Almost 19,000 new cases of acute myeloid leukemia and 10,500 deaths from the blood and bone marrow cancer could strike Americans this year, according to the American Cancer Society. Chemotherapy, when used as primary treatment, is successful in about 65 percent of patients with the cancer, and remission rates vary depending on patients’ individual characteristics, according to the organization.
A few years ago, a second-line immunotherapy treatment approved by the Food and Drug Administration was withdrawn from the market after a decade of use because of safety concerns. Now, a team of chemical and biomolecular engineers at the University of Houston is exploring a different approach to immunotherapy treatment for acute myeloid leukemia.
Gabrielle Romain, post-doctoral research fellow in the UH Cullen College of Engineering, recently published a paper in the journal, Blood, which is a publication of the American Society of Hematology. Her research, conducted with principal investigator, Navin Varadarajan, assistant professor of chemical and biomolecular engineering at the Cullen College, is a preliminary study of an innovative immunotherapy that targets acute myeloid leukemia tumor cells with engineered monoclonal antibodies to improve the quality and quantity of killing by natural killer immune cells.
“The disease does not have enough treatment options, so there is a need for alternative therapies,” Romain said. “So with a new mutation inserted in an existing antibody, we hope to revive interest in this strategy to treat leukemia.”
The UH chemical engineering team is collaborating with the teams of Badri Roysam, chair of the Cullen College’s electrical engineering department, George Georgiou, professor of chemical and biomedical engineering at the University of Texas at Austin, and Dean Lee, professor of biomedical engineering in the pediatrics division of UT M.D. Anderson Cancer Center. In addition to standard bulk testing, the University of Houston is contributing its single-cell assay to the project.
“It’s a good collaboration merging the expertise of engineers and clinicians, and the result is that we can focus on immunotherapeutic treatment for leukemia,” Romain said.
Prior to this study, Romain and her colleagues developed the single-cell assay, Timelapse Imaging Microscopy in Nanowell Grids, or TIMING, which is a soft, biocompatible polymer grid that creates 20,000 nanowells when placed atop a glass slide. Each nanowell, which is about the size of a speck of dust, captures approximately one to three cells, and the objective is to capture and observe the interaction between an immune cell and one or more tumor cells.
“With TIMING, we are not only imaging but also measuring characteristics of the immune cells,” Romain said.
The researchers can quantify singular dynamics of natural killer cell-mediated killing of tumor cells with the single-cell assay. This innovative technology complements bulk testing, which is limited to observation of end results, such as total amounts of targeted tumor cells killed when engineered antibodies are mixed with tumor and immune cells.
The previous antibody, which the FDA eventually removed from the market, was bound to a toxin that targeted the acute myeloid leukemia cells. Romain and the other researchers used a slightly different strategy. They targeted the same antigen, but their antibody was engineered to improve recruitment and efficiency of immune cells rather than to deliver toxins to tumor cells.
Surfaces of different types of tumor cells express unique molecular patterns, and researchers work to identify the tumor-associated antigens so they can engineer particular antibodies to target them. In this study, the mutation involved interchanging three amino acids in the constant region of the antibody, which conferred an affinity for natural killer immune cells. Romain coated the CD33 tumor cells with the engineered antibodies during an incubation process before she loaded them with the immune cells onto the biocompatible grid of nanowells. The coating facilitated recognition of the tumor cells by natural killer immune cells.
“We observed under the microscope that the interactions between the immune and tumor cells were better with the help of engineered antibodies,” Romain said. “The natural killer immune cells killed faster and increased their serial killing ability.”
The addition of the engineered antibodies as intermediates allowed immune cells to triple the overall amplitude and to double the speed of their targeted killing in preliminary studies. The next step is to translate those results in animal models.
“Antibody immunotherapy is now an established treatment modality,” Romain said. “And these engineered antibodies can reinvigorate interest in antibody immunotherapy for acute myeloid leukemia.”