Immunotherapy Commons^™

Hypoxia Acts As An Environmental Cue For The Human Tissue-Resident Memory T-Cell Differentiation Program, Farah Hasan

Dissertations and Theses (Open Access)

Tissue-resident memory T-cells (T_RM) provide frontline defense against viral diseases and can contribute to anti-tumor immunity; however, aside from the necessity of TGF-β, little is known regarding cues for T_RM differentiation. Oxygen tension is an environmental cue that distinguishes peripheral tissues from the circulation and here, we demonstrate that differentiation of human CD8+ T-cells under hypoxic conditions in the presence of TGF-β1 led to the development of a T_RM phenotype, characterized by a greater than five-fold increase in CD69+CD103+ cells expressing human T_RM hallmarks and enrichment for endogenous human T_RM gene signatures, including increased …

Assessing The Outcomes Of Blocking Ccl2-Ccr2 Signaling Axis On Breast Cancer Brain Metastasis, Yutao Qi

Dissertations and Theses (Open Access)

Breast cancer brain metastases have remained one of the most intense challenges for precision cancer therapeutics, but current treatment options are limited and not curative. Recently, our lab reported that adoptive PTEN downregulation in metastatic breast tumor cells activates PI3K/NF-ƙB signaling and increases the secretion of the chemokine CCL2, which enhances the chemotaxis of CCR2⁺ myeloid cells, a major subpopulation of bone marrow-derived myeloid cells (BMDMs), from peripheral blood into the brain tumor microenvironment (TME), eventually promoting brain metastasis outgrowth by driving immune suppression. Here, in this project we have been aiming to develop effective therapies by immune-modulating the …

Unraveling Host-Gut Microbiota Dialogue And Its Impact On Response To Immune Checkpoint Blockade, Alexandria Cogdill

Dissertations and Theses (Open Access)

Cancer is a disease with only one degree of separation, affecting one in two men and one in three women in their lifetimes; accounting for 1 of every 6 deaths. While cancer mortality rates continue to improve, incidence rates are expected to rise and shift through 2050 due to epidemiological and demographic transitions worldwide. As such, it is imperative to continue to investigate and improve our understanding of both disease etiology and hallmarks of response to treatment. Currently, conventional therapies include, but are not limited to, surgery, chemotherapy, and radiotherapy. However, within the past decade, major advances have been made …

Subclonal Evolution Of Chronic Lymphocytic Leukemia After Allogeneic T Cell Therapies, Haven Garber

Dissertations and Theses (Open Access)

Subclonal evolution of chronic lymphocytic leukemia after allogeneic T-cell therapies

Haven Garber, MD

Advisory Professor: Jeffrey Molldrem, MD

Intratumoral genetic heterogeneity describes the molecular differences among subclones within a tumor and is a major barrier to effective therapy in many solid and liquid cancers, including chronic lymphocytic leukemia (CLL). Rare, treatment-resistant subclones can expand to compose relapsed disease during tumor evolution. Examination of malignant evolution in the context of specific treatment provides insight into the molecular lesions that mediate therapeutic response and resistance. Both chemotherapy and targeted therapy were shown to precipitate CLL subclonal evolution. We hypothesized that allogeneic T-cell …

Reversal Of Neurodegeneration By Engineered Monocytes In Alzheimer’S Disease, Chao-Hsien Chen

Dissertations and Theses (Open Access)

The health challenges posed by Alzheimer’s disease (AD) continue to grow as societies age worldwide. Accumulation of Tau-associated pathology correlates with clinical cognitive deterioration in AD. Resident myeloid cells within the central nervous system (CNS) have a limited capacity to uptake and degrade Tau; however, the resulting secretion of proinflammatory cytokines only acts to accelerate neurodegeneration. Therapeutic antibodies can reduce the neurotoxic oligomeric form of Tau (o-Tau), but in doing so they also aggravate inflammation. Attenuating mutation of the antibody Fc region can silence inflammation but also eliminates its capacity to mediate o-Tau clearance by CNS myeloid cells. Thus, there …

Elucidating The Roles Of Il-15 In The Tumor Microenvironment, Rosa Maria Santana Carrero

Dissertations and Theses (Open Access)

ELUCIDATING THE ROLES OF IL-15 IN THE TUMOR MICROENVIRONMENT

Rosa M. Santana Carrero, B.S.

Advisory Professors: Shao-Cong Sun, Ph.D. & Kimberly S. Schluns, Ph.D.

Interleukin-15 (IL-15) is a factor that promotes activation, proliferation, cytotoxicity, and survival of CD8 T cells and NK cells, and has been shown to have anti-tumor effects. Moreover, loss of IL-15 expression in human colorectal tumors correlates with increased risk of relapse, diminished survival, decreased density and proliferation of T cells. All together these findings suggest that IL-15 expressed locally in the tumor microenvironment (TME) is an important mediator of anti-tumor responses by tumor infiltrating lymphocytes …

Micrornas Associated With Melanoma Inflammation And Response To Pd-1 Inhibition, Robert Szczepaniak Sloane

Dissertations and Theses (Open Access)

Melanoma is an aggressive malignancy of melanocytes with historically poor outcomes. Melanoma therapy has improved markedly over the past decade with advances in molecularly targeted agents and immunotherapies. Immune checkpoint inhibitors achieve T-cell mediated anti-tumor efficacy by blocking engagement of inhibitory checkpoints on T-cells to overcome immunosuppressive signals from tumor cells and the broader microenvironment. Despite these advances, there are a significant proportion of patients who do not benefit from existing immunotherapy strategies making it a priority to identify and target the mechanisms that confer resistance to therapy. We demonstrate that microRNAs are accurate markers of microenvironment composition with prognostic …

Bringing Til Therapy Beyond Melanoma: Advancing The Treatment Of Advanced Pancreatic And Ovarian Cancers, Donald Sakellariou-Thompson

Dissertations and Theses (Open Access)

The success of checkpoint blockade immunotherapy (CBI) has reinvigorated the cancer therapy field, particularly for advanced melanoma which has doubled the survival rates compared to 20 years ago. However, there are many solid tumor types that are yet to receive substantial benefit from this groundbreaking therapy, two of which are pancreatic cancer (PDAC) and ovarian cancer (OvCa). As such, the 5-year survival rate for PDAC and OvCa stand at 9% and 28% respectively. Despite the lack of efficacy of CBI so far, there is still evidence for the role of immune control in these cancers as evidenced by presence of …

Modulating Avidity Of H8f4-Car By Regulation Of Expression Via Codon Modification, Rolando Vedia

Dissertations and Theses (Open Access)

Despite recent advances in the field of cancer immunotherapy and chimeric antigen receptor (CAR) therapies for the treatment of acute myeloid leukemia (AML), there is a need for more unique and innovative modalities to improve these therapies. Our group has extensively studied and demonstrated the potential of targeting the leukemia-associated antigen PR1 in the setting of AML. PR1 is an HLA-A2-restricted nonameric peptide derived from serine proteases neutrophil elastase and proteinase 3, is overexpressed on myeloid leukemia cells, and expressed at normal low levels in healthy hematopoietic cells. We have demonstrated efficacy in targeting PR1/HLA-A2 via the novel development of …

Putative Roles Of Cd200 In The Leukemogenesis And Immune Evasion Of Leukemia Stem Cells, Shelley Herbrich

Dissertations and Theses (Open Access)

Acute myeloid leukemia (AML) stem cells (LSC) are capable of surviving current standard chemotherapy and are the likely source of deadly, relapsed disease. While stem cell transplant serves as proof-of-principle that AML LSCs can be eliminated by the immune system, the translation of existing immunotherapies to AML have been met with limited success. Consequently, understanding and exploiting the unique immune mechanisms of AML LSCs is critical. To identify novel immunotherapeutic targets, we sourced multiple large, publicly available datasets and identified CD200 as a potential stem-cell specific immune checkpoint in AML. We hypothesized that CD200 was a stem-cell specific mechanism of …

Immunotherapy In Hepatocellular Cancer Patients With Mild To Severe Liver Dysfunction: Adjunctive Role Of The Albi Grade, David J Pinato, Takahiro Kaneko, Anwaar Saeed, Tiziana Pressiani, Ahmed Kaseb, Yinghong Wang, David Szafron, Tomi Jun, Sirish Dharmapuri, Abdul Rafeh Naqash, Mahvish Muzaffar, Musharraf Navaid, Chieh-Ju Lee, Anushi Bulumulle, Bo Yu, Sonal Paul, Neil Nimkar, Dominik Bettinger, Hannah Hildebrand, Yehia I Abugabal, Celina Ang, Thomas U Marron, Uqba Khan, Nicola Personeni, Lorenza Rimassa, Yi-Hsiang Huang

Faculty, Staff and Students Publications

Immune checkpoint inhibitors (ICI) have shown positive results in patients with hepatocellular carcinoma (HCC). As liver function contributes to prognosis, its precise assessment is necessary for the safe prescribing and clinical development of ICI in HCC. We tested the accuracy of the albumin-bilirubin (ALBI) grade as an alternative prognostic biomarker to the Child-Turcotte-Pugh (CTP). In a prospectively maintained multi-centre dataset of HCC patients, we assessed safety and efficacy of ICI across varying levels of liver dysfunction described by CTP (A to C) and ALBI grade and evaluated uni- and multi-variable predictors of overall (OS) and post-immunotherapy survival (PIOS). We studied …

Combined Lenvatinib And Pembrolizumab As Salvage Therapy In Advanced Adrenal Cortical Carcinoma, Sara Bedrose, Kevin Charles Miller, Lina Altameemi, Mohamed S Ali, Sameh Nassar, Naveen Garg, Marilyne Daher, Keith D Eaton, Jeffrey Thomas Yorio, Davey B Daniel, Matthew Campbell, Keith C Bible, Mabel Ryder, Ashish V Chintakuntlawar, Mouhammed Amir Habra

Faculty, Staff and Students Publications

BACKGROUND: There is no effective systemic therapy for metastatic adrenal cortical carcinoma (ACC) after failure of platinum-based chemotherapy. The efficacies of single-agent oral multikinase inhibitors (MKIs) or salvage immune checkpoint inhibitors (CPIs) have been very limited. It is unknown whether combining CPIs, such as pembrolizumab (PEM), with other therapies, such as MKIs, could yield higher response rates in ACC, yet this combination has shown promise in other cancers. Herein, we describe the first case series using PEM in combination with the MKI lenvatinib (LEN) in patients with progressive, metastatic ACC.

METHODS: A retrospective case series describing the use of LEN/PEM …

Effects Of Penfluridol On Integrin-Fak Signaling And Tumor Cell Killing In Combination With Oncolytic Hsv In Glioblastoma, Mitra Nair

Dissertations and Theses (Open Access)

Integrins are known to play an important role in activating multiple intracellular pathways, one of which is focal adhesion kinase (FAK). Phosphorylation of FAK can lead to the activation of various downstream signaling pathways that can increase tumor cell growth and proliferation, making it an ideal target for cancer therapeutics. Due to the fact that many FAK inhibitors are limited in their penetration of the blood brain barrier, we investigated the use of Penfluridol, an antipsychotic drug known to attenuate integrin expression at a transcriptional level, in combination with oncolytic herpes simplex I virus (oHSV) in a glioblastoma model. We …

Exosomal Communication By Metastatic Osteosarcoma Cells Modulates Alveolar Macrophages To An M2 Tumor-Promoting Phenotype And Inhibits Tumoricidal Functions, Kerri Wolf

Dissertations and Theses (Open Access)

Osteosarcoma metastasizes to the lung, and there is a link between the predominance of tumor promoting immunosuppressive M2 macrophages in the metastases and poor patient survival. By contrast, M1macrophage predominance correlates with longer survival. M2 macrophages can be induced by various stimuli in the tumor microenvironment, including exosomes, which are 40- to 150-nm vesicles that are involved in intercellular communication and contribute to tumor progression and immune evasion. Recognizing that tumor cells can influence the tumor microenvironment to make it more permissive and because of the link between M2 dominance and curtailed patient survival, we evaluated the effect of …

Loss Of Caspase-8 Function In Combination With Smac Mimetic Treatment Sensitizes Head And Neck Squamous Carcinoma To Radiation Through Induction Of Necroptosis., Burak Uzunparmak

Dissertations and Theses (Open Access)

Caspase-8 (CASP8) is one of the most frequently mutated genes in Head and Neck Squamous Carcinomas (HNSCC), and mutations of CASP8 are associated with poor overall survival. The distribution of these mutations in HNSCC suggests that they are likely to be inactivating. Inhibition of CASP8 has been reported to sensitize cancer cells to necroptosis, a unique cell death mechanism. Here, we evaluated how CASP8 regulates necroptosis in HSNCC using cell line models and syngeneic mouse xenografts. In vitro, knockdown of CASP8 rendered HNSCCs susceptible to necroptosis induced by a second mitochondria-derived activator of caspase (SMAC) mimetic, Birinapant, when combined …