Neoantigen-Based T-Cell Receptor Therapy Offers New Option for Patients With AML, MDS

A new study published in Cell highlights the potential of neoantigen-based T-cell receptor (TCR) T-cell therapies as a novel immunotherapeutic strategy for patients with myeloid leukemia.

The study was conducted in collaboration with researchers from the Memorial Sloan Kettering (MSK) Cancer Center in New York, New York, and the Fred Hutchinson Cancer Center in Seattle, Washington.

“There are currently no effective immunotherapies for most patients with MDS and AML,” Omar Abdel-Wahab, MD, Chair of the Molecular Pharmacology Program at MSK and co-senior author of the study, told Heme Today. “One major limitation to developing effective immunotherapies for AML/MDS patients is the challenge in identifying cell surface proteins unique to the MDS/AML cells that are not expressed on vital normal tissues.”

Identifying Neoantigens

RNA splicing factor gene mutations such as SF3B1, SRSF2, U2AF1, and ZRSR2 are prevalent in AML and chronic myelomonocytic leukemia and are observed in 50% to 70% of patients with MDS, according to Dr. Abdel-Wahab and colleagues. These mutations affect alternative RNA splicing in healthy cells while creating new RNA isoforms observed across patients with the same mutations.

First, the researchers identified neoantigens derived from RNA mis-splicing in patients with SRSF2 and ZRSR2 mutations. Using these neoantigens, they constructed HLA-I dextramers to discover rare, circulating neoantigen-reactive CD8+ T cells in patients, examine their transcriptional characteristics, and isolate their TCRs. T cells engineered from neoantigen-reactive TCRs were ultimately able to recognize and kill SRSF2-mutant leukemia cells.

In Vivo Mice Models

Next, the researchers tested the antitumor activity of neoantigen-reactive TCR-T cells in vivo. In a xenograft model, mice infused with SRSF2-mutant AML were randomized to receive phosphate-buffered saline (PBS; n=5), cytomegalovirus-reactive TCR-T cells as a specificity control (n=5), or CLK3 TCR9-T cells (n=8). Mice treated with CLK3 TCR9-T cells had a “significantly lower tumor burden” compared with mice that received PBS or CMV TCR-T controls.

“If successful, this therapeutic approach could develop a selective cell therapy that could be administered to [more than] 50% of patients with MDS and [more than] 25% of patients above the age of 60 with AML,” Dr. Abdel-Wahab told Heme Today.

References

Grisham J. Accessed May 5, 2025. https://www.mskcc.org/news/new-cellular-immunotherapy-approach-may-offer-treatment-for-aml-and-mds

Kim WJ, et al. Cell. Published online April 21, 2025. doi:10.1016/j.cell.2025.03.047