|The following article features coverage from the 2021 Annual Meeting of the Society of Hematologic Oncology (SOHO). Click here to read more of Hematology Advisor‘s conference coverage.|
Researchers have successfully used a mass spectrometry-based approach to design a T cell receptor (TCR)-mimic chimeric antigen receptor (CAR) T-cell specific to the kinetochore protein NDC80 that targets multiple cancer cell lines.
The study was presented by Martin G. Klatt, MD, of Memorial Sloan Kettering Cancer Center, New York, NY, at the Annual Meeting of the Society of Hematologic Oncology (SOHO).
“[A] big advantage of T cell mimic antibodies is that they’re able to target the peptide-MHC complex independent of the target’s immunogenicity, and this is, of course, a big advantage compared to TCRs,” explained Dr Klatt.
The investigators hypothesized that mass spectrometry-based analysis of the presented human leukocyte antigen (HLA) ligands of multiple cancer cell lines can be used to identify a shared, tumor-associated HLA ligand, which can then be targeted by TCR-mimic CAR-T cells specific to that HLA ligand.
The team conducted mass spectrometry of HLA ligands from both hematological and non-hematological cancer cell lines and identified a shared, nonimmunogenic, HLA-A*02 restricted ligand (ALNEQIARL) derived from the kinetochore-associated protein NDC80. They found that more than 90% (20/22) A*02-positive cell lines tested were positive for the ligand.
In collaboration with Eureka Therapeutics, positive and negative selection of a phage library containing 1011 antibody clones were used to identify the NDC80 clone. The team then prepared a TCR-mimic single-chain fragment variable against the epitope (NDC80-C) and transduced CAR-T cells with it.
The TCR-mimic CAR-T cells directed against the ALNEQIARL:HLA-A*02 complex demonstrated high sensitivity and specificity for recognizing and killing multiple cancer types and appeared to have a high preference for hematological malignancies, including cells derived from acute myeloid leukemia, acute lymphocytic leukemia, diffuse large B-cell lymphoma, and anaplastic large cell lymphoma.
They also demonstrated that the NDC80 TCR-mimic antibody does not bind healthy leukocytes and does not mediate toxicity against peripheral blood mononuclear cells or hematopoietic stem cells from A*02-positive and -negative donors.
Toxicity studies of NDC80-C CAR-T cells are ongoing in murine models. Preliminary studies demonstrated that NDC80-C CAR-T cells were efficacious in mouse models against human mesothelioma and leukemia.
According to the investigators, “This strategy lays the groundwork for a potential antibody platform therapy or CAR-T cell with efficacy against highly proliferative A*02-positive cancer cells, independent of the respective cancer type.”
Disclosure: This research was supported by Eureka Therapeutics. Please see the original reference for a full list of disclosures.
Read more of Hematology Advisor’s coverage of SOHO 2021 by visiting the conference page.
Klatt MG, Dao T, Yang Z, et al. A tumor-agnostic TCR-mimic CAR-T cell specific for NDC80 targets multiple hematological malignancies. Paper presented at: Annual Meeting of the Society of Hematologic Oncology (SOHO); September 8-11, 2021. Abstract CT-080.