Translational Medical Research Commons^™

A Novel Approach To Target Tumor Immune Microenvironment And Improve Checkpoint Immunotherapies, Poornima Devi Shaji, Ana Martinez, Melida Flores Cantu, Anupam Dhasmana, Meena Jaggi, Stephen W. Behrman, Murali M. Yallapu, Subhash C. Chauhan, Sheema Khan

Research Colloquium

Background: Pancreatic cancer remains 3^rd deadliest disease, with less than 7-10% survival rate. Little progress has been seen in patient’s outcome due to high desmoplasia and chemo-resistance. Immunotherapy has shown promising results in cancers, except pancreatic cancer due to their characteristic fibrotic tumor microenvironment. The therapies are unable to penetrate fibrotic tumor leading to insufficient availability of therapeutic drugs at the tumor site. A recently identified mucin, MUC13 is aberrantly expressed in pancreatic tumors but not in normal pancreas, that makes it an excellent protein tumor target. This study is unique as it utilizes MUC13Ab for targeting the pancreatic …

Early Development Of C3ar1-Targeting Chimeric Antigen Receptor T Cells For The Treatment Of Glioblastoma Multiforme, Cameron Fraser

Electronic Theses, Projects, and Dissertations

Glioblastoma multiforme is the most aggressive type of glioma, demonstrating extremely low long-term survival despite modern therapies. Chimeric antigen receptor T cells have shown extreme levels of success in the treatment of B cell lymphomas through persistent anti-tumor activity. Prior research has demonstrated the therapeutic potential in targeting the C3a-C3aR1 pathway as it acts in an autocrine loop, maintaining the proliferation and survival of cancer stem cells within the tumor. Here, we reorient the treatment to target C3aR1 for the treatment of glioblastoma multiforme. In order to achieve this, Jurkat immortalized T cells will express various chimeric antigen receptor designs …

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

Dissertations & 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 …

A Novel Immunostimulatory Platform For Amplifying The Abscopal Response Rates Of Radiation Therapy, Patrick A. Paez

Theses and Dissertations

Radiation therapy (RT) is one of the primary treatment modalities for head and neck squamous cell carcinoma (HNSCC). At the time of diagnosis two-thirds of HNSCC patients have local-advanced disease and 50-60% of these patients will experience a local-regional or metastatic relapse within three years. Improving the immunogenic response of RT may help address this clinical problem. However, current RT regimens have failed to reliably generate robust antitumor immunity as evidenced by the rarity of clinical abscopal responses. Recently we engineered a chimeric fusion molecule called Flagrp170, a novel immunostimulatory agent highly capable of promoting antigen presentation and T-cell activation. …

Eftilagimod Alpha, A Soluble Lymphocyte Activation Gene-3 (Lag-3) Protein Plus Pembrolizumab In Patients With Metastatic Melanoma, Victoria Atkinson, Adnan Khattak, Andrew Haydon, Melissa Eastgate, Amitesh Roy, Prashanth Prithviraj, Christian Mueller, Chrystelle Brignone, Frederic Triebel

Research outputs 2014 to 2021

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. BACKGROUND: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of eftilagimod alpha (efti), a soluble lymphocyte activation gene-3 protein, in combination with the programmed cell death-1 (PD-1) antagonist pembrolizumab. METHODS: The study was divided into two parts; parts A and B, where part A was the dose escalation part and part B was an extension part of the study. Patients with metastatic melanoma were treated with efti plus the standard dose of pembrolizumab. Blood samples were assayed to determine …

First Results On Survival From A Large Phase 3 Clinical Trial Of An Autologous Dendritic Cell Vaccine In Newly Diagnosed Glioblastoma, Linda M. Liau, Keyoumars Ashkan, David D. Tran, Jian L. Campian, John E. Trusheim, Charles S. Cobbs, Jason A. Heth, Michael Salacz, Sarah Taylor, Stacy D. D'Andre, Fabio M. Iwamoto, Edward J. Dropcho, Yaron A. Moshel, Kevin A. Walter, Clement P. Pillainayagam, Robert Aiken, Rekha Chaudhary, Samuel A. Goldlust, Daniela A Bota, Paul Duic, Jai Grewal, Heinrich Elinzano, Steven A. Toms, Kevin O. Lillehei, Tom Mikkelsen, Tobias Walbert, Steven R. Abram, Andrew J. Brenner, Steven Brem, Matthew G. Ewend, John L. Villano

Internal Medicine Faculty Publications

Background: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax^®-L) to standard therapy for newly diagnosed glioblastoma.

Methods: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS).

Results: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months …

First Results On Survival From A Large Phase 3 Clinical Trial Of An Autologous Dendritic Cell Vaccine In Newly Diagnosed Glioblastoma., Linda M. Liau, Keyoumars Ashkan, David D. Tran, Jian L. Campian, John E. Trusheim, Charles S. Cobbs, Jason A. Heth, Michael Salacz, Sarah Taylor, Stacy D. D'Andre, Fabio M. Iwamoto, Edward J. Dropcho, Yaron A. Moshel, Kevin A. Walter, Clement P. Pillainayagam, Robert Aiken, Rekha Chaudhary, Samuel A. Goldlust, Daniela A. Bota, Paul Duic, Jai Grewal, Heinrich Elinzano, Steven A. Toms, Kevin O. Lillehei, Tom Mikkelsen, Tobias Walbert, Steven R. Abram, Andrew J. Brenner, Steven Brem, Matthew G. Ewend, Simon Khagi, Jana Portnow, Lyndon J. Kim, William G. Loudon, Reid C. Thompson, David E Avigan, Karen L. Fink, Francois J. Geoffroy, Scott Lindhorst, Jose Lutzky, Andrew E. Sloan, Gabriele Schackert, Dietmar Krex, Hans-Jorg Meisel, Julian Wu, Raphael P Davis, Christopher Duma, Arnold B. Etame, David Mathieu, Santosh Kesari, David Piccioni, Manfred Westphal, David S. Baskin, Pamela Z. New, Michel Lacroix, Sven-Axel May, Timothy J. Pluard, Victor Tse, Richard M. Green, John L. Villano, Michael Pearlman, Kevin Petrecca, Michael Schulder, Lynne P Taylor, Anthony E. Maida, Robert M. Prins, Timothy F. Cloughesy, Paul Mulholland, Marnix L. Bosch

Department of Medical Oncology Faculty Papers

BACKGROUND: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax

METHODS: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS).

RESULTS: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly …

Muc4 Based Immunotherapy For Pancreatic Cancer, Kasturi Banerjee

Theses & Dissertations

Pancreatic Cancer (PC) is a lethal disease claiming approximately 45000 lives in the US in 2018, and it establishes an elaborate immunosuppressive tumor microenvironment that aids in disease pathogenesis. Immunotherapy has emerged as a strategy to target tumor cells by reprogramming patient’s immune system. Challenges present in PC immunotherapy are: i) identifying a tumor-associated antigen that could be targeted, ii) identifying adjuvants that could efficiently deliver antigens, iii) eliciting robust anti-tumor responses and iv) overcoming peripheral tolerance and immunosuppression elicited by the tumor.

Firstly, we detected circulating autoantibodies to MUC4 present in PC patients and observed that IgM autoantibodies to …

Improving Nk Cell Therapy For Osteosarcoma, Jennifer Foltz

Dissertations & Theses (Open Access)

Osteosarcoma (OS) is the most common primary bone tumor. Despite new treatment options, 5-year survival for metastatic OS has remained at only 30% for the last 30 years. Adoptive transfer of Natural Killer (NK) cells holds promise for a new, non-toxic therapy for OS. NK cells are part of the innate immune system and readily kill metastatic and chemotherapy-resistant OS in vitro and in murine models. However, there is little data regarding their efficacy in animal models with an intact immune system. In addition, the OS tumor microenvironment is highly suppressive, producing TGFβ which impedes NK cell killing of solid …

Developing Novel Approaches To Improve Response To T Cell Based Cancer Immunotherapy, Rina M. Mbofung

Dissertations & Theses (Open Access)

Recently, T cell based immunotherapies have moved to the forefront of cancer immunotherapy with the success of Adoptive T cell therapy (ACT) and Immune checkpoint blockade.ACT, where patients are treated with tumour infiltrating T cells (TILs), conferred a clinical response rate of ~50%. Treatment with anti-CTLA4 and anti –PD1 therapy, conferred response rates of up to 50%, greatly improving the overall survival of patients with advanced melanoma amongst other cancer types. Despite the encouraging outcomes, there are relatively low response rates coupled with the delay of weeks to months before tumour shrinkage can be appreciated. Thus, understanding what tumour intrinsic …

Investigating The Role Of The Retinoblastoma Protein In The Expression Of Immunosuppressive Factors, Felipe Pérez Deliz, Pedro Santiago-Cardona, Phd, J. González, Phd, Jaileene Pérez-Morales, Meng

Journal of Health Disparities Research and Practice

Lung cancer remains one of the deadliest types of cancer, causing approximately 160,000 deaths per year in the US alone. Because of its poor detection techniques and highly invasive abilities, conventional treatments -such as radiation and chemotherapy- fail to improve long-term survival of patients. At the moment, the 5-year survival rate for all stages of lung cancer is only 16%. Recent breakthroughs in cancer research establish immunotherapy, which involves the stimulation of the immune system to target and attack cancer cells, as a highly promising alternative treatment against this deadly disease. However, the efficiency of this treatment varies on each …

Immunotherapy Of Cancer: Reprogramming Tumor/Immune Cellular Crosstalk To Improve Anti-Tumor Efficacy, Kyle K. Payne

Theses and Dissertations

Immunotherapy of cancer has been shown to be promising in prolonging patient survival. However, complete elimination of cancer and life-long relapse-free survival remain to be major challenge for anti-cancer therapeutics. We have previously reported that ex vivo reprogramming of tumor-sensitized immune cells by bryostatin 1/ionomycin (B/I) and the gamma-chain (γ-c) cytokines IL-2, IL-7, and IL-15 resulted in the generation of memory T cells as well as CD25+ NKT cells and CD25+ NK cells. Adoptive cellular therapy (ACT) utilizing these reprogrammed immune cells protected FVBN202 mice from tumor challenge, and overcame the suppressive functions of myeloid-derived suppressor cells (MDSCs). We then …