The immune system in childhood cancer: Mobilizing the troops
Dr. Mackall began her scientific career under the mentorship of Dr. Ronald Gress in the National Cancer Institute (NCI). During her postdoctoral work, she made pioneering discoveries regarding thymic function in humans and elucidated fundamental principles of T-cell homeostasis. In 1998, she initiated an independent research program in the Immunology Section of NCI’s Pediatric Oncology Branch. Here, she has continued to make important contributions to our understanding of the biology of T-cell homeostasis. She led the clinical development of interleukin-7 as a therapeutic immunorestorative and conducted translational studies focused on pediatric-tumor immunology. Dr. Mackall leads a cutting-edge clinical immunotherapy program that incorporates adoptive cellular therapies using genetically engineered T cells, adoptive natural-killer-cell therapies, dendritic-cell vaccines, cytokines, and checkpoint inhibitors.
The promise of treating cancer with the host’s own immune system has long held allure for scientists and physicians, but successes have been modest and inconsistent until recently. For the past two decades, Dr. Mackall’s research has focused on developing immune-based therapies for childhood cancer. She began by describing the impact of standard cancer therapies on T-cell homeostasis and identifying factors that limit T-cell restoration in children and adults. This work has elucidated powerful homeostatic mechanisms that support T-cell expansion when lymphocyte numbers are reduced, thus opening the window for adoptive T-cell therapies for cancer. Recent advances in genetic engineering have allowed Dr. Mackall’s laboratory and others to rapidly and reproducibly generate large numbers of tumor-specific T cells for adoptive transfer. Using this approach to target CD19 has proven highly effective against B-cell acute lymphoblastic leukemia, the most common cancer of childhood, but has revealed several limitations. First, antigen-loss immune escape can result when immune responses are restricted to one antigen and likely necessitates multivalent approaches to adoptive T-cell therapy. Second, her lab has identified T-cell exhaustion as a primary factor limiting the effectiveness of adoptive cellular therapies. Exhaustion can occur as a result of high tumor burdens but is also induced in T cells bearing non-native receptors due to tonic, antigen-independent signaling. Work is underway to engineer receptors that do not tonically signal and to develop novel approaches to prevent or reverse this exhaustion. Dr. Mackall predicts that her lab’s work will further improve the efficacy of emerging adoptive cellular therapies for cancer.
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