T lymphocytes are divided in two main categories based on T cell receptor type; αß and γδ T cells. Whereas αß T cells have specific reactivity to peptides presented via HLA antigens, γδ T cells are activated by non-peptide antigens. Human γδ T cells are classified based on their receptor Vδ chain, with Vγ9Vδ2 T cells being the predominant subpopulation in circulation. These Vγ9Vδ2 T cells represent a potent class of proinflammatory immune effector cells with an immune surveillance function. Vγ9Vδ2 T cells are able to sense the presence of small phosphorylated metabolite antigens termed phosphoantigens, which are often expressed at high levels by tumor cells. Binding of the γδ T cell receptor to the butyrophilin-phosphoantigen complex leads to Vγ9Vδ2 T cell activation, tumor cell killing, secretion of pro-inflammatory cytokines and tumor-infiltration. In addition, these cells can act as antigen-presenting cells, priming the adaptive immune system.
Vγ9Vδ2 T cells can provide effective anti-tumor immune responses against both solid and haematological malignancies. The presence of Vγ9Vδ2 T cells correlates with increased survival for a wide range of cancers (Tosolini M. et al. 2017). Interestingly, Vγ9Vδ2 T cells, in contrast to ab T cells, infiltrate tumors independent of mutational tumor load.
Support for the potential of γδ T cell-based therapies is provided by Buccheri S. et al. 2014, showing favourable clinical outcomes and low toxicity in a meta-analysis of γδ T cell-based immunotherapies both performed by adoptive cell therapies and in vivo activation with compounds such as synthetic γδ T cell ligands or aminobisphosphonates.
LAVA’s bispecific γδ T cell engagers uniformly and specifically bind to the conserved T cell receptor of Vγ9Vδ2 T cells, providing a tumor target dependent response, avoiding generalized T cell activation known to induce side effects.
Proof of principle has been established by in vitro and in/ex vivo studies in which Vγ9Vδ2 T cell engagers demonstrate potent tumor lysis of both tumor cell lines and primary patient materials.
The company is currently working on several lead bispecific Vγ9Vδ2 T cell engager candidates that are progressing towards the clinic.