Affinity-Tuned T-Cell Engagers for Dual Targeting of B-Myeloid Mixed Phenotype Acute Leukemia

We are developing a new treatment for a rare and aggressive type of leukemia called mixed-phenotype acute leukemia (MPAL). This cancer is difficult to treat because the leukemia cells show characteristics of two subtypes of leukemia-lymphoid and myeloid, on the same cell. Current treatments are not very effective for either children or adults, especially for patients who respond poorly to conventional chemotherapy. We are designing and testing a new immunotherapy drug, or molecule, that can recognize and attach to two specific markers (CD19 and CD33) found on the surface of MPAL cancer cells. This molecule is designed to also attract immune cells (T cells) to attack the cancer. The key innovation is that this molecule is designed to only work effectively when both markers are present together on the surface of a single leukemia cell, which is unique to MPAL. This approach could potentially selectively kill the cancer cells while minimizing damage to individual healthy cells such as B or myeloid cells which have CD19 or CD33 on their surface. We hypothesize that this will thus spare toxicities on healthy normal cells that occur when we harness the immune system for CD19 or CD33 positive leukemia cells.  We also know from the clinic that short-term side effects from this type of immunotherapy are common—for example, blinatumomab is a commercially available agent that targets CD19 positive B-leukemias and we know that this medicine can wipe out healthy CD19 positive B-cells resulting in patients needing to receive monthly immunoglobulin therapies.    Early cell culture experiments and animal studies that have tested our proteins have shown highly promising results. We plan to further optimize the design of this molecule by fine-tuning how strongly it can bind to these surface markers and conduct more pre-clinical trials in our mouse models. If successful, this could lead to a new, more targeted treatment for MPAL, potentially improving outcomes for patients with this hard-to-treat cancer. The goal is to ultimately move this research towards human clinical trials.