180P - Recalling pre-existing microbiota-specific T cells to target tumors

Background

The gut microbiome has the singular property of shaping the immune system through a multitude of antigens that educate the T cell repertoire. Since microbial peptides can share similarities with tumor antigens, cross-reactive memory T cells that recognize both bacterial and tumor-derived peptides can thus emerge from the imprinting of the T cell repertoire by gut commensals. Harnessing the full potential of cross-reactive CD8+ T cells against tumor cells could therefore be achieved through the rational design of a microbiota-derived peptide vaccine.

Methods

Enterome developed a novel peptide-based immunotherapy built on the principle of T cell cross-reactivity and molecular mimicry between bacterial-derived peptides called OncoMimics^TM peptides (OMP) and Tumor-Associated Antigens (TAA). HLA-A2-restricted OMP candidates targeting human TAA were first selected in silico from our proprietary metagenomic bank of human gut microbiota and then confirmed through in vitro binding assays, and in vivo evaluations of their immunogenicity and capacity to induce cross-reactive T cell responses against TAA in HLA-A2/DR1 humanized mice. Finally, the prevalence and functionality of OMP-specific T cells were assessed in human blood from healthy donors using tetramers, in vitro stimulation, and cytotoxicity assays.

Results

Selected OMPs could elicit cross-reactive cytotoxic T cell (CTL) responses against human TAA. This was demonstrated by the propensity of these CTL to secrete IFN-γ upon recognition of OMP or TAA peptides, reject TAA peptide-pulsed splenocytes as well as tumors ectopically expressing the selected TAA targets. We finally demonstrated that OMP-specific memory CD8+ T cells pre-exist in human blood, with high prevalence (>80% in the population), and harbor strong CTL functions against TAA when activated ex vivo with OMPs.

Conclusions

We show that gut microbiota-derived peptides mimicking TAAs can elicit strong immune responses against tumors. The pre-existence of these cross-reactive CD8+ T cells in healthy donors exemplifies the strong promises of this innovative approach to develop efficient therapeutic cancer immunotherapies. To date, two OMP-based immunotherapies are evaluated in 3 clinical trials (Glioblastoma, Adrenal cancers, B lymphomas).

Legal entity responsible for the study

Enterome.

Funding

Enterome SA.

Disclosure

All authors have declared no conflicts of interest.