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For acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients who don’t respond to treatment or who have relapsed, there are limited options. The average survival rate is less than six months, creating a need for newer and faster treatment options.

Chimeric antigen receptor T-cell therapy, or CAR T, involves removing T cells from the blood and modifying them in a lab to recognize and destroy cancer cells once infused back into the body. CAR T therapy has produced durable remission for patients with acute lymphoblastic leukemia and lymphoma, but is not approved for AML and MDS patients and has shown limited success in clinical trials.

While the CD33 antigen is highly expressed in most AML patients and could be a target for CAR T cells, there are barriers to the treatment being successful, including challenges with efficacy, potential toxicity and a long manufacturing period.

“These patients are often critically sick with severely low blood counts,” said Dr. David Sallman, a hematologist in the Malignant Hematology Program at Moffitt Cancer Center. “A lot of these patients can’t wait for a traditional CAR T-cell manufacturing process that takes three to four weeks.”

These patients are often critically sick with severely low blood counts. A lot of these patients can’t wait for a traditional CAR T cell manufacturing process that takes three to four weeks.
Dr. David Sallman, Malignant Hematology Program

A phase 1b study that was presented at the 2021 American Society of Hematology annual meeting looks at the safety and efficacy of a new type of CAR T called UltraCAR-T™ therapy for myeloid malignancies. UltraCAR-T cells express CD33 and membrane bound IL-15. And unlike current CAR T cells, which utilize viruses to attach the CAR to the T cells, UltraCAR-T uses a nonviral gene delivery system and a rapid manufacturing process.

“The CAR product is unique in that from leukopoiesis until infusion only takes two days,” said Sallman, the trial’s principal investigator. “This is done through a rapid manufacturing process with electroporation utilizing a sleeping beauty plasmid, ultimately making a CAR T cell targeting CD33. Importantly, it also has membrane bound IL-15 incorporated to allow for in vivo proliferation within the patient.” 

The study is testing if UltraCAR-T is safe and effective for two sets of myeloid patients: those who receive lymphodepleting chemotherapy prior to the treatment and those who don’t. So far, low dose levels of the treatment have showed promising results with good safety, no manufacturing failure and some early evidence of clinical activity. UltraCAR-T also has a kill switch for safety. Because all of the main targets for MDS and AML are also expressed on normal stem cells, there is a concern the treatment could also attack healthy cells and eliminate the body’s ability to make blood. The kill switch would stop the treatment and eliminate the CAR if ultimately needed. There has been no usage of the kill switch to this point.

According to Sallman, no objective responses were seen without lymphodepletion, and of the first six patients treated with lymphodepletion, three had objective responses

“One patient has been bridged to allogeneic transplant and now is in continued, complete remission one year out from transplant,” said Sallman. “Two others had excellent remissions that lasted for about three months. This is proof in principle that CD33 CAR T therapy can have efficacy in patients with relapsed refractory AML, has been overall very safe and dose escalation continues with dose expansion plans in 2022.”