Medical Sciences Commons^™

Autologous T Cell Therapy For Prame, Martin Wermke, Dejka M Araujo, Manik Chatterjee, Apostolia M Tsimberidou, Tobias A W Holderried, Amir A Jazaeri, Ran Reshef, Carsten Bokemeyer, Winfried Alsdorf, Katrin Wetzko, Peter Brossart, Katrin Aslan, Linus Backert, Sebastian Bunk, Jens Fritsche, Swapna Gulde, Silvana Hengler, Norbert Hilf, Mohammad B Hossain, Jens Hukelmann, Mamta Kalra, Delfi Krishna, M Alper Kursunel, Dominik Maurer, Andrea Mayer-Mokler, Regina Mendrzyk, Ali Mohamed, Karine Pozo, Arun Satelli, Marilena Letizia, Heiko Schuster, Oliver Schoor, Claudia Wagner, Hans-Georg Rammensee, Carsten Reinhardt, Harpreet Singh-Jasuja, Steffen Walter, Toni Weinschenk, Jason J Luke, Cedrik M Britten

Faculty, Staff and Student Publications

In contrast to chimeric antigen receptor T cells, T cell receptor (TCR)-engineered T cells can target intracellular tumor-associated antigens crucial for treating solid tumors. However, most trials published so far show limited clinical activity. Here we report interim data from a first-in-human, multicenter, open-label, 3 + 3 dose-escalation/de-escalation phase 1 trial studying IMA203, an autologous preferentially expressed antigen in melanoma (PRAME)-directed TCR T cell therapy in HLA-A*02+ patients with PRAME+ recurrent and/or refractory solid tumors, including melanoma and sarcoma. Primary objectives include the evaluation of safety and tolerability and the determination of the maximum tolerated dose (MTD) and/or recommended dose …

Tumour And Microenvironment Crosstalk In Nsclc Progression And Response To Therapy, Zahraa Rahal, Roy El Darzi, Seyed Javad Moghaddam, Tina Cascone, Humam Kadara

Faculty, Staff and Student Publications

The treatment landscape of non-small-cell lung cancer (NSCLC) is evolving rapidly, driven by advances in the development of targeted agents and immunotherapies. Despite this progress, some patients have suboptimal responses to treatment, highlighting the need for new therapeutic strategies. In the past decade, the important role of the tumour microenvironment (TME) in NSCLC progression, metastatic dissemination and response to treatment has become increasingly evident. Understanding the complexity of the TME and its interactions with NSCLC can propel efforts to improve current treatment modalities, overcome resistance and develop new treatments, which will ultimately improve the outcomes of patients. In this Review, …

Mis-Splicing-Derived Neoantigens And Cognate Tcrs In Splicing Factor Mutant Leukemias, Won Jun Kim, Edie I Crosse, Emma De Neef, Inaki Etxeberria, Erich Y Sabio, Eric Wang, Jan Philipp Bewersdorf, Kuan-Ting Lin, Sydney X Lu, Andrea Belleville, Nina Fox, Cynthia Castro, Pu Zhang, Takeshi Fujino, Jennifer Lewis, Jahan Rahman, Beatrice Zhang, Jacob H Winick, Alexander M Lewis, Robert F Stanley, Susan Dewolf, Brigita Meškauskaitė Urben, Meril Takizawa, Tobias Krause, Henrik Molina, Ronan Chaligne, Priya Koppikar, Jeffrey Molldrem, Mathieu Gigoux, Taha Merghoub, Anthony Daniyan, Smita S Chandran, Benjamin D Greenbaum, Christopher A Klebanoff, Robert K Bradley, Omar Abdel-Wahab

Faculty, Staff and Student Publications

Mutations in RNA splicing factors are prevalent across cancers and generate recurrently mis-spliced mRNA isoforms. Here we identified a series of bona fide neoantigens translated from highly stereotyped splicing alterations promoted by neomorphic, leukemia-associated somatic splicing machinery mutations. We utilized feature-barcoded peptide-MHC dextramers to isolate neoantigen-reactive T cell receptors (TCRs) from healthy donors, patients with active myeloid malignancy, and following curative allogeneic stem cell transplant. Neoantigen-reactive CD8+ T cells were present in the blood of patients with active cancer and had a distinct phenotype from virus-reactive T cells with evidence of impaired cytotoxic function. T cells engineered with TCRs recognizing …

Olaparib And Radiotherapy Induce Type I Interferon- And Cd8+ T Cell-Dependent Sensitization To Immunotherapy In Pancreatic Cancer, Victoria M Valvo, Qiang Zhang, Long Jiang, Erin A Holcomb, Ashley N Pearson, Anna G Edmunds, Hailey G Faulkner, Jadyn G James, Akshay Tate, Amanda K Huber, Zhuwen Wang, Yupei Guo, David Karnak, Leslie A Parsels, Joshua D Parsels, Yu L Lei, Alnawaz Rehemtulla, Heng Lin, Eileen S Carpenter, Daniel R Wahl, Vaibhav Sahai, Theodore S Lawrence, Michael D Green, Meredith A Morgan

Faculty, Staff and Student Publications

PARP inhibitors sensitize pancreatic ductal adenocarcinoma (PDAC) to radiation by inducing DNA damage and replication stress. These mechanisms also have the potential to enhance radiation-induced type I interferon (T1IFN) mediated anti-tumoral immune responses. We hypothesized that the PARP inhibitor olaparib would also potentiate radiation-induced T1IFN to promote anti-tumor immune responses and sensitization of otherwise resistant PDAC to immunotherapy. To test this hypothesis, we assessed the effects of olaparib and radiation on T1IFN production and sensitivity to αPD-L1 immunotherapy, as well as on the tumor microenvironment by single-cell RNA sequencing (scRNA-seq). We found that olaparib enhanced T1IFN production following radiation and …

Tumor Microenvironment Governs The Prognostic Landscape Of Immunotherapy For Head And Neck Squamous Cell Carcinoma: A Computational Model-Guided Analysis, Priyan Bhattacharya, Alban J Linnenbach, Andrew P. South, Ubaldo E. Martinez-Outshoorn, Joseph M. Curry, Jennifer M. Johnson, Larry A. Harshyne, Mỹ G. Mahoney, Adam J. Luginbuhl, Rajanikanth Vadigepalli

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

Immune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune escape of the tumor cells. Increasing evidence suggests that the onset, progression, and lack of/no response of HNSCC to ICI are emergent properties arising from the interactions within the tumor microenvironment (TME). Deciphering how the diversity of cellular and molecular interactions leads to distinct HNSCC TME subtypes subsequently governing the ICI response remains largely unexplored. We developed a cellular-molecular model of the HNSCC TME that incorporates multiple cell types, cellular states, and transitions, and molecularly …

Mutation Of Smarca4 Induces Cancer Cell-Intrinsic Defects In The Enhancer Landscape And Resistance To Immunotherapy, Yawen Wang, Ismail M Meraz, Md Qudratullah, Sasikumar Kotagiri, Yanyan Han, Yuanxin Xi, Jing Wang, Kadir C Akdemir, Jack A Roth, Yonathan Lissanu

Faculty, Staff and Student Publications

Cancer genomic studies have identified frequent alterations in genes encoding components of the SWI/SNF chromatin remodeling complex, including SMARCA4 and ARID1A. Importantly, clinical reports indicate that SMARCA4-mutant lung cancers respond poorly to immunotherapy and have dismal prognosis. In this study, we corroborated the clinical findings by using immune-humanized, syngeneic, and genetically engineered mouse models of lung cancer harboring SMARCA4 deficiency. Specifically, models with SMARCA4 loss showed decreased response to anti-PD-1 immunotherapy associated with significantly reduced infiltration of dendritic cells and CD4+ T cells into the tumor microenvironment. SMARCA4 loss in tumor cells led to profound downregulation of STING1, IL1β, and …

Targeted Sting Activation Using Modified Ultrasound-Responsive Microbubbles Enhances Immune Checkpoint Blockade Against Melanoma, Sina Khorsandi, Kristin Huntoon, Yifan Wang, Adam Woodward, Abin Antony, Connor Endsley, Nazia Hafeez, Jared L Edwards, Nicole Mccuen, Prasanna G Alluri, Betty Y S Kim, Wen Jiang, Jacques Lux

Faculty, Staff and Student Publications

Despite the recent successes of immune checkpoint inhibitors (ICIs) in treating advanced melanoma, durable clinical responses still remain limited. To boost immune responses, agents that target immune regulators, such as the Stimulator of Interferon Genes (STING) agonist cyclic GMP-AMP (cGAMP), are being investigated. However, their clinical translation is impeded by poor serum stability, rapid tissue clearance, and T-cell death due to off-target activation. Recently, a novel strategy termed Microbubble-assisted UltraSound-guided Immunotherapy of Cancer (MUSIC) has been reported to selectively deliver cGAMP directly into the cytosol of antigen-presenting cells with spatiotemporal control. The resulting activation of STING and downstream proinflammatory pathways …

Anti-Viral Cd8 Central Memory Veto Cells As A New Platform For Car T Cell Therapy, Wei-Hsin Liu, Anat Globerson Levin, Assaf Lask, Galit Horn, Tova Waks, Bar Nathansohn Levi, Irit Milman Krentsis, Einav Shoshan, Xiaohua Su, Maksim Mamonkin, Richard E Champlin, Yair Reisner, Esther Bachar Lustig

Faculty, Staff and Student Publications

Central memory CD8 T cells exhibit marked veto activity enhancing engraftment in several mouse models of T cell-depleted bone marrow (TDBM) allografting. Graft-versus-host disease (GVHD) can be prevented by stimulation of mouse or human memory CD8 T cells against their cognate antigens under cytokine deprivation, in the early phase of culture followed by further expansion with IL21, IL15, and IL7. Thus, human anti-viral CD8 central memory veto T cells generated from CMV and EBV-positive donors are currently evaluated in a clinical trial at MD Anderson Cancer Centre (MDACC). Results in 15 patients indicate a low risk of GVHD. Considering that …

Role Of Systemic Therapy In Localized Renal Cell Carcinoma: Where Do We Stand And Where Are We Heading?, Deepa Raghavan, Viktoriya Gibatova, Nikhil Vojjala, Nagaishwarya Moka, Aihua Edward Yen

Faculty, Staff and Students Publications

The effectiveness of immunotherapy and targeted therapy has been well established in metastatic renal cell cancer (mRCC). These therapies demonstrated higher overall response rates and led to prolonged survival. In contrast, in localized RCC, conventional treatment is either partial or complete nephrectomy. While surgery is a curative option in early stages, high recurrence rates remain a concern, with survival rates ranging from 53% to 85%, depending on the initial stage at the time of diagnosis. Given favorable outcomes with systemic therapies in the metastatic setting, there has also been an increased interest in utilizing these therapies for the localized stage …

Immunotherapy With Nebulized Pattern Recognition Receptor Agonists Restores Severe Immune Paralysis And Improves Outcomes In Mice With Influenza-Associated Pulmonary Aspergillosis, Jezreel Pantaleón García, Sebastian Wurster, Nathaniel D Albert, Uddalak Bharadwaj, Keerthi Bhoda, Vikram K Kulkarni, Mbaya Ntita, Paris Rodríguez Carstens, Madeleine Burch-Eapen, Daniela Covarrubias López, Jania Foncerrada Lizaola, Katherine E Larsen, Lauren M Matula, Seyed J Moghaddam, Yongxing Wang, Dimitrios P Kontoyiannis, Scott E Evans

Faculty, Staff and Student Publications

Influenza-associated pulmonary aspergillosis (IAPA) is a potentially deadly superinfection in patients with influenza pneumonia, especially those with severe disease, underlying immunosuppression, corticosteroid therapy, or requiring intensive care support. Given the high mortality of IAPA, adjunct immunomodulatory strategies remain a critical unmet need. Previously, the desensitization of pattern recognition pathways has been described as a hallmark of IAPA pathogenesis and a predictor of mortality in IAPA patients. Therefore, we studied the impact of nebulized Toll-like receptor 2/6/9 agonists Pam2 CSK4 (Pam2) and CpG oligodeoxynucleotides (ODNs) on infection outcomes and pulmonary immunopathology in a corticosteroid-immunosuppressed murine IAPA model. Mice with IAPA receiving …

Identification And Preclinical Assessment Of Novel Therapeutic Modalities In Environmental Exposure-Induced Lung Disease, Aaron D. Schwab

Theses & Dissertations

Environmental lung diseases are preventable respiratory conditions either caused or made worse by inhaled environmental exposures. Contemporarily, environmental lung diseases are most associated with workplace exposures given specific occupational processes aerosolize inflammatory agents that can be inhaled at high concentrations. Although a considerable amount is known regarding immunoglobulin (Ig)E-mediated responses to environmental exposures, little is known about non-IgE mediated respiratory conditions resulting from lipopolysaccharide (LPS)-enriched organic dust exposure(s). Chronic respiratory diseases such as asthma, hypersensitivity pneumonitis, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis have all been identified as environmental lung diseases caused or exacerbated by such environmental dusts. Therapeutic …

Allogeneic Chimeric Antigen Receptor T-Cell Products Cemacabtagene Ansegedleucel/Allo-501 In Relapsed/Refractory Large B-Cell Lymphoma: Phase I Experience From The Alpha2/Alpha Clinical Studies, Frederick L Locke, Javier L Munoz, Michael T Tees, Lazaros J Lekakis, Sven De Vos, Rajneesh Nath, Don A Stevens, Shahbaz A Malik, Geoffrey P Shouse, Mehdi Hamadani, Olalekan O Oluwole, Miguel-Angel Perales, David B Miklos, Paul W Fisher, Amy Feng, Lynn Navale, John B Le Gall, Sattva S Neelapu

Faculty, Staff and Student Publications

Purpose: Off-the-shelf, allogeneic CD19 chimeric antigen receptor (CAR) T-cell products may improve access to treatment versus autologous ones. We report the phase I experience of the allogeneic CD19 CAR T-cell product cemacabtagene ansegedleucel (cema-cel) and its predecessor, ALLO-501, in CD19 CAR T-naïve patients with relapsed/refractory large B-cell lymphoma (R/R LBCL).

Methods: In the ALPHA2/ALPHA studies, the safety and efficacy of allogeneic CD19 CAR T cells were evaluated in CD19 CAR T treatment-naïve patients with R/R LBCL. Patients received healthy donor-derived, human leukocyte antigen-unmatched cema-cel/ALLO-501 following a 3-day lymphodepletion regimen of fludarabine (30 mg/m2 once daily), cyclophosphamide (300 or 500 mg/m2 …

Metabolic Reprogramming Driven By Ant2 Deficiency Augments T Cell Function And Anti-Tumor Immunity In Mice, Omri Yosef, Leonor Cohen-Daniel, Oded Shamriz, Zahala Bar-On, Wajeeh Salaymeh, Amijai Saragovi, Ifat Abramovich, Bella Agranovich, Veronika Lutz, Joseph Tam, Anna Permyakova, Eyal Gottlieb, Magdalena Huber, Michael Berger

Faculty, Staff and Student Publications

T cell activation requires a substantial increase in NAD+ production, often exceeding the capacity of oxidative phosphorylation (OXPHOS). To investigate how T cells adapt to this metabolic challenge, we generate T cell-specific ADP/ATP translocase-2 knockout (Ant2-/-) mice. Loss of Ant2, a crucial protein mediating ADP/ATP exchange between mitochondria and cytoplasm, induces OXPHOS restriction by limiting ATP synthase activity, thereby impeding NAD+ regeneration. Interestingly, Ant2-/- naïve T cells exhibit enhanced activation, proliferation and effector functions compared to wild-type controls. Metabolic profiling reveals that these T cells adopt an activated-like metabolic program with increased mitobiogenesis and anabolism. Lastly, pharmacological inhibition of ANT …

Immune-Related Adverse Events Associated With Pembrolizumab In Dmmr/Msi-H Colorectal Cancer: A Single Arm Safety Meta-Analysis, Joshi Simran, Saman Javid, Gaurav Sharma, Corinne Caissie, Armando Dominguez-Diaz

Posters

Pembrolizumab, a PD-1 checkpoint inhibitor, enhances immune response and has proven effective against various cancers, including melanoma, non-small cell lung cancer, and head and neck squamous cell carcinoma.

Clinical trials have also shown its efficacy in treating various types of cancers with different mismatch-repair statuses. However, the spectrum and frequency of immune-related adverse events (irAEs) in the dMMR (deficient mismatch repair) / MSI-H (microsatellite instability-high) colorectal cancer remain underexplored.

Therefore, this meta-analysis aims to evaluate pembrolizumab's safety profile in this colorectal cancer subset.

Fc Gamma Receptors Facilitate Antigenic Modulation Of Lilrb4 And Function As Predictive Biomarkers In Acute Monocytic Leukemia, Joshua Morse

Dissertations and Theses (Open Access)

Acute monocytic leukemia (monocytic AML) is a subtype of AML marked by a proliferation of abnormal monoblasts. This subtype represents approximately 10% of AML cases. The prognosis of monocytic AML is poor, with a 5-year survival of ~30%. Most patients are diagnosed at an age when they are unlikely to survive first-line non-targeted cytotoxic chemotherapy as a bridge to hematopoietic stem cell transplant (HSCT). Even patients who achieve remission commonly relapse. This population of patients would greatly benefit from precision-targeted therapies but currently there are none approved for monocytic AML.

Leukocyte immunoglobulin-like receptor B4 (LILRB4) is an immune checkpoint expressed …

Clinical Implications Of Mismatch Repair Deficiency In Pancreatic Ductal Adenocarcinoma, Zachary Kaplan, Elizabeth Prezioso, Aditi Jain, Harish Lavu, Charles Yeo, Wilbur Bowne, Avinoam Nevler

Kimmel Cancer Center Faculty Papers

BACKGROUND: Pancreatic cancer is a highly aggressive and lethal disease, characterized by a limited response to chemotherapy and overall poor prognosis. Pancreatic cancers with a distinct mismatch repair deficiency, although relatively rare, have been shown to be associated with markedly better outcomes in comparison. Furthermore, whereas pancreatic cancers are generally unresponsive to current immunotherapy, this specific group of tumors has been shown to have a notable susceptibility to immune checkpoint inhibitors.

AIMS: In this review, we aim to summarize the relevant literature regarding mismatch-repair associated pancreatic cancers, the impacted biological mechanisms, and the resulting vulnerabilities for potential opportunistic immunotherapeutic treatment …

Long-Term Safety Of Epicutaneous Immunotherapy In Peanut-Allergic Children: An Open-Label Active Treatment (Realise Study), Jacqueline A Pongracic, Rémi Gagnon, Gordon Sussman, Dareen Siri, Roxanne C Oriel, Terri F Brown-Whitehorn, Sara Anvari, William E Berger, J Andrew Bird, Edmond S Chan, R Sharon Chinthrajah, Hey J Chong, Stanley M Fineman, David M Fleischer, Erika Gonzalez-Reyes, Edwin H Kim, Bruce J Lanser, Andrew Macginnitie, Hemalini Mehta, Daniel Petroni, Ned Rupp, Lynda C Schneider, Amy M Scurlock, Lawrence D Sher, Wayne G Shreffler, Sayantani B Sindher, Robert Wood, William H Yang, Hugh A Sampson, Timothée Bois, Todd D Green, Dianne E Campbell, Katharine J Bee, Philippe Bégin

Faculty, Staff and Students Publications

Background: Owing to limited treatment options for peanut allergy, patients remain at risk for allergic reactions due to accidental exposure. Epicutaneous immunotherapy (EPIT) is a novel treatment being investigated for peanut allergy.

Objective: This study assessed long-term safety of EPIT with VIASKIN peanut patch 250 μg (VP250) via an open-label extension of the REAL Life Use and Safety of EPIT (REALISE) trial.

Methods: REALISE was a phase 3 trial in peanut-allergic children aged 4 through 11 years that included a 6-month, randomized, double-blind, placebo-controlled treatment phase, followed by an open-label, single-arm, active treatment period for up to 36 months.

Results: …

Pembrolizumab In Patients With Advanced Miscellaneous Rare Cancers: Results From A Phase 2 Basket Trial, Mirella Nardo, Camila Braganca Xavier, Bettzy Stephen, Jeffrey A How, Justin Moyers, Vivek Subbiah, David S Hong, Aung Naing

Faculty, Staff and Student Publications

Introduction: Rare solid tumors account for one-quarter of cancers among adults in the United States, but few resources have been devoted to their treatment. We evaluated the efficacy of pembrolizumab, a programmed cell death-1 inhibitor, in patients with rare solid tumors.

Methods: We conducted a phase 2 basket trial that included patients with rare, advanced tumors. Patients were enrolled in the study in nine tumor-specific and a 10th cohort of miscellaneous rare histologies. Patients received pembrolizumab 200 mg intravenously every 21 days. The primary endpoint was the non-progression rate at 27 weeks per immune-related Response Evaluation Criteria in Solid Tumors …

Comic: A Bayesian Dose Optimization Design For Drug Combination In Multiple Indications With Application To Car-T Therapies, Kai Chen, Kentaro Takeda, Ying Yuan

Faculty, Staff and Student Publications

Project Optimus, initiated by the US Food and Drug Administration (FDA), seeks to shift the focus of dose finding and selection from the maximum tolerated dose to the optimal dose that offers the most favorable risk-benefit balance. However, applying this paradigm shift to drug combination trials presents challenges, particularly due to limited sample sizes and a large two-dimensional dose exploration space. These challenges are amplified when trials involve multiple indications. To address this, we developed a two-stage Bayesian dose optimization design, called COMIC (Combination Optimization in Multiple IndiCations), to efficiently identify Optimal Biological Dose Combinations (OBDC) for multiple indications. The …

Lefitolimod In Combination With Ipilimumab In Patients With Advanced Solid Tumors: A Phase I Trial, Mirella Nardo, Mohamed A Gouda, Matthew J Reilley, Amadeo B Biter, Joann Lim, Stacie A Bean, Ly M Nguyen, Priya R Bhosale, Casey R Ager, Coline A Couillault, Sarina A Piha-Paul, Siqing Fu, Apostolia M Tsimberidou, Timothy A Yap, Aung Naing, Jordi Rodon, Vivek Subbiah, Daniel D Karp, Michael A Curran, David S Hong

Faculty, Staff and Student Publications

Introduction: TLR9 agonists are immunomodulators that have been of interest for combined use with cancer immunotherapy. TLR9 agonists, such as lefitolimod (MGN1703), significantly increased Th1 response in preclinical models and have demonstrated efficacy in early clinical trials. This trial assessed the safety and preliminary efficacy of the combination of lefitolimod and ipilimumab in patients with advanced solid tumors.

Methods: This was a single-center, open-label, investigator-initiated phase I trial conducted at The University of Texas MD Anderson Cancer Center. Patients received leftolimod either subcutaneously (at escalating doses of 15-120 mg) or intratumorally (at the maximum feasible dose) in combination with ipilimumab …

Immune Landscape Of Early Liver Metastatic Lesions In A Novel Immunocompetent Murine Colorectal Cancer Metastasis Model, Alaa Mohamed

Dissertations and Theses (Open Access)

Colorectal cancer minimal residual disease (MRD) represents a major clinical problem for colorectal cancer patients, with failure rates of surgery and adjuvant chemotherapy between 5% to 40% depending on stage of disease. In our study, we simulated MRD using genetically engineered organoids with precise somatic editing of APC and TP53, creating a murine model that mimics human liver metastatic colorectal cancer. By implementing a meticulously timed experimental metastatic model, we could detect microscopic tumor lesions. Through genomic and transcriptomic analyses, we pinpointed the importance of macrophages, particularly those expressing high levels of CSF1R, in these microscopic metastatic focal lesions. We …

Chemotherapy-Free Treatment With Radiotherapy And Immunotherapy For Locally Advanced Non-Small Cell Lung Cancer, M Zeeshan Ozair, Balazs Halmos, Angelica D'Aiello, Jaewon Yun, Andrea R Filippi, Andreas Rimner, Steven H Lin, Charles B Simone, Nitin Ohri

Faculty, Staff and Student Publications

Background: Concurrent chemoradiotherapy (CRT) followed by immunotherapy is a standard treatment for locally advanced non-small cell lung cancer (LA-NSCLC), yet many patients are ineligible due to treatment-related toxicity or poor functional status. Chemotherapy-free approaches using radiotherapy (RT) and immunotherapy may offer a safer and equally effective alternative in select patient populations.

Methods: A comprehensive literature review was conducted using PubMed, Google Scholar, and relevant conference proceedings focusing on trials between 2000 and 2024. Studies investigating chemotherapy-free regimens combining RT and immunotherapy in LA-NSCLC were analyzed, with emphasis on clinical outcomes, biomarker use, treatment sequencing, radiation dose/fractionation, and safety.

Results: Multiple …

Differential Antibody Response To Ebv Proteome Following Ebvst Immunotherapy In Ebv-Associated Lymphomas, Yomani D Sarathkumara, Nathan W Van Bibber, Zhiwei Liu, Helen E Heslop, Rayne H Rouce, Anna E Coghill, Cliona M Rooney, Carla Proietti, Denise L Doolan

Faculty, Staff and Students Publications

Epstein-Barr virus (EBV) is associated with a diverse range of lymphomas. EBV-specific T-cell (EBVST) infusions have shown promise in safety and clinical effectiveness in treating EBV-associated lymphomas; however, not all patients respond to T-cell immunotherapies. To identify EBV antigen–specific antibody responses associated with clinical outcomes, we comprehensively characterized antibody responses to the complete EBV proteome using a custom protein microarray in 56 patients with EBV-associated lymphoma who received EBVST infusions in phase 1 clinical trials. Responders (nonprogressors) and nonresponders (progressors) had distinct antibody profiles against EBV. Twenty-five immunoglobulin G (IgG) antibodies were significantly elevated in higher levels in nonresponders than …

Hif Regulates Multiple Translated Endogenous Retroviruses: Implications For Cancer Immunotherapy, Qinqin Jiang, David A Braun, Karl R Clauser, Vijyendra Ramesh, Nitin H Shirole, Joseph E Duke-Cohan, Nancy Nabilsi, Nicholas J Kramer, Cleo Forman, Isabelle E Lippincott, Susan Klaeger, Kshiti M Phulphagar, Vipheaviny Chea, Nawoo Kim, Allison P Vanasse, Eddy Saad, Teagan Parsons, Melissa Carr-Reynolds, Isabel Carulli, Katarina Pinjusic, Yijia Jiang, Rong Li, Sudeepa Syamala, Suzanna Rachimi, Eva K Verzani, Jonathan D Stevens, William J Lane, Sabrina Y Camp, Kevin Meli, Melissa B Pappalardi, Zachary T Herbert, Xintao Qiu, Paloma Cejas, Henry W Long, Sachet A Shukla, Eliezer M Van Allen, Toni K Choueiri, L Stirling Churchman, Jennifer G Abelin, Cagan Gurer, Gavin Macbeath, Richard W Childs, Steven A Carr, Derin B Keskin, Catherine J Wu, William G Kaelin

Faculty, Staff and Student Publications

Clear cell renal cell carcinoma (ccRCC), despite having a low mutational burden, is considered immunogenic because it occasionally undergoes spontaneous regressions and often responds to immunotherapies. The signature lesion in ccRCC is inactivation of the VHL tumor suppressor gene and consequent upregulation of the HIF transcription factor. An earlier case report described a ccRCC patient who was cured by an allogeneic stem cell transplant and later found to have donor-derived T cells that recognized a ccRCC-specific peptide encoded by a HIF-responsive endogenous retrovirus (ERV), ERVE-4. We report that ERVE-4 is one of many ERVs that are induced by HIF, translated …

Zp4: A Novel Target For Car-T Cell Therapy In Triple Negative Breast Cancer, Lauren K Somes, Jonathan T Lei, Xinpei Yi, Diego F Chamorro, Paul Shafer, Ahmed Z Gad, Lacey E Dobrolecki, Emily Madaras, Nabil Ahmed, Michael T Lewis, Bing Zhang, Valentina Hoyos

Faculty, Staff and Students Publications

Triple-negative breast cancer (TNBC) remains one of the most challenging subtypes of breast cancer to treat due to a lack of effective targeted therapies. Chimeric antigen receptor (CAR)-T cells hold promise, but their efficacy in solid tumors is often limited by on-target/off-tumor toxicities. Through comprehensive bioinformatic analysis of public RNA and proteomic data, we identified zona pellucida glycoprotein 4 (ZP4) as a novel target for TNBC. ZP4 RNA and protein were detected in a subset of TNBC patient samples and patient-derived xenograft (PDX) models, with expression otherwise restricted to oocytes. We generated 89 ZP4-specific novel monoclonal antibodies and used the …

Prdm1 Is A Key Regulator Of The Nkt-Cell Central Memory Program And Effector Function, Gengwen Tian, Gabriel A Barragan, Hangjin Yu, Claudia Martinez-Amador, Akshaya Adaikkalavan, Xavier Rios, Linjie Guo, Janice M Drabek, Osmay Pardias, Xin Xu, Antonino Montalbano, Chunchao Zhang, Yanchuan Li, Amy N Courtney, Erica J Di Pierro, Leonid S Metelitsa

Faculty, Staff and Students Publications

Natural killer T cells (NKTs) are a promising platform for cancer immunotherapy, but few genes involved in the regulation of NKT therapeutic activity have been identified. To find regulators of NKT functional fitness, we developed a CRISPR/Cas9-based mutagenesis screen that uses a guide RNA (gRNA) library targeting 1,118 immune-related genes. Unmodified NKTs and NKTs expressing a GD2-specific chimeric antigen receptor (GD2.CAR) were transduced with the gRNA library and exposed to CD1d+ leukemia or CD1d-GD2+ neuroblastoma cells, respectively, over six challenge cycles in vitro. Quantification of gRNA abundance revealed enrichment of PRDM1-specific gRNAs in both NKTs and GD2.CAR NKTs, a result …

Combined Systemic Immunotherapy And Intrathecal Dexamethasone In Febrile Infection Related Epilepsy Syndrome, Kristen S Fisher, Alexander Ankar, Jon Cokley, Eyal Muscal, James J Riviello, Yi-Chen Lai

Faculty, Staff and Students Publications

Febrile infection related epilepsy syndrome (FIRES) is a rare presentation of refractory status epilepticus with immune dysregulation as a potential pathologic mechanism. Despite promising results from second-line immunomodulators, approximately 30% remain refractory to treatment. We describe two children with FIRES who were unable to wean from anesthetic infusions with immunomodulatory treatment and subsequently received concurrent intrathecal dexamethasone and anakinra/tocilizumab as escalation of therapy. Following the initiation of this combined regimen, anesthetic infusions were decreased while maintaining seizure freedom. These cases demonstrate proof of principle that a multi-modal approach may be beneficial and should be considered in the treatment of FIRES.

Il-12-Producing Cytokine Factories Induce Precursor Exhausted T Cells And Elimination Of Primary And Metastatic Tumors, Amanda Nash, Jonathon Debonis, Danna Murungi, Bertha Castillo, Boram Kim, Fangheng Hu, Courtney Chambers, Annie Nguyen, Andrea Hernandez, Zeshi Wang, Peter D Rios, Sofia Ghani, Ira Joshi, Douglas Isa, Ningbo Zheng, Weiyi Peng, Oleg A Igoshin, Jose Oberholzer, H Courtney Hodges, Nathan Reticker-Flynn, Omid Veiseh

Faculty, Staff and Students Publications

Background: Curative responses to immunotherapy require the generation of robust systemic immunity with limited toxicity. Recruitment of T cell populations such as precursor exhausted T cells (Tpex) from lymphoid tissues to tumors is a hallmark of effective treatment. However, the ability to efficiently induce this recruitment is lacking in current immunotherapy approaches. Furthermore, systemic administration of immunotherapies frequently results in dose-limiting toxicities, yielding an inadequate therapeutic window for eliciting durable responses.

Methods: In this investigation, we evaluated the safety and antitumor efficacy of locally administered interleukin 12 (IL-12) using a clinically translatable cytokine delivery platform (NCT05538624) to identify …

Soluble Mesothelin-Related Peptide As A Prognosticator In Pleural Mesothelioma Patients Receiving Checkpoint Immunotherapy, Sonali Mitra, Hee-Jin Jang, Allen Kuncheria, Sung Wook Kang, Jong Min Choi, Ji Seon Shim, Claire Lee, Priyanka Ranchod, Peter Jindra, Maheshwari Ramineni, Meera Patel, R Taylor Ripley, Shawn S Groth, Shanda H Blackmon, Bryan M Burt, Hyun-Sung Lee

Faculty, Staff and Students Publications

Background: Immune checkpoint therapy (ICT) has significantly impacted the treatment of malignant pleural mesothelioma (MPM). Despite some promising results from combination therapies, nearly half of MPM patients do not benefit, underscoring the urgent need for reliable predictive biomarkers. This study assesses the prognostic value of serum soluble mesothelin-related peptide (SMRP) and PD-L1 levels in MPM patients receiving ICT.

Methods: We conducted a retrospective analysis of 125 MPM patients treated with ICT by measuring pre-ICT serum levels of SMRP and PD-L1. We also examined the correlation of these serum levels with tumor mRNA expressions of mesothelin and PD-L1. Both univariable and …

Real-World Effectiveness Of Chemoimmunotherapy And Novel Therapies For Patients With Relapsed/Refractory Aggressive Large B-Cell Lymphoma, Loretta J Nastoupil, Clark R Andersen, Amy Ayers, Yucai Wang, Thomas M Habermann, Dai Chihara, Brad S Kahl, Brian K Link, Jean L Koff, Jonathon B Cohen, Peter Martin, Izidore S Lossos, Michele Stanchina, Sara Haddadi, Carla Casulo, Sabarish Ayyappan, Ruitao Lin, Ziyi Li, Melissa A Larson, Matthew J Maurer, Lynn Huynh, Chi Gao, Ramya Ramasubramanian, Mei Sheng Duh, Alex Mutebi, Tongsheng Wang, Monika Jun, Anthony Wang, Rajesh Kamalakar, Anupama Kalsekar, James R Cerhan, Christopher R Flowers

Faculty, Staff and Student Publications

Introduction: Clinical trials provide meaningful data regarding the safety and efficacy of novel therapies but there is often a lag between the time of new drug approval and information on posttreatment clinical outcomes in real-world practice. This study evaluated clinical outcomes in a large real-world population of patients with relapsed and/or refractory large B-cell lymphoma (r/r LBCL) treated with chemoimmunotherapy or novel therapies in second or later lines of therapy (2L+).

Materials and methods: Data from the Lymphoma Epidemiology of Outcomes (LEO) Consortium of Real-World Evidence (CReWE) cohort (1/1/2015-2/15/2023) were analyzed. Patients' demographic and clinical characteristics were described and response …