Project Term
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Project Summary
The combination of hypomethylating agents (HMA) and venetoclax (Ven) is a standard of care to treat acute myeloid leukemia (AML). However, HMA+Ven is not curative, and most patients will ultimately relapse without effective treatment options available thereafter. Our institution has discovered a novel AML target and pioneered the development of a best-in-class chimeric antigen receptor T cell therapy (CART64) for patients who have relapsed after HMA+Ven treatment. We now propose to demonstrate safety and effectiveness of CART64 in a phase 1, first-in-human, clinical trial in patients with advanced AML and high-risk myelodysplastic syndromes (HR-MDS).
Lay Abstract
Acute myeloid leukemia (AML) is a highly aggressive blood cancer that will be diagnosed in roughly 20,000 Americans in 2025. Standard treatment of newly diagnosed patients is a choice between high-intensity or low-intensity chemotherapies. Since AML is more common in older or medically frail adults, most patients receive a low-intensity treatment combination of a hypomethylating agent (HMA) with venetoclax (Ven). While HMA+Ven usually causes complete remissions (i.e., no detectable AML), these remissions are not cures and almost all patients will eventually relapse (i.e., develop AML again). The average survival of AML relapse after treatment with HMA+Ven is roughly 2 months. Thus, novel therapies with new ways to target AML are desperately needed to improve patient outcomes and their quality of life.
Cellular therapies are a class of targeted therapy that are potentially curative treatments for patients with other blood cancers, such as lymphoma and myeloma. However, early clinical trials testing cellular therapies against AML have had limited success. Our group at the University of Colorado has discovered a novel protein, called CD64, that is highly expressed on AML cells at time of relapse after treatment with Ven and could be used as a highly effective cellular therapy target. We have further engineered a best-in-class CD64 chimeric antigen receptor T cell therapy product (CART64) that showed high potency against AML cells that express CD64 in the lab and in animal models. Now, the overall goal of this Academic Clinic Trials Program Award proposal is to clinically translate CART64 to patients who have failed standard AML treatment.
In this proposal, we will perform a phase 1, first-in-human clinical trial to determine the safety and preliminary effectiveness of CART64 in adult patients with relapsed AML who have failed HMA+Ven. Patients with high-risk myelodysplastic syndrome (MDS; considered to be a “pre-AML” disease state) will also be included. We will measure all side effects that result from CART64 infusion, as well as the number of patients that survive with and without any further AML or MDS (the remissions). We will also assess patient-reported outcomes (PROs) to quantify treatment tolerability across four patient-centered domains. If CART64 is as effective as we have seen in laboratory models, there is high potential that patients can achieve a complete remission within 1 month of treatment, a sustained remission for several months or years (with the potential for cure), reduced complications related to low blood counts from AML or MDS (such as blood transfusions, infections, and hospitalizations), and overall, an improved quality of life. Importantly, safety data from CART64-treated adults will inform a planned tandem trial testing CART64 in children with AML. We believe CART64 may serve as an entirely new class of AML therapeutic for a patient population that otherwise has extremely limited options and dismal outcomes.
Program
