blood cancers but has proven less effective against solid tumors, where the broad activation of all CD3-positive cells has caused dose-limiting toxicities. Gamma-delta T cells use stress markers to differentiate between malignant and healthy cells, potentially making TCEs targeting the cells less toxic.

London-based Cytospire has secured funding for its preclinical pipeline of pan-gamma-delta TCEs. The biotech is performing IND-enabling studies and GMP manufacturing of its lead candidate, CYT X300, to support clinical trials of the asset in indications including colorectal, head and neck, and non-small cell lung cancer. 

Cytospire aims to advance CYT X300 to clinical proof of concept using money from its 4BIO Capital-led Series A round. The recently created Servier Ventures participated in the round, choosing Cytospire as its first investment. Sound Bioventures, British Business Bank and Criteria Bio Ventures also put money into the biotech, as did existing Cytospire investors Abingworth and LifeArc Ventures. 

Cytospire builds on earlier Abingworth successes. The biotech is led by Natalie Mount, an executive who specializes in gamma delta T cells. As GammaDelta Therapeutics’ chief scientific officer, Mount helped put the Abingworth-backed biotech on a track that led to a takeover by Takeda. Two years before the Takeda takeover, GammaDelta worked with Abingworth and Takeda to create Adaptate Biotherapeutics.

Mount became CEO of Adaptate as part of the spinoff. At the biotech, Mount oversaw the development of gamma-delta T-cell engagers to treat cancers. Takeda also bought Adaptate in 2022, exercising the right it secured under the build-to-buy deal agreed to create the biotech.

Selecting gamma-delta targets

Cytospire is building on the work of GammaDelta, Adaptate and other developers of gamma delta T-cell engagers. Lava Therapeutics focused on variable delta 2 gamma-delta T cells, moving candidates into the clinic and licensing a molecule to Seagen before suffering setbacks and being acquired by Xoma Royalty. Seagen, now part of Pfizer, is running a phase 1 trial of the EGFR-targeting TCR.

Variable delta 2 gamma-delta T cells are found in the blood, leading researchers to investigate whether other types of the immune cells may be a better fit for treating solid tumors. GammaDelta and Adaptate both focused on variable delta 1 gamma-delta T cells. Cytospire is taking a pan-gamma-delta approach, targeting the variable delta 1, 2 and 3 forms of the immune cells. 

The biotech’s lead candidate, CYT X300, targets an epitope found on all gamma-delta T cells, including the variable delta 1 and 3 cells present in tumors and tissue. Cytospire designed CYT X300 to engage the epitope and EGFR, a receptor expressed in several solid tumor types. The mechanism could activate gamma-delta T cells to drive the destruction of EGFR-expressing cancer cells.

Cytospire found CYT X300 is very well tolerated in non-human primates, which were free from the severe toxicities associated with EGFRxCD3 TCEs. The preclinical studies offer early support for the hypothesis that gamma-delta T cells’ ability to differentiate between healthy and malignant cells will support better safety and tolerability profiles than are possible when targeting CD3.