SUMMARY OF INVENTION
Adoptive cell therapies (ACT) have provided significant improvements in the treatment of B cell lymphomas and multiple myeloma but have thus far struggled to replicate this success in solid tumors. Intrinsic cellular programs may partially underlie the lack of durable activity against solid tumors, as effector T-cells responsible for mounting cytotoxic responses are short-lived due to both cellular ‘exhaustion’ following extended antigen presentation and their inability to survive or self-renew over the long-term. As a result, several companies are currently evaluating methods to enrich for memory-like T-cell phenotypes to extend ACT’s in vivo persistence and anti-tumor activity.
To enhance the persistence and anti-tumor activity of adoptive cell therapies, MSK scientists performed an unbiased screen for microRNAs that influence cytotoxic T lymphocyte (CTL) function. Researchers identified microRNA miR200c which, when overexpressed in CTLs, significantly enhanced anti-tumor activity and translated into improved survival in several rodent cancer models. CTLs overexpressing miR-200c or EpCAM (a downstream gene increased by miR-200c overexpression) displayed both increased survival and inflammatory cytokine secretion. Although miR-200c overexpressing CTLs displayed high expression of TCF1 and Bcl2, which are consistent with stem cell memory T-cells (Tscm), the cells did not display reduced proliferation or cytokine secretion, suggesting that miR-200c CTLs exhibit a distinct cell phenotype well-suited to durably engraft and eliminate tumor cells.
- The invention provides a means to improve the engraftment, survival, and anti-tumor activity of adoptive cell therapies in both solid and liquid tumors.
- Suppression of tumor growth and increased rodent survival was further improved by the addition of anti-PD-1 antibodies which outperformed both anti-PD-1 and CTL miR200c overexpression alone.
- No side effects have yet been observed in in vivo experiments, suggesting that the approach could be readily adapted to ACT protocols in humans.
There is a strong unmet need to develop adoptive cell therapies that are efficacious in solid tumors. While multiple CAR T-cell therapies have proved highly effective in treating liquid tumors, comparable clinical gains have yet been achieved in solid tumors which represent approximately 90% of adult human cancers.
STAGE OF DEVELOPMENT
PCT application PCT/US2022/016921 filed February 18, 2022.
Zhang et al., (2021) Ectopic activation of the miR-200c–EpCAM axis enhances antitumor T cell responses in models of adoptive cell therapy, Science Translational Medicine (PubMed link).
Morgan Huse, PhD, Laboratory Head, Immunology Program, Memorial Sloan Kettering Cancer Center
James Delorme, PhD