Browsing by Subject "Cancer Biology"

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    Development of Novel Therapeutic Approaches for NF1 Deficient Peripheral Nerve Sheath Tumors
    (2023) Nikrad, Julia
    Malignant Peripheral Nerve Sheath Tumors (MPNSTs) associated with Neurofibromatosis Type 1 (NF1) pose a significant clinical challenge due to their aggressive nature and limited treatment options. This thesis endeavors to address this challenge by developing innovative therapeutic approaches for NF1-deficient PNSTs. The first objective of this research focused on the development of oncolytic adenovirus therapy specifically tailored for MPNSTs. Through the utilization of conditionally replicating adenoviruses (CRAds), we aimed to elucidate their cytotoxic and anti-tumor properties against MPNSTs. Our findings revealed that these adenoviruses exhibit a remarkable affinity for MPNST cells, leading to preferential replication and cell death compared to non-tumor control cells. Moreover, intratumoral injection of CRAds in murine models resulted in improved survival rates. In immunocompetent murine models, an increased intratumoral CD8+ T cell infiltrate was observed, promising a potential immunotherapeutic dimension to this approach. These results collectively underscore the feasibility of oncolytic virotherapy development as a novel strategy for combating MPNSTs. The second key objective of this study involved the identification of synthetic lethal targets specific to MPNSTs through a genome-wide CRISPR/Cas9 synthetic lethal screen. Our screening process unveiled a multitude of potential synthetic lethal interactors in the context of NF1-null and NF1/SUZ12-null Schwann cells and MPNST cells. Furthermore, the initial validation of these candidate interactors yielded promising results, substantiating the need for additional development and investigation. These findings hold significant promise for the use of genetic screens to identify and develop novel therapeutic interventions targeting MPNSTs.
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    Untitled
    (2022-05) Sunil Arvindam, Upasana
    Natural Killer (NK) cells are cytotoxic innate immune cells that are important components of anti-tumor immunity. They make up 5-15% of total lymphocytes and are derived from the common lymphoid progenitor. Their phenotype is determined by the marker CD56 that divides them into two groups, CD56bright and CD56dim cells. CD56bright cells have a lower cytotoxic capacity but show high proliferation and cytokine secretion upon stimulation. CD56dim cells display high cytotoxic capacity. NK cells can recognize and killer tumor cells through a wide array of germline encoded receptors. They can facilitate broader immune system activation through the secretion of pro-inflammatory cytokines. NK cell-based treatments can be divided into two main areas; biologics that enhance endogenous NK cell function and adoptive transfer of NK cells. Both these treatments are being developed to increase targeting of therapeutic NK cells towards tumor cells. We have established a series of NK cell biologics called trispecific killer engagers (TriKETM). To target acute myeloid leukemia (AML) cells, we developed a TriKE containing an anti-CD16 portion that activates NK cells, an IL-15 molecule that drives NK cell priming, expansion and survival, and a portion against the AML antigen, CLEC12A (CLEC12A TriKE). The CLEC12A TriKE induced robust NK cell proliferation, enhanced killing of both AML cell lines and primary patient derived AML blasts and reduced tumor burden in pre-clinical mouse models. For TriKE based treatments to be successful in solid tumors, we need to address the additional mechanisms of immune suppression that exist in the solid tumor microenvironment (TME). We focused on the role of low oxygen or hypoxia (1% O2) on NK cell function and found that hypoxia strongly inhibits NK cell proliferation and cytotoxicity. There is a decrease in the expression of activating receptors, cytotoxicity markers and key transcription factors (Tbet and Eomes). There is change in NK cell metabolism with a switch to glycolysis. Hypoxia results in a remodeling of the transcriptome and epigenome. We investigated the impact of exogenous therapeutics on NK cells under hypoxia with the addition of recombinant IL-15 or TriKE and the use of NK cells that have been expanded on K562 feeder cells containing 4-1BBL and IL-21. These therapeutics improved NK cell killing under hypoxia. Future directions include combination therapies with biologics and adoptive transfer of genetically modified NK cells that function better in suppressive TMEs.