Tumor downstaging with small molecule therapeutics to enhance Uveal Melanoma metastasis eradication by B7-H3 CAR T cells

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Project summary Uveal Melanoma (UM) is a rare cancer with an incidence of 5 cases per million in the United States. Nearly half UM patients develop isolated liver metastases due to the high tendency of UM cells to spread to the liver. No cure has been found for patients with metastatic UM (mUM). Tebentafusp, is the only FDA-approved therapy for mUM. However, it has shown modest improvements in terms of overall response and progression-free survival and its applicability is limited to only 40% of mUM patients. The lack of effective treatment options for mUM has prompted us to design a novel combinatorial immunotherapeutic strategy based on the use of Chimeric Antigen Receptor (CAR) T cells specifically redirected against B7-H3. The latter has been selected as the target of our immunotherapeutic strategy, since it is highly expressed on UM cell lines and mUM tumor tissue samples, but has a limited expression on normal tissues. It is a general experience that CAR T cell-based immunotherapy is not effective in eradicating solid tumors both in preclinical and clinical investigations. This result is likely caused by multiple mechanisms, among which the major role is played by their use in hosts with high tumor load; the resulting unfavorable effector to target (E:T) ratio in the tumor microenvironment has a negative impact on the antitumor activity of CAR T cells, as indicated by the results generated by preclinical and clinical investigations. The information in the literature and our preliminary results have provided the rationale to design a strategy which applies first a tumor debulking approach to reduce tumor load and then CAR T cell- based immunotherapy to eradicate UM metastases. We will use the combination of trametinib, a mitogen-activated protein kinase kinase inhibitor (MEKi) and of panobinostat, a histone deacetylase inhibitor (HDACi), since this combination has been shown to induce marked regression of UM liver metastases in mice. Furthermore, this combination does not affect B7- H3 expression by UM cells and the antitumor activity of B7-H3 CAR T cells. Therefore, after having shown that B7-H3 CAR T cells can recognize and eliminate UM cells surviving the treatment with the MEKi and HDACi combination, we will investigate whether tumor debulking induced by the MEKi and HDACi combination can enhance the ability of B7-H3 CAR T cells to eradicate UM liver metastases in NSG mice. Since one major limitation of CAR T cell-based therapy is represented by its potential toxicity and/or cytokine release syndrome, we have incorporated in our CAR construct an inducible caspase 9 safety switch which allows rapid elimination of CAR T cells in case of unexpected toxicities. If the results generated by our experiments are positive, they will have a major impact on the treatment of mUM.