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.
