Research in the Varkey Lab
Ashley Varkey primarily focuses on two projects in regards to her research, both with the clinical target of pediatric acute myeloid leukemia (AML). AML is a blood cancer that remains difficult to treat, particularly when it relapses or is refractory to treatment. Immunotherapies have been successful in other blood cancers but pose difficulty in targeting AML cells in that these cells share surface markers with healthy hematopoietic stem cells, meaning that targeting the cancer can also destroy healthy cells, otherwise known as on target, off tumor toxicity.
Her research introduces two non-protein targets that are ideal for developing safer immunotherapies as they are found on malignant cells but are absent on healthy ones. These targets are high mannose (Man9) oligosaccharides and phosphatidylserine (PS). Man9 arises from an error in cell glycan assembly, while PS flips from the inner to the outer cell membrane during malignant transformation.
In partnership with the biotech company Vitruviae, we developed molecules that specifically bind to Man9 and PS and flow cytometry assays showed that these molecules had highly specific binding to nine AML cell lines and eight patient samples, all while sparing healthy cells. A trispecific T cell engager that binds to Man9, PS, and human CD3 was created and this molecule directs the body’s T cells to attack Man9 and/ or PS positive cancer cells while having no affinity for healthy cells. In vitro studies demonstrated excellent anti-leukemia activity against AML cell lines and initial toxicology studies in mice showed that the molecule was well- Tolerated.
In conclusion, two highly promising non-protein targets for AML immunotherapy were validated and an innovative T cell engager that avoids the toxicity and resistance issues of current treatments were developed. The goal of this project is to develop a first-in-class Man9 x PS x CD3 trispecific T cell engager for AML patients.
Her second primary focus involves B cell maturation antigen (BCMA), which has emerged as a prominent immunotherapeutic target in multiple myeloma (MM) due to its restricted expression on MM cells, plasma cells and mature B cells, with minimal presence in other normal tissues. In this study, we demonstrate through RNA sequencing and flow cytometry analyses of acute myeloid leukemia (AML) cell lines and primary patient samples that BCMA is also a relevant AML-associated antigen. Its robust surface expression on AML cells positions it as a promising candidate for targeted immunotherapy.
Functionally, our findings indicate that BCMA in AML operates similarly to its role in MM – engaging the NF-κB pathway upon ligand binding, thereby activating gene expression programs that support leukemia cell survival and proliferation. We assessed several BCMA-targeted immunotherapeutic strategies, including bispecific T-cell engagers (TCE) and chimeric antigen receptor (CAR) transduced T-cells, NK-cells, and macrophages. We found that TCE treatment and BCMA CAR engineering markedly improved effector cell mediated cytotoxicity against AML cells, underscoring BCMA’s potential as a viable therapeutic target in AML.
Furthermore, BCMA- directed TCE therapy significantly augmented the anti-leukemic activity of adoptively transferred CD8 + T-cells in a human AML xenograft model. Taken together, these findings support BCMA as a novel immunotherapeutic target in AML. Leveraging existing BCMA-directed treatments developed for MM could enable rapid clinical translation and broaden immunotherapy options for patients with AML.
Selected Publications
Ashley Varkey, Mark Batistick, Manpreet Bariana, Shaina Anuncio, Elena Cassella, Johannes Zakrzewski. B Cell Maturation Antigen (BCMA) As a Novel and Promising Target for Immunotherapy for Acute Myeloid Leukemia. Transplantation and Cellular Therapy. 2024