Screening and Development of Constitutively Synergistic Combination Drug Formulations for T Cell Acute Lymphoblastic Leukemia

Abstract

Advances in multiagent chemotherapy have led to recent improvements in overall survival for patients with acute lymphoblastic leukemia (ALL); however, a significant fraction do not respond to frontline chemotherapy or later relapse with recurrent disease, after which long-term survival rates remain low. To address the challenge of developing new, effective treatment options for these patients, we conducted a series of high-throughput combination drug screens to identify chemotherapies that synergize in a lineage-specific manner with MRX-2843, a small molecule dual MERTK and FLT3 kinase inhibitor currently in clinical testing for treatment of relapsed/refractory leukemias and solid tumors. Using experimental and computational approaches, we found that MRX-2843 synergized strongly - and in a ratio-dependent manner - with vincristine chemotherapy to inhibit T-ALL cell expansion and, based on these findings, we developed multiagent lipid nanoparticle formulations of these drugs that not only constitutively maintained ratiometric drug synergy following T-ALL cell delivery, but also improved anti-leukemic activity following drug encapsulation. To determine the clinical relevance of these combination drug formulations and the therapeutic impact of ratiometric drug synergy, we compared the efficacy of lipid nanoparticles comprising synergistic, additive, and antagonistic ratios of MRX-2843 and vincristine, and observed that trends in in vitro synergy were directly recapitulated in primary T-ALL patient samples. Together, these findings present a systematic approach to high-throughput combination drug screening and multiagent drug delivery that maximizes the therapeutic potential of combined MRX-2843 and vincristine in T-ALL. This broadly generalizable approach could lead to the development of constitutively synergistic combination products for the treatment of cancer and other diseases.

Immunotherapy Study on Non-small-Cell Lung Cancer (NSCLC) Combined with Cytotoxic T Cells and miRNA34a

“…For example, combining CAR-T therapy with PD-1 inhibitors and cytokines such as IL-4 has shown promise in treating solid tumors . Jurkat T cells are also being used in drug screening to evaluate the efficacy of various compounds and potential immunotherapeutic agents . This aids in the identification of novel drugs that can enhance the anticancer immune response and improve treatment outcomes .…”

“… 18 Jurkat T cells are also being used in drug screening to evaluate the efficacy of various compounds and potential immunotherapeutic agents. 19 This aids in the identification of novel drugs that can enhance the anticancer immune response and improve treatment outcomes. 20 Jurkat T cells are cornerstones in cancer immunotherapy research and development.…”