“Dr. Walter and I are clinicians, who treat patients with acute myeloid leukemia (AML) and see far too many die from relapsed/refractory disease,” explains Dr. Sam Fiorenza, physician-scientist and first author on a recent article published in Molecular Therapy Oncology. A collaboration between members of Dr. Cameron Turtle's lab (formerly at Fred Hutch and now at the University of Sydney) and Dr. Roland Walter's lab, their article describes the development and preclinical testing of a novel immunotherapy to treat AML patients.
After diagnosis, AML patients typically receive a regimen of chemotherapy drugs designed to clear the blood and bone marrow of leukemia cells and put the cancer into remission—so-called “remission induction therapy”. Although many patients are successfully treated in this way, a substantial proportion of patients relapse or are refractory to the treatment. For these patients, there are very few reliable treatment options and their prognosis is poor.
Targeted approaches to treat AML have focused on CD33, a cell-surface protein that is found on virtually all AML cells, although the level of expression is found to vary widely between and even within patients. Several different approaches to targeting CD33 on AML cells have been investigated but have not been a resounding success as was hoped. In 2000, Mylotarg, a CD33 antibody-drug conjugate (ADC) that delivers a potent chemotherapy drug to CD33-expressing cells, was approved for the treatment of AML. Of note, Mylotarg was developed through the work of Dr. Irv Bernstein at the Hutch in the 1990s. Despite widespread CD33 expression, many AML patients do not respond to Mylotarg and other ADCs targeting CD33 have failed in clinical trials. Therefore, efforts are ongoing to develop more potent CD33-targeted therapies.
An alternative approach in development is chimeric antigen receptor (CAR)-T cell therapy, in which T cells from a cancer patient are reprogrammed to recognize and kill cancer cells. “In CAR-T cell therapy, a specific protein on the surface of the tumor is targeted (CD33 for AML) by the genetically modified CAR-T cells,” explains Dr. Fiorenza. “CAR-T cell therapy has been successfully used to treat another leukemia, B-cell Acute Lymphoblastic Leukemia (B-ALL). Yet responses in AML have been underwhelming.”
One explanation for why CD33-targeted ADCs and CAR-T cells are not efficiently killing CD33-expressing AML cells is that they may not be targeting the most optimal part of the CD33 molecule. CD33 contains two extracellular domains: the V-set and C2-set. Current CD33 ADCs and CAR-T cells recognize the V-set, which is located at the N terminus of the protein, further from the cell membrane. “Previous studies, including those from our own laboratory, have shown that the part of the V-set targeted by these existing antibodies may restrain the full force of immunotherapy by not creating the optimal T-to-tumor cell interaction,” says Dr. Fiorenza. Another possibility is that AML cells can produce alternatively spliced CD33 molecules that lack the V-set but retain the C2-set. Therefore, these CD33 isoforms won’t be recognized by current CD33-targeted therapies.
