ABSTRACT This Phase II application will advance MT-401, a novel multi-tumor associated antigen (mTAA)-specific T cell product for the treatment of acute myeloid leukemia (AML) and other cancers. In the USA, ~3,500 AML patients receive hematopoietic stem cell therapy (HSCT) every year, but overall survival remains <30%, with an estimated median survival of <1 year. Although AML is sensitive to immune-/T cell-based interventions, these are limited due to: 1) lack of one antigen with sufficient tumor specificity, 2) tumor immune escape, and 3) requirement for lymphodepletion which helps prevent engagement of the endogenous immune system (epitope spreading) and leads to adverse events. mTAA-specific T cells target multiple tumor associated antigens simultaneously, thereby minimizing tumor escape. MT-401 targets 4 antigens highly expressed in AML, but with absent or low expression levels in healthy tissue. Manufactured from allogeneic apheresis material from the HSCT donor, MT-401 recognizes target cells via native T cell receptors (TCRs), by interacting with both class I and II MHC, leading to killing of cells expressing any of these antigens, as well activation of other immune cells. mTAA-specific T cell products attacking the same targets as MT-401 exhibited specific killing of HLA-matched cells expressing these antigens and reduction of tumor growth in animal models. mTAA-specific therapy was also shown to be clinically safe in >170 patients with various kinds of cancer. In a heavily pretreated AML population with active disease post-HSCT, this therapy demonstrated complete (CR) or partial (PR) responses in some of the patients, while adjuvant patients remained in remission longer than expected. Importantly, epitope spreading was observed leading to more durable responses versus other cellular therapies. In order to enhance the efficacy of MT-401, we treated AML cells with hypomethylating agents (HMA), which upregulate some of the tumor antigens targeted by MT-401, followed by MT-401. Our in vitro data shows enhanced killing when treating with HMA followed by MT-401, supporting this regimen in relapsed AML patients post-HSCT. In this study, we are proposing a Phase II clinical trial of MT-401 following HMA as bridging therapy in relapsed AML patients post-HSCT to prepare for future commercialization. Specific Aim 1 includes evaluation of efficacy and safety of MT-401. Specific Aim 2 includes immune monitoring of patient samples including T cell expansion, persistence, clonality, anti-tumor immune effects, tumor antigen expression, and epitope spreading. Successful completion of this grant will lead to future BLA filing and commercial approval of MT-401 as a revolutionary T cell therapy for AML patients.

NARRATIVE This application will advance a novel therapy, whereby white blood cells are trained in the laboratory to recognize and kill cancer cells. These killer cells have the capacity to recognize multiple surface markers expressed by the tumor cells but not healthy cells. To date, more than 170 patients have been treated in clinical studies with this therapy with no serious side effects. This project will advance cell therapy in combination with existing chemotherapy to treat patients with acute myeloid leukemia (AML), a type of blood cancer with minimal treatment options and low survival rates, with the ultimate objective of getting marketing authorization to benefit more patients.