Immunotherapy Commons^™

A Highly Selective Humanized Ddr1 Mab Reverses Immune Exclusion By Disrupting Collagen Fiber Alignment In Breast Cancer, Junquan Liu, Huai-Chin Chiang, Wei Xiong, Victor Laurent, Samuel C Griffiths, Jasmin Dülfer, Hui Deng, Xiujie Sun, Y Whitney Yin, Wenliang Li, Laurent P Audoly, Zhiqiang An, Thomas Schürpf, Rong Li, Ningyan Zhang

Faculty, Staff and Student Publications

BACKGROUND: Immune exclusion (IE) where tumors deter the infiltration of immune cells into the tumor microenvironment has emerged as a key mechanism underlying immunotherapy resistance. We recently reported a novel role of discoidin domain-containing receptor 1 (DDR1) in promoting IE in breast cancer and validated its critical role in IE using neutralizing rabbit monoclonal antibodies (mAbs) in multiple mouse tumor models.

METHODS: To develop a DDR1-targeting mAb as a potential cancer therapeutic, we humanized mAb9 with a complementarity-determining region grafting strategy. The humanized antibody named PRTH-101 is currently being tested in a Phase 1 clinical trial. We determined the binding …

Development Of Wiskott-Aldrich Syndrome Knock Out Protocol For Drug Substance Assay Development, Julia C. Hanna

Master's Theses

Wiskott-Aldrich Syndrome (WAS) is a rare X-linked primary immunodeficiency affecting approximately 1 in 100,000 live XY births in North America and is caused by a mutation to the WAS gene which is expressed across hematopoietic lineages. The WAS protein (WASp) plays a role in regulating actin polymerization. On a cellular level, there are a variety of effects of a lack of WASp or expression of a dysfunctional WASp protein for patients including issues with migration, adhesion, chemotactic response, phagocytosis, activation, and proliferation across different cell types in addition to reduced platelet size and output. This can lead to several systematic …

Selective Immune Suppression Using Interleukin-6 Receptor Inhibitors For Management Of Immune-Related Adverse Events, Faisal Fa'ak, Maryam Buni, Adewunmi Falohun, Huifang Lu, Juhee Song, Daniel H Johnson, Chrystia M Zobniw, Van A Trinh, Muhammad Osama Awiwi, Nourel Hoda Tahon, Khaled M Elsayes, Kaysia Ludford, Emma J Montazari, Julia Chernis, Maya Dimitrova, Sabina Sandigursky, Jeffrey A Sparks, Osama Abu-Shawer, Osama Rahma, Uma Thanarajasingam, Ashley M Zeman, Rafee Talukder, Namrata Singh, Sarah H Chung, Petros Grivas, May Daher, Ala Abudayyeh, Iman Osman, Jeffrey Weber, Jean H Tayar, Maria E Suarez-Almazor, Noha Abdel-Wahab, Adi Diab

Faculty, Staff and Student Publications

BACKGROUND: Management of immune-related adverse events (irAEs) is important as they cause treatment interruption or discontinuation, more often seen with combination immune checkpoint inhibitor (ICI) therapy. Here, we retrospectively evaluated the safety and effectiveness of anti-interleukin-6 receptor (anti-IL-6R) as therapy for irAEs.

METHODS: We performed a retrospective multicenter study evaluating patients diagnosed with de novo irAEs or flare of pre-existing autoimmune disease following ICI and were treated with anti-IL-6R. Our objectives were to assess the improvement of irAEs as well as the overall tumor response rate (ORR) before and after anti-IL-6R treatment.

RESULTS: We identified a total of 92 patients …

Ocular Toxicity Profile Of Targeted Cancer Therapy (Tct) At A Us Tertiary Cancer Center, Moe Ameri, Nagham Al Zubidi, Azadeh Razmandi, Andrew Whyte, Aung Naing, Nimisha A Patel, Dan S Gombos

Faculty, Staff and Student Publications

PURPOSE: Targeted cancer therapy (TCT) is a significant advancement in oncology with promising survival improvement in patients with cancer and remarkable effects on various cancers. There is evidence suggesting a connection between specific TCT classes and the occurrence of immune-related adverse events (irAEs). Our study aims to investigate the potential ocular toxicities of different classes of TCT, provide a better understanding of these toxicities, and aid in the future development of screening and management recommendations for ocular irAEs.

DESIGN: Retrospective observational case series.

PARTICIPANTS: Only ocular immune-related AEs were included in the study; patients on TCT who received a new …

Society For Immunotherapy Of Cancer (Sitc) Clinical Practice Guideline On Immunotherapy For The Treatment Of Gynecologic Cancer, Mary L Disis, Sarah F Adams, Jyoti Bajpai, Marcus O Butler, Tyler Curiel, Shelley A Dodt, Laura Doherty, Leisha A Emens, Claire F Friedman, Margaret Gatti-Mays, Melissa A Geller, Amir Jazaeri, Veena S John, Katherine C Kurnit, John B Liao, Haider Mahdi, Anne Mills, Emese Zsiros, Kunle Odunsi

Faculty, Staff and Student Publications

Advanced gynecologic cancers have historically lacked effective treatment options. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration for the treatment of cervical cancer and endometrial cancer, offering durable responses for some patients. In addition, many immunotherapy strategies are under investigation for the treatment of earlier stages of disease or in other gynecologic cancers, such as ovarian cancer and rare gynecologic tumors. While the integration of ICIs into the standard of care has improved outcomes for patients, their use requires a nuanced understanding of biomarker testing, treatment selection, patient selection, response evaluation and surveillance, …

Novel Natural Compounds Derived From Tcm In The Treatment Of Food Induced Anaphylaxis, Ibrahim Musa

NYMC Student Theses and Dissertations

Food allergy is a highly prevalent disease affecting about 30 million people in the U.S. It is managed primarily by food avoidance due to lack of promising treatment options. ASHMI (anti-asthma herbal intervention) which consists of three components, Sophorae flavescentis, Ganoderma lucidum, Glycyrrhiza uralensis has been shown to inhibit allergic lung inflammation in antigen sensitized and challenged mice. In this study we isolate and identify the active compound in Sophorae flavescentis, characterized the mechanism of IgE inhibitory effect, biomarkers and potential to prevent food anaphylaxis.

To separate and identify the compounds we used column chromatography, high-performance liquid chromatography, mass …

Modeling The Immune Response To Immunotherapy And Triple Negative Breast Cancer In Mice, Dayton J. Syme, Angelica Davenport, Yun Lu, Anna G. Sorace, Nicholas G. Cogan

Biology and Medicine Through Mathematics Conference

No abstract provided.

Impact Of Early Relapse Within 24 Months After First-Line Systemic Therapy (Pod24) On Outcomes In Patients With Marginal Zone Lymphoma: A Us Multisite Study, Narendranath Epperla, Rina Li Welkie, Pallawi Torka, Geoffrey Shouse, Reem Karmali, Lauren Shea, Andrea Anampa-Guzmán, Timothy S Oh, Heather Reaves, Montreh Tavakkoli, Kathryn Lindsey, Irl Brian Greenwell, Emily Hansinger, Colin Thomas, Sayan Mullick Chowdhury, Kaitlin Annunzio, Beth Christian, Stefan K Barta, Praveen Ramakrishnan Geethakumari, Nancy L Bartlett, Alex F Herrera, Natalie S Grover, Adam J Olszewski

Department of Medicine Faculty Papers

Progression of disease within 24 months (POD24) from diagnosis in marginal zone lymphoma (MZL) was shown to portend poor outcomes in prior studies. However, many patients with MZL do not require immediate therapy, and the time from diagnosis-to-treatment interval can be highly variable with no universal criteria to initiate systemic therapy. Hence, we sought to evaluate the prognostic relevance of early relapse or progression within 24 months from systemic therapy initiation in a large US cohort. The primary objective was to evaluate the overall survival (OS) in the two groups. The secondary objective included the evaluation of factors predictive of …

Functional Characterization Of Age-Dependent P16 Epimutation Reveals Biological Drivers And Therapeutic Targets For Colorectal Cancer, Li Yang, Xiaomin Chen, Christy Lee, Jiejun Shi, Emily B Lawrence, Lanjing Zhang, Yumei Li, Nan Gao, Sung Yun Jung, Chad J Creighton, Jingyi Jessica Li, Ya Cui, Sumimasa Arimura, Yunping Lei, Wei Li, Lanlan Shen

Faculty, Staff and Students Publications

BACKGROUND: Methylation of the p16 promoter resulting in epigenetic gene silencing-known as p16 epimutation-is frequently found in human colorectal cancer and is also common in normal-appearing colonic mucosa of aging individuals. Thus, to improve clinical care of colorectal cancer (CRC) patients, we explored the role of age-related p16 epimutation in intestinal tumorigenesis.

METHODS: We established a mouse model that replicates two common genetic and epigenetic events observed in human CRCs: Apc mutation and p16 epimutation. We conducted long-term survival and histological analysis of tumor development and progression. Colonic epithelial cells and tumors were collected from mice and analyzed by RNA …

Using Cancer Proteomics Data To Identify Gene Candidates For Therapeutic Targeting, Diana Monsivais, Sydney E Parks, Darshan S Chandrashekar, Sooryanarayana Varambally, Chad J Creighton

Faculty, Staff and Students Publications

Gene-level associations obtained from mass-spectrometry-based cancer proteomics datasets represent a resource for identifying gene candidates for functional studies. When recently surveying proteomic correlates of tumor grade across multiple cancer types, we identified specific protein kinases having a functional impact on uterine endometrial cancer cells. This previously published study provides just one template for utilizing public molecular datasets to discover potential novel therapeutic targets and approaches for cancer patients. Proteomic profiling data combined with corresponding multi-omics data on human tumors and cell lines can be analyzed in various ways to prioritize genes of interest for interrogating biology. Across hundreds of cancer …

Clinical Outcomes Of Immunotherapy Continued Beyond Radiographic Disease Progression In Older Adult Patients With Advanced Non-Small Cell Lung Cancer, Eric K Singhi, Frank Mott, Michelle Worst, Cheuk Hong Leung, J Jack Lee, Brett Carter, Carolyn J Presley, John V Heymach, Mehmet Altan

Faculty, Staff and Student Publications

Immunotherapy is an effective and generally well-tolerated treatment strategy for older adult patients (aged ≥70 years) with advanced non-small cell lung cancer (NSCLC). Unfortunately, most patients who receive immunotherapy eventually exhibit disease progression during treatment. The present study reports on a subset of older adult patients with advanced NSCLC who could effectively continue immunotherapy beyond radiographic disease progression due to perceived clinical benefit. Local consolidative radiotherapy may be used in select older adult patients to prolong the duration of immunotherapy they receive, with a particular consideration of their preexisting co-morbidities, performance status and tolerance of potential toxicities associated with combined …

Oncolytic Virus Immunotherapy: Development And Potential For Cancer Treatment, Olivia Guinness

Honors Scholar Theses

The American Cancer Society estimates that in 2023, 1,958,310 new cancer cases and 609,820 cancer deaths will occur in the United States [16]. A promising therapeutic option that has been supported by recent clinical trials is the use of oncolytic viruses to treat malignant tumors. The mechanism of action of existing treatments, such as chemotherapy, radiotherapy, and surgery, differs from that of oncolytic virus therapy because oncolytic viruses are able to affect cancer cells with specificity, minimizing side effects. When infecting a normal, non-cancerous cell, oncolytic viruses do not replicate, leaving healthy cells unaffected. In tumor cells, oncolytic viruses will …

The Cx3cl1-Cx3cr1 Chemokine Axis Contributes To Tumor Immune Evasion And Its Blockade Enhances Responses To Anti-Pd-1 Immunotherapy, Apoorvi Chaudhri

Dissertations and Theses (Open Access)

CX3CL1 secreted in the tumor microenvironment serves as a chemoattractant playing a critical role in metastasis of CX3CR1 expressing cancer cells. While CX3CR1 can be expressed in both cancer and immune-inhibitory myeloid cells to facilitate their migration, the mechanisms employed by this axis on these cells to mediate immune suppression remain poorly understood. Here, we explore the immune evasion strategies implemented by this axis and find that it initiates a resistance program in cancer cells that results in 1) facilitation of tumor cell migration, 2) secretion of soluble mediators to generate a pro-metastatic niche, 3) secretion of mediators to attract …

Uncovering Molecular Targets To Overcome Immunosuppression In Non-Small Cell Lung Cancer With Acquired Tki Resistance, Sonia A. Patel

Dissertations and Theses (Open Access)

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. Targeted therapeutic agents, such as epidermal-like growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) or monoclonal antibodies targeting vascular endothelial growth factor (VEGF/R), can effectively inhibit upregulated signaling pathways driving tumorigenesis in NSCLC and many other cancers. Unfortunately, however, resistance to such targeted therapies inevitably arise in most patients and can occur through a variety of resistance mechanisms including genomic alterations and upregulation of bypass pathways. Additionally, patients who have acquired resistance to these targeted agents typically have tumors characterized by an immunosuppressive tumor microenvironment and thus …

Kir-Based Inhibitory Cars Overcome Car-Nk Cell Trogocytosis-Mediated Fratricide And Tumor Escape, Ye Nmn Li

Dissertations and Theses (Open Access)

Trogocytosis is an active process that transfers surface material from targeted to effector cells. Using multiple in vivo tumor models and clinical data, we report that chimeric antigen receptor (CAR) activation in natural killer (NK) cells promoted the transfer of the CAR-cognate-antigen from tumor to NK cells, resulting in (1) lower tumor antigen density, thus impairing the ability of CAR-NK cells to engage with their targets, (2) induced self-recognition and continuous CAR-mediated engagement, resulting in fratricide of trogocytic antigen expressing NK cells (NK^TROG+) and NK cell hyporesponsiveness. This phenomenon could be offset by a dual-CAR system incorporating both …

Hypoxia Activated Prodrug And Anti-Angiogenic Therapy Cooperate To Treat Pancreatic Cancer But Elicit Immune Suppressive G-Mdsc Infiltration, Arthur Liu

Dissertations and Theses (Open Access)

We previously showed that the hypoxia-activated prodrug TH-302 (Evofosfamide) reduces intratumoral hypoxia through a tissue remodeling process, initiates tumor vasculature reorganization, and sensitizes aggressive, spontaneous murine models of prostate cancer to immune checkpoint blockade (ICB). In a clinical trial testing the combination of TH-302 with cytotoxic T-lymphocyte-associated protein (CTLA-4) blockade (NCT03098160) a subset of metastatic, ICB refractory patients showed prolonged progression free survival. While these studies highlight hypoxia as therapeutically tractable, we lack a complete understanding of the contribution of the tumor vasculature to hypoxia reduction therapy, as well as the downstream consequences of hypoxia reduction on the cellular composition …

Preclinical Evaluation Of Immunomodulatory Effects Of Aurora Kinase Inhibition In Human Papillomavirus Positive Cancers, Pragya Sinha

Dissertations and Theses (Open Access)

Human papillomavirus (HPV) is the causative agent of cervical cancer and some cancers of the penis, vulva, vagina, anus, and oropharynx. Current therapies for these cancers include a combination of surgery, radiotherapy, and chemotherapy that often results in permanent, life altering adverse effects. Immunotherapy is partially effective, but with significant recurrence and lower long-term survival. Importantly, there are no few biomarker-selective targeted therapies for these cancers. To address this unmet need, our collaborators conducted a large-scale drug screen and identified Aurora Kinase (AK) inhibitors as a unique class of reagents to induce selective apoptosis in HPV+, but not HPV- human …

Translational Studies Using The Malt1 Inhibitor (S)-Mepazine To Induce Treg Fragility And Potentiate Immune Checkpoint Therapy In Cancer, Mauro Di Pilato, Yun Gao, Yi Sun, Amina Fu, Carina Grass, Thomas Seeholzer, Regina Feederle, Irina Mazo, Samuel W Kazer, Kevin Litchfield, Ulrich H Von Andrian, Thorsten R Mempel, Russell W Jenkins, Daniel Krappmann, Peter Keller

Faculty, Staff and Student Publications

Introduction

Regulatory T cells (Tregs) play a critical role in the maintenance of immune homeostasis but also protect tumors from immune-mediated growth control or rejection and pose a significant barrier to effective immunotherapy. Inhibition of MALT1 paracaspase activity can selectively reprogram immune-suppressive Tregs in the tumor microenvironment to adopt a proinflammatory fragile state, which offers an opportunity to impede tumor growth and enhance the efficacy of immune checkpoint therapy (ICT).

Methods

We performed preclinical studies with the orally available allosteric MALT1 inhibitor (S)-mepazine as a single-agent and in combination with anti-programmed cell death protein 1 (PD-1) ICT to …

Targeting Pd-L2-Rgmb Overcomes Microbiome-Related Immunotherapy Resistance, Joon Seok Park, Francesca S Gazzaniga, Meng Wu, Amalia K Luthens, Jacob Gillis, Wen Zheng, Martin W Lafleur, Sarah B Johnson, Golnaz Morad, Elizabeth M Park, Yifan Zhou, Stephanie S Watowich, Jennifer A Wargo, Gordon J Freeman, Dennis L Kasper, Arlene H Sharpe

Faculty, Staff and Student Publications

The gut microbiota is a crucial regulator of anti-tumour immunity during immune checkpoint inhibitor therapy. Several bacteria that promote an anti-tumour response to immune checkpoint inhibitors have been identified in mice1-6. Moreover, transplantation of faecal specimens from responders can improve the efficacy of anti-PD-1 therapy in patients with melanoma7,8. However, the increased efficacy from faecal transplants is variable and how gut bacteria promote anti-tumour immunity remains unclear. Here we show that the gut microbiome downregulates PD-L2 expression and its binding partner repulsive guidance molecule b (RGMb) to promote anti-tumour immunity and identify bacterial species that mediate this effect. PD-L1 and …

Cancer-Specific Perturbations To Arginine Metabolism Blunt Replication And Performance Of Oncolytic Myxoma Virus, Parker Dryja

MUSC Theses and Dissertations

Oncolytic virotherapy (OV) is a class of immunotherapy for treatment of malignancy. Using viruses that exhibit natural coincidental tropisms for cancer, or others that have been engineered to the same effect, intentional infection of lesions leads to two therapeutically beneficial effects: (1) direct destruction of the infected tumor through virally-mediated cell lysis, and (2) recruitment of an otherwise blunted or absent anti-cancer immune response to affect both local and disseminated disease. A surfeit of cancer-specific changes are accumulated during progression from first genetic insult to clinical detection, presenting a dramatically altered underlying biology of cell and tissue. The viruses employed …