CGEN009/JHU001 IS A NOVEL REGULATOR OF MYELOID CELL BIOLOGY IN HEALTH AND HUMAN DISEASE

Immunotherapy represents the 4th pillar of cancer therapy and has the potential to result in a transformative treatment modality for patients for whom conventional therapies fail. This is based upon numerous results from clinical trials that demonstrate incredible efficacy for patients with diverse types of metastatic cancers. However, despite initial successes, these results are often limited to a handful of individuals with certain cancers, and immunotherapy has not panned out for individuals in many of the deadliest malignancies. As an alternative, we recognize the growing appreciation for the role of myeloid cells in cancer and their ability to impact tissue homeostasis. In this thesis, we provide a framework to challenge the current dogma in order to investigate the intersection between the immune system in cancer and predict important nodes whose perturbation may yield potential clinical breakthroughs. We identify a novel regulator of myeloid cell biology that is critical to tumor fitness and lipid metabolism. In chapter 1, we propose a novel paradigm that uses the perspective of evolution to understand the role of the immune system in cancer. In this manner, we are able to explain the successes and failures of immunotherapy, current challenges, and identify key features of future targets that may result in clinical benefits. In chapter 2, we delve into the biology of CGEN009/JHU001, a putative, previously uncharacterized protein of unknown function in mouse models. We show the effect of CGEN009/JHU001 on host homeostasis as well as it’s role in tumor biology that is dependent on myeloid cells. Finally, we identify key cell populations whose biology is dependent on the CGEN009/JHU001 path. In chapter 3, we investigate the biology of CGEN009/JHU001 in humans and find a unique transcriptional signature indicative of CGEN009/JHU001 signaling. We explore the presence of this transcriptional signature in a variety of disease states and reveal CGEN009/JHU001 as the upstream signal that induces the Trem2 myeloid signature. In chapter 4, we interrogate renal cell carcinoma clinical samples to identify a host of other myeloid-related proteins for future investigation. Overall, this work emphasizes the importance of myeloid cells in maintaining tissue homeostasis in health and disease

HIDE1 IS A NOVEL REGULATOR OF MYELOID CELL BIOLOGY IN HEALTH AND HUMAN DISEASE

Immunotherapy represents the 4th pillar of cancer therapy and has the potential to result in a transformative treatment modality for patients for whom conventional therapies fail. This is based upon numerous results from clinical trials that demonstrate incredible efficacy for patients with diverse types of metastatic cancers. However, despite initial successes, these results are often limited to a handful of individuals with certain cancers, and immunotherapy has not panned out for individuals in many of the deadliest malignancies. As an alternative, we recognize the growing appreciation for the role of myeloid cells in cancer and their ability to impact tissue homeostasis. In this thesis, we provide a framework to challenge the current dogma in order to investigate the intersection between the immune system in cancer and predict important nodes whose perturbation may yield potential clinical breakthroughs. We identify a novel regulator of myeloid cell biology that is critical to tumor fitness and lipid metabolism. In chapter 1, we propose a novel paradigm that uses the perspective of evolution to understand the role of the immune system in cancer. In this manner, we are able to explain the successes and failures of immunotherapy, current challenges, and identify key features of future targets that may result in clinical benefits. In chapter 2, we delve into the biology of HIDE1, a putative, previously uncharacterized protein of unknown function in mouse models. We show the effect of HIDE1 on host homeostasis as well as it’s role in tumor biology that is dependent on myeloid cells. Finally, we identify key cell populations whose biology is dependent on the HIDE1 path. In chapter 3, we investigate the biology of HIDE1 in humans and find a unique transcriptional signature indicative of HIDE1 signaling. We explore the presence of this transcriptional signature in a variety of disease states and reveal HIDE1 as the upstream signal that induces the Trem2 myeloid signature. In chapter 4, we interrogate renal cell carcinoma clinical samples to identify a host of other myeloid-related proteins for future investigation. Overall, this work emphasizes the importance of myeloid cells in maintaining tissue homeostasis in health and disease

Metastatic Extrapulmonary Small Cell Carcinoma to the Cerebellopontine Angle: A Case Report and Review of the Literature

Extrapulmonary small cell carcinomas (EPSCC) are rare malignancies with poor patient prognoses. We present the case of a 63-year-old male who underwent surgical resection of a poorly differentiated small cell carcinoma, likely from a small intestinal primary tumor that metastasized to the cerebellopontine angle (CPA). A 63-year-old male presented with mild left facial paralysis, hearing loss, and balance instability. MRI revealed a 15 mm mass in the left CPA involving the internal auditory canal consistent with a vestibular schwannoma. Preoperative MRI eight weeks later demonstrated marked enlargement to 35 mm. The patient underwent a suboccipital craniectomy and the mass was grossly different visually and in consistency from a standard vestibular schwannoma. The final pathology revealed a poorly differentiated small cell carcinoma. Postoperative PET scan identified avid uptake in the small intestine suggestive of either a small intestinal primary tumor or additional metastatic disease. The patient underwent whole brain radiation therapy and chemotherapy and at last follow-up demonstrated improvement in his symptoms. Surgical resection and radiotherapy are potential treatment options to improve survival in patients diagnosed with NET brain metastases. We present the first documented case of skull base metastasis of a poorly differentiated small cell carcinoma involving the CPA

Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma

Background Glioblastoma (GBM) is a poorly immunogenic neoplasm treated with focused radiation. Immunotherapy has demonstrated synergistic survival effects with stereotactic radiosurgery (SRS) in murine GBM. GITR is a co-stimulatory molecule expressed constitutively on regulatory T-cells and by effector T-cells upon activation. We tested the hypothesis that anti-GITR monoclonal antibody (mAb) and SRS together would confer an immune-mediated survival benefit in glioma using the orthotopic GL261 glioma model.Methods Mice received SRS and anti-GITR 10 days after implantation. The anti-GITR mAbs tested were formatted as mouse IgG1 D265A (anti-GITR (1)) and IgG2a (anti-GITR (2a)) isotypes. Mice were randomized to four treatment groups: (1) control; (2) SRS; (3) anti-GITR; (4) anti-GITR/SRS. SRS was delivered to the tumor in one fraction, and mice were treated with mAb thrice. Mice were euthanized on day 21 to analyze the immunologic profile of tumor, spleen, and tumor draining lymph nodes.Results Anti-GITR (1)/SRS significantly improved survival over either treatment alone (p < .0001) with a cure rate of 24 % versus 0 % in a T-lymphocyte-dependent manner. There was elevated intratumoral CD4+ effector cell infiltration relative to Treg infiltration in mice treated with anti-GITR (1)/SRS, as well as significantly elevated IFNγ and IL-2 production by CD4+ T-cells and elevated IFNγ and TNFα production by CD8+ T-cells. There was increased mRNA expression of M1 markers and decreased expression of M2 markers in tumor infiltrating mononuclear cells. The anti-GITR (2a)/SRS combination did not improve survival, induce tumor regression, or result in Treg depletion.Conclusions These findings provide preclinical evidence for the use of anti-GITR (1) non-depleting antibodies in combination with SRS in GBM