Work

822 CYT X300, a novel EGFR x pan-gamma delta T cell engager for the treatment of solid tumors

Year: 2026

Type: conference-abstract

Abstract: Background CD3 T cell engagers (TCEs) are an emerging immunotherapeutic modality, however, their application in solid tumors has so far been limited by a paucity of truly tumor restricted antigens leading to unacceptable toxicity from healthy tissue damage and cytokine release syndrome (CRS).Methods Cytospire’s approach enables TCE development using well-validated TAAs by engaging specific subsets of cytotoxic immune cells capable of distinguishing between malignant and non-malignant cells and killing whilst producing lower levels of CRS-causing cytokines. Gamma delta (γδ) T cells are a promising class of cells acting at the nexus of innate and adaptive immunity. γδT cells drive potent anti-cancer activity, while utilising functionally redundant stress markers to discriminate tumor from healthy cells. Due to this biology, γδ TCEs are considered to have great potential as effectors for next generation TCEs. To date, clinical-stage γδ TCEs have leveraged blood-resident (Vδ2) γδT cells. However, a growing literature showing that favourable patient outcomes in a range of solid tumors are driven by tumor resident γδT cells (Vδ1 and Vδ3 cells), elevating these as essential cells to leverage with novel γδ TCEs.Results Here, we present preclinical characterisation of CYT X300, a novel pan-γδ TCE targeting EGFR, a broadly expressed, clinically validated TAA on solid tumors. CYT X300 incorporates a novel antibody binder to an epitope present on all γδT cells including tumor resident Vδ1 and Vδ3 cells, coupled with a clinically validated anti-EGFR antibody domain and a silenced Fc. CYT X300 activates all subsets of γδT cells and induces their proliferation. CYT X300 drives potent killing of cancer cells with EC50s in the picomolar range across a range of EGFR expression levels. In vivo, CYT X300 has robust anti-tumor activity in two murine cancer models, and ex vivo potently activates primary γδT cells from non-small cell lung cancer (NSCLC) patient tumor samples. Crucially, CYT X300 does not induce killing of primary, EGFR-positive healthy cells nor excessive production of cytokines (IL-6 and TNFα) that drive CRS. Studies in non-human primates demonstrate that CYT X300 is very well tolerated and doesn’y induce the severe toxicities that have been a hallmark of EGFR x CD3 engagers.Conclusions Based on these data, CYT X300 is being advanced through IND-enabling preclinical studies and GMP manufacturing. A first-in-human clinical study is being planned to evaluate CYT X300 as a treatment for a range of EGFR-positive solid tumors including colorectal, head and neck and non-small cell lung cancers.Ethics Approval NSCLC ex vivo tumor experiments were performed in the Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy under their local ethics approval and informed consent. The protocol was approved by the ethical Committee and IRB of Humanitas Research Hospital with approval number 3631. Animal studies described were performed under ethics approvals obtained by our CRO partners performing the work. These CROs were Crown Bio (China), Charles River Labs (Germany) and WuXi Biologics (China).

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.0822