Marker Therapeutics, Inc. reported non-clinical data on its lead multi- tumor-associated antigen (multiTAA)-specific T cell product candidate, MT-401, which showed increased anti-tumor activity against an acute myeloid leukemia (AML) cell line after treatment with hypomethylating agents (HMA). Marker further announces that the Company has been awarded a $2 million grant from the National Institutes of Health (NIH) Small Business Innovation Research (SBIR) program to support the development of MT-401 for the treatment of patients with AML after hematopoietic stem cell transplant (HSCT). The multiTAA-specific T cell technology from Marker uses a novel non-genetically modified T cell therapy approach that recognizes multiple antigens expressed on tumor cells, thereby designed to minimize tumor escape.

MT-401 was designed to specifically target four different antigens (Survivin, PRAME, WT-1 and NY-ESO-1), which are upregulated in AML but have limited expression on normal cells. In March 2023, Marker reported clinical updates from the Company sponsored ARTEMIS clinical trial (clinicaltrials.gov identifier: NCT04511130) highlighting the potential benefit of MT-401 in patients with AML who have measurable residual disease (MRD+) after HSCT. Given the promising responses in patients who are MRD+, Marker has been investigating clinical opportunities to further improve AML patient outcomes.

One such opportunity is to combine multiTAA-specific T cell therapy with agents that make cancer cells more visible to cancer killing cells. This opportunity has practical merit because HMAs that do this, such as 5'-Azacytidine and Decitabine, are commonly used as therapies for AML. It also has scientific merit because these agents inhibit DNA methylation, a process which regulates gene expression.

By reducing DNA methylation, HMAs can restore physiological gene expression patterns, including the upregulation of tumor suppressor genes, and the inhibition of oncogenes. HMAs have also been found to upregulate the expression of tumor antigens, including MT-401-specific tumor antigens, previously silenced by DNA methylation (Wong et al, Front Oncol, 2021). Due to this mechanism of action, Laura S. Angelo, Ph.D., and her team at Marker investigated in a set of in vitro experiments, the capacity of MT-401 to inhibit or kill THP-1 cells, an aggressive treatment-resistant AML cell line, after the cells were exposed to HMA.

The results of this non-clinical study have been posted on the Investor Relations section of the Marker website, and highlights are briefly summarized below: In this i in vitro model of treatment resistant AML, tumor cells exposed to HMA for 72 hos upregulated d tumor-associated antigen targets of MT-401, including Survivin. The THP-1 cell line was bioluminescent modified to allow real-time long-term assessment of cancer cell growth. THP-1 cells continued to grow both in the absence and presence of DMSO, the vehicle used to dissolve 5'-Azacytidine.

The growth of THP-1 cells was reduced in the presence of 5'-Azacytidine (after exposure to the drug for 72 hours). The growth of THP-1 cells was also reduced in the presence of MT-401 (manufactured from donors that were partially HLA-matched to THP-1 cells). THP-1 cell growth, however, was significantly decreased when MT-401 was added after exposure to 5'-Azacytidine compared to MT-401 or 5'-Azacytidine administration alone, suggesting a synergistic effect between the two agents.

These in vitro data demonstrate that administration of MT-401 following HMA infusion enhanced AML cell killing and could offer a new therapeutic option for AML patients post-HSCT.