Development of natural killer (NK) cell-based therapies to treat MYC-high pediatric lymphoid cancers
Srividya Swaminathan
PhDBeckman Research Institute of the City of Hope
Project Term: July 1, 2021 - June 30, 2024
Refractory pediatric B- and T- lymphoid cancers exhibit hyperactivation of MYC and its downstream pathways. Experimentally, MYC inactivation sustains tumor regression. However, MYC’s requirement in normal B/T-cells has hampered the development of MYC inhibitors. Recently, we showed that MYC-High B/T-Lymphoid Neoplasms (B/T-MLN) evade Natural Killer (NK) cell surveillance. Hence, we propose to develop targeted off-the-shelf NK therapies as an alternative to MYC inhibition for treating B/T-MLN.
Many high-grade B and T-lymphoid childhood cancers including Burkitt’s Lymphoma (BL), and Acute Lymphoblastic Leukemia (ALL) exhibit high levels of the ‘MYC’ protein, and therefore, respond poorly to conventional chemotherapies. The ideal way to treat these cancers would be to directly block MYC. However, since MYC is required for the survival of non-malignant healthy lymphocytes, inhibiting it will cause significant damage and toxicity to normal cells in a patient. Hence, safe therapeutic alternatives to direct MYC inhibition that specifically recognize and kill malignant lymphocytes must be developed. Our research is aimed at identifying the unique vulnerabilities of malignant lymphocytes that have much higher levels of MYC protein in comparison to normal cells. Toward this end, we are comparing and contrasting the effects of normal and lymphoid cancer-inducing MYC on the host immune system. Understanding how MYC impacts anti-cancer immunity will enable the identification of treatments that alert the patient’s immune system to specifically attack the malignant cells. In order to identify targeted immunotherapies against MYC-driven lymphoid cancers, we recently mapped the immune landscape during the development of MYC-induced T-ALL in mice. We demonstrated that MYC-driven lymphoid cancers display an abnormal immune signature that is restored to normalcy upon blocking MYC. We observed that MYC specifically suppresses and removes anti-tumor immune cells known as Natural Killer (NK) cells from the T-ALL site, to escape recognition by host immunity. Based on our results, we hypothesize that restoring these ‘excluded’ NK cells may represent a non-toxic strategy to effectively combat pediatric B/T-lymphoid cancers without directly inhibiting the MYC protein. Hence, we propose to engineer a safe human NK cell-based therapeutic that targets MYC-High malignant lymphocytes, but spares the surrounding MYC-low normal lymphocytes in aggressive pediatric B and T cell cancers.