Medical Specialties Commons^™

Standardization Of Objectives And Response Criteria For Neoadjuvant Immunotherapy In Resectable Squamous Cell Carcinoma Of The Head And Neck, Carlo Resteghini, Athanassios Argiris, Pierre Blanchard, Irene Braña, Anna Maria Camarda, Anthony T. C. Chan, Robert Ferris, Vincent Gregoire, Kevin J. Harrington, Ingeborg Tinhofer, Senada Koljenović, Nancy Y. Lee, C. René Leemans, Jean-Pascal Machiels, Hisham Mehanna, Robert Metcalf, Brian O'Sullivan, Sjoukje Oosting, Ester Orlandi, Vinidh Paleri, Amanda Psyrri, Nabil F F. Saba, Sandra Schmitz, Christian Simon, Makoto Tahara, Vincent Vander Poorten, Milan Vošmik, Paolo Bossi

Department of Medical Oncology Faculty Papers

The management of locally-advanced, resectable head and neck squamous cell carcinoma (HNSCC) is undergoing a major shift driven by the integration of neoadjuvant immunotherapy (nIO). The rationale for nIO lies in its administration within an immunologically active, treatment-naïve microenvironment that enhances immune priming and anti-tumor response. Despite encouraging clinical data, including the pivotal KEYNOTE-689 trial and multiple phase II studies, methodological heterogeneity in trial design, endpoint definitions, and response criteria currently hampers data comparability and the establishment of new standards of care. This expert narrative review proposes a structured framework for standardizing clinical, pathologic, imaging, and translational endpoints in HNSCC …

Chemotherapeutic Induction Of Cytosolic Single-Stranded Dna Accumulation Sensitizes Triple-Negative Breast Cancer To Immunotherapy, Yong Du, Li Yang, Hui Dai, Jianli Zhou, Zhicheng Zhou, Ruoxi Yuan, Rui Ye, Anh Thai Quynh Nguyen, Kishor Bhatia, Shiaw-Yih Lin

Faculty, Staff and Students Publications

Background: Despite the widespread adoption of chemoimmunotherapy in triple-negative breast cancer (TNBC), the mechanisms by which cytotoxic chemotherapy engages antitumor immunity remain poorly defined. Identifying tumor-intrinsic immunogenic programs that predict and enhance responsiveness to immune checkpoint blockade (ICB) is therefore of critical clinical importance.

Methods: Transcriptomic signatures of TREX1 deficiency were generated from CRISPR-engineered TNBC models and applied to multiple independent TNBC cohorts treated with chemoimmunotherapy. Cytosolic single-stranded DNA (ssDNA) accumulation was quantified using a flow cytometry-based assay to functionally screen chemotherapeutic agents. Immune activation and therapeutic efficacy were evaluated using in vitro assays, syngeneic mouse tumor models, flow cytometry, …

Prevalence Of Adverse Events Following T-Cell Redirecting Therapies In Patients With Metastatic Castration-Resistant Prostate Cancer: A Pooled Analysis, Abhiraj Saxena, Marc Yorker, Nicholas Zorko, Vivek Narayan, Bilal Siddiqui, Biren Saraiya, William Tester, Patrick Mille, Amy Shaver, Nikita Nikita, Grace Lu-Yao, W. Kevin Kelly, Kevin K. Zarrabi

Department of Medical Oncology Faculty Papers

BACKGROUND: T-cell redirecting therapies, including T-cell engagers (TCEs) and Chimeric Antigen Receptor T-cell (CAR-T), are under investigation in metastatic castration-resistant prostate cancer (mCRPC). Despite their promising therapeutic potential, these therapies remain in early stages of development due to treatment-related adverse events (TRAEs). This study aims to quantify the frequency and severity of adverse events in clinical trials with a pooled analysis.

MATERIALS AND METHODS: A systematic search of PubMed, CINHAL, Scopus, and Ovid was conducted to identify clinical trials evaluating TCEs or CAR-T in patients with mCRPC. Types and frequencies of TRAEs were collected and analyzed using a random-effects model. …

Comparative Effectiveness Of Immunotherapy Alone Or With Chemotherapy As First-Line Treatment For Marginal Zone Lymphoma, Adam Olszewski, Thomas Ollila, Dai Chihara, Geoffrey Shouse, Natalie Grover, Reem Karmali, Pallawi Torka, Colin Thomas, Praveen Ramakrishnan Geethakumari, Stefan Barta, Nancy Bartlett, Narendranath Epperla

Cardeza Foundation for Hematologic Research

No abstract provided.

A Multidomain Peptide Hydrogel-Liposome Composite For Controlled Release Of A Cyclic Dinucleotide In Oral Cancer, Joseph W R Swain, Andrea H Molina, Gemalene M Sunga, Danielle Chew-Martinez, Neeraja Dharmaraj, Alejandra Cobos Perez, Arghadip Dey, Ephraim J Vázquez-Rosado, Simon Young, Jeffrey D Hartgerink

Faculty, Staff and Student Publications

While immunotherapy is a promising treatment strategy for cancer, the majority of head and neck squamous cell carcinoma (HNSCC) patients treated with single-agent immunotherapy do not respond. Therefore, researchers are investigating combination treatments with immunostimulatory molecules that can maximize anti-tumor responses. Cyclic dinucleotides (CDNs) are STING agonists that hold promise in combination approaches, but they require frequent intratumoral administration when used in both preclinical models of HNSCC and clinical trials. To reduce administration frequency, we have created a peptide hydrogel–liposome composite system, K2-Lip(CDN), for local and prolonged availability of CDN. We investigated the loading limits of cationic liposomes in both …

Multiparametric Mri To Predict Response To Irreversible Electroporation Plus Anti-Pd-1 Immunotherapy In Pancreatic Ductal Adenocarcinoma, Qizhen Cao, Mark D Pagel, Charles V Kingsley, Jingfei Ma, James P Long, Xiaoxia Wen, Seth T Gammon, Jorge Delacerda, Sanaz Javadi, Chun Li

Faculty, Staff and Student Publications

Purpose: To investigate contrast-enhanced T1-weighted MRI and diffusion-weighted magnetic resonance imaging (DWI) for early prediction of tumor response to combined irreversible electroporation (IRE) and anti-PD-1 immunotherapy.

Methods: Murine pancreatic ductal adenocarcinoma (PDAC) cells KRAS* were inoculated into the pancreas of C57BL/6 mice. IRE was performed when tumors became palpable. After IRE, mice received six intraperitoneal injections of anti-PD-1 over 2 weeks. T2-weighted MRI, T1-weighted MRI with macromolecular contrast agent poly(L-glutamic acid)-conjugated gadolinium (PG-Gd), and DWI were performed before and after IRE. Survival was analyzed using Kaplan-Meier curves. Mice surviving at least 100 days without recurrence after IRE were considered complete …

Immunotherapy Of Tsa-1.C4 Or In Combination With Bnz Confers Protection Against Trypanosoma Cruzi Infection With A Distinct Cytokine Response, Landy Magaly Pech-Pisté, Victor Dzul-Huchim, Christian Florian Teh-Poot, Fabian Gusovsky, Kathryn Jones, Peter Hotez, Liliana Estefanía Villanueva-Lizama, Maria Elena Bottazzi, Jaime Ortega-Lopez, Julio Vladimir Cruz-Chan

Faculty, Staff and Students Publications

Chagas disease is a poverty-related neglected tropical disease caused by the protozoan Trypanosoma cruzi affecting approximately 6.3 million people, predominantly in the Americas. Approximately 30% of T. cruzi infections progress to chronic cardiomyopathy and 10% of these cases end in death from cardiac failure. The first-line drug Benznidazole (BNZ) require a prolonged treatment regimen and can be highly toxic. Here, we evaluate a therapeutic vaccine in T. cruzi-infected mice, based on the recombinant Trypomastigote Surface Antigen 1 (TSA-1.C4) protein and the emulsified adjuvant E6020, and in combination with a suboptimal dose of BNZ. We observed a reduced burden parasite in …

High Dietary Fiber Is Associated With Improved Outcomes In Patients With Melanoma And Sarcoma Treated With Immunotherapy Regardless Of Gut Microbiome Dysbiosis And Social Vulnerability, Brittany C Fields, Raymond S Traweek, Kai Jiang, Russell G Witt, Ashish Damania, Yi-Ju Chiang, Nadim Ajami, Elise Nassif-Haddad, Emily Z Keung, Manoj Chelvanambi, Xiaotao Zhang, Christine B Peterson, Jennifer A Wargo, Carrie R Daniel, Christina L Roland, Ashley M Holder

Faculty, Staff and Student Publications

Background: Social vulnerability, dietary fiber, and the gut microbiome have been individually implicated in clinical outcomes for melanoma and sarcoma patients. This study hypothesized that increasing social vulnerability is associated with insufficient dietary fiber intake and negatively associated with microbiome composition and clinical outcomes.

Methods: Clinicopathologic data, baseline fiber intake, and gut microbiome profiles were assessed in 153 patients with melanoma or sarcoma treated with immune checkpoint blockade (ICB) and prospectively followed. Patients' social vulnerability index (SVI) and fiber intake were evaluated for associations with microbiome composition, treatment response, and overall survival (OS).

Results: SVI percentile was 0.4 (interquartile ratio …

Influence Of Body Composition On The Efficacy Of Nivolumab Plus Ipilimumab For Metastatic Clear Cell Renal Cell Carcinoma, Kabir Grewal, Maria Julia Moura Nascimento Santos, Pankaj Kumar Chauhan, Kai Yu, Nizar M Tannir, Sagar S Mukhida, Neha Venkatesh, Amishi Y Shah, Amado J Zurita, Andrew C Johns, Matthew T Campbell, Sangeeta Goswami, Jianjun Gao, Eric Jonasch, Jennifer L Mcquade, Omar Alhalabi, Pavlos Msaouel, Andrew W Hahn

Faculty, Staff and Student Publications

Background: Immune checkpoint inhibitor therapy (ICI) with nivolumab+ipilimumab is a first-line (1L) standard for metastatic clear cell renal cell carcinoma (ccRCC), yet outcomes remain heterogeneous. Increasing evidence suggests that host factors influence the tumor microenvironment and response to ICI. Although higher body mass index (BMI) has been associated with improved outcomes in several malignancies, BMI is an imprecise surrogate for underlying adipose and muscle compartments. We evaluated the association between body composition and outcomes with 1L nivolumab+ipilimumab in metastatic ccRCC.

Methods: We retrospectively analyzed patients with mccRCC treated with 1L nivolumab+ipilimumab at MD Anderson Cancer Center between June 2015 and …

Fgl2-Knockout Tumor Cells Serve As A Vaccine Inducing Long-Duration Brain-Resident Memory T Cells That Reject Subsequent Intracranial Tumor Cell Challenges, Sheng Zhang, Yining Jin, Zhiliang Jia, Xueqing Xia, Yang Li, Qi Wang, Jing Wang, Jian Wang, Joya Chandra, Gregory K Friedman, Shulin Li

Faculty, Staff and Student Publications

The failure to prevent brain tumors, including both recurrent primary and metastatic brain tumors, is the primary cause of patients' mortality. We developed a novel whole tumor-cell vaccine to rapidly induce long-duration brain-resident memory T (TRM) cells that prevent brain tumor progression. Ten Fgl2-KO primary and metastatic tumor cell lines, generated via CRISPR/Cas9, were used to vaccinate mice and for intracranial challenges with the WT tumor cells. Not only did vaccinated mice reject these tumor cell challenges, but also more than half of these mice became long-duration survivors. Transplanting brain immune cells from vaccinated mice into naïve mice enabled this …

Vibostolimab Coformulated With Pembrolizumab Versus Pembrolizumab Alone As Adjuvant Therapy For High-Risk Stage Iib–Iv Melanoma (Keyvibe-010): A Randomised, Double-Blind, Phase 3 Study, Reinhard Dummer, Jun Guo, Jason J. Luke, Matteo S. Carlino, Dirk Schadendorf, Muhammad A. Khattak, Axel Hauschild, Paolo A. Ascierto, Yu Chen, Sang Joon Shin, Piotr Rutkowski, Zhiguo Luo, Jing Chen, Gareth Rivalland, Corlia Coetzee, Antoni Ribas, Karmele Mujika, Gal Markel, Rodrigo U. Villarroel, Omer Dizdar, Christian Caglevic, Dmitri Grebennik, Kevin Donovan, Clemens Krepler, Georgina V. Long

Research outputs 2022 to 2026

Background Combination therapy with vibostolimab plus pembrolizumab has previously shown promising antitumor activity in melanoma. We aimed to evaluate the efficacy and safety of vibostolimab coformulated with pembrolizumab as adjuvant therapy for high-risk resected melanoma. Methods This randomised, double-blind, phase 3 study was done at 205 global sites (hospitals and cancer centres). Participants aged 12 years or older with surgically resected, stage IIB–IV cutaneous melanoma per the American Joint Committee on Cancer Cancer Staging Manual 2017 (8th edition), with no evidence of metastatic disease after resection, were randomly assigned (1:1) to receive vibostolimab 200 mg coformulated with pembrolizumab 200 mg …

The Emerging Role Of Tertiary Lymphoid Structures As Predictive And Prognostic Biomarkers Of Immunotherapy In Cancer, Lidia B. Medhin, Rodas Amanuel, Lydia Warburton, Leslie Calapre, Benhur Amanuel, Elin S. Gray

Research outputs 2022 to 2026

Background: Immune checkpoint inhibitors (ICIs) have improved outcomes across several cancers, yet many patients do not respond, highlighting the need for robust predictive biomarkers. Tertiary lymphoid structures (TLS), ectopic lymphoid aggregates that support local antigen presentation and adaptive immune activation, have emerged as potential indicators of favourable prognosis and immunotherapy responsiveness. Methods: This review summarises current clinical and translational evidence examining the prognostic and predictive value of TLS in solid malignancies. Studies assessing TLS presence, organisation, and biological function were identified through searches of major scientific databases and evaluated with respect to their association with patient outcomes and responses to …

Predicting And Managing Hepatocellular Carcinoma Recurrence After Liver Transplant: A Single-Center Experience 2012-2024, Jesse Civan, Madison Force, Ali Raza Shaikh, Adam Bodzin, Daniel Lin

Division of Gastroenterology and Hepatology Faculty Papers

Background: Hepatocellular carcinoma (HCC) is a major cause of mortality in the United States, but it can be cured with orthotopic liver transplant (OLT) in selected patients. Despite curative intent, post-OLT recurrence can occur in up to 15% of patients. The need for a program of post-OLT surveillance is widely accepted but the specifics of an optimal program have not been established. There is interest in identifying lower-risk cohorts of patients in whom an abbreviated strategy of surveillance may prove adequate, utilizing tools such as the RETREAT score. Unique challenges are posed in the post-transplant population regarding safety and …

The Path Forward For T Cell Engagers In Patients With Prostate Cancer, Sumit K. Subudhi, Bilal A. Siddiqui, Kevin K. Zarrabi, William K. Kelly, Charles G. Drake

Department of Medical Oncology Faculty Papers

T cell engagers (TCEs) recruit T cells to the tumor microenvironment (TME) to induce antitumor immune responses. TCEs have demonstrated promising clinical responses in patients with metastatic castration-resistant prostate cancer and have advanced into phase 3 clinical trials. Here we provide an overview of the mechanisms of action of TCEs, including both CD3-targeted and CD28-targeted agents, and review the clinical development of these agents for prostate cancer. We propose a path forward for TCEs in prostate cancer, in which innovative clinical trials will facilitate a biological understanding of mechanisms of efficacy and toxicity to inform: (1) development of predictive biomarkers …

Syndecan-1-Targeted Therapeutic Antibody Impairs Macropinocytosis And Elicits Antitumor Immunity In Pancreatic Cancer, Zecheng Yang, Madelaine S Theardy, Shuaitong Chen, Yongkun Wei, Mitsunobu Takeda, Yue Zeng, Xiaofei Wang, Jun Yao, Jennifer Li, Prapassorn Thirasastr, Jangho Park, Yangxi Zheng, Long T Vien, Khalida M Wani, Huamin Wang, Sisi Gao, Tim Heffernan, Lawrence Kwong, Ignacio I Wistuba, Laura Bover, Giulio F Draetta, Haoqiang Ying, Wantong Yao

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with a 5-year survival rate of just 13%. While the development and early clinical use of small molecules targeting oncogenic KRAS mutations, key drivers of PDAC, have shown promise, resistance to these targeted therapies remains a significant challenge. We recently identified Syndecan-1 (SDC1), a highly expressed heparan sulfate proteoglycan, as a critical KRAS effector protein that promotes nutrient salvage and tumor growth. Here, we report the development of a human-specific monoclonal antibody (anti-SDC1 mAb) that inhibits PDAC cell proliferation in vitro and suppresses PDAC tumor growth in vivo. Mechanistically, …

Retrospective Analysis Of Cutaneous Immune-Related Adverse Events Following Checkpoint Inhibitor Therapy In Melanoma Patients Reveals Increased Risk Associated With The Hla-B*51:01 Allele, Mckenzie Dileo, Samantha Oglesby, Cheuk Hong Leung, Kristen E Pauken, Sahira Farooq, Lauren E Haydu, Shelby L Kubicki, Rebeca Martinez, Macartney Welborn, Sana Zahiruddin, Jun Zou, Kai Cao, Anisha B Patel

Faculty, Staff and Student Publications

Background: While immune checkpoint inhibitors (ICIs) have shown significant efficacy, a common side effect is cutaneous immune-related adverse events (irAEs). This study focuses on exploring the association between specific human leukocyte antigen (HLA) alleles and the development of cutaneous irAEs in melanoma patients undergoing ICI monotherapy and combination therapy. As certain HLA types are indicative of susceptibility to autoimmune diseases, it was hypothesized that HLA typing could serve as a potential screening tool for identifying patients at increased risk for developing irAEs.

Methods: A retrospective chart review was performed of 515 patients with melanoma who underwent ICI therapy, either as …

Precision Targeting Of Sting: Challenges, Innovations, And Clinical Outlook For Cancer Therapy, Jiaqi Shi, Yingying Zhang, Na Zhao, Ekihiro Seki, Li Ma, Gordana Kocic, Xiaobo Li, Janoš Terzić, Tongsen Zheng

Faculty, Staff and Student Publications

The stimulator of interferon genes (STING) pathway plays a crucial role in immune responses and has emerged as a compelling target in cancer therapy. Despite promising preclinical studies, clinical trials of STING agonists have largely failed to deliver durable efficacy, with no agents progressing to phase III trials. This review examines the biological, pharmacological, and clinical barriers limiting STING pathway activation in cancer treatment. We discuss the inherent limitations of STING agonists as well as host-related resistance driven by tumor heterogeneity, immune suppression, and chronic STING activation. Mechanisms of acquired resistance, such as immune checkpoint upregulation and suppression of effector …

Deep-Learning Serial Ct Prediction Of Survival In Immunotherapy-Treated Non-Small Cell Lung Cancer., Chiharu Sako, Brenda F Kurland, Taly G Schmidt, Jing He, Marius De Groot, Arpan A Patel, Dwight H Owen, Arya Amini, Brendan D Curti, Ronan J Kelly, Ray D Page, Aurelie Swalduz, Jean-Paul Beregi, Jan Chrusciel, Stephane Sanchez, Jakob Weiss, An Liu, Olivier Gevaert, Alma Hart, George R Simon, Ravi B Parikh, Jasper Van Der Aart, Petr Jordan

Oncology Articles

IMPORTANCE: Reliable early response biomarkers for overall survival (OS) are lacking for patients receiving immune checkpoint inhibitor (ICI) therapy for advanced non-small cell lung cancer (NSCLC). Existing imaging-based measures, such as Response Evaluation Criteria in Solid Tumors (RECIST) and tumor volume change (TVC), have limited predictive value for long-term outcomes, and advanced imaging-based biomarkers may enhance decision-making in clinical practice and clinical trials.

OBJECTIVE: To develop and validate a fully automated deep-learning imaging-based biomarker using pretherapy and 12-week follow-up computed tomography (CT) scans.

DESIGN, SETTING, AND PARTICIPANTS: This prognostic study used retrospectively collected HER data from routine clinical practice (RCP) …

Persistence Of Pet Scan Positivity After Chemoimmunotherapy For Dlbcl, James O. Armitage, Matthew A. Lunning, Julie M. Vose, Dan L. Longo

Journal Articles: Oncology and Hematology

Approximately 80% of patients with diffuse large B-cell lymphoma achieve a complete response after chemoimmunotherapy as defined by positron emission tomography (PET) scan. However, not all patients who fail to achieve a metabolic complete response are destined to relapse. In a number of these patients, the PET scan is falsely positive (ie, 20%-40% in several large series), particularly when the PET scan has a Deauville score of 4. Reflexively intervening with salvage systemic therapy or radiotherapy in these patients is potentially harmful. It seems that very sensitive measurements of circulating tumor DNA might be able to differentiate between patients who …

Ovarian Cancer Immunology And Immunotherapy: Editorial Note, Chris D. Platsoucas

Biological Sciences Faculty Publications

[Introduction] As the guest editor of the Special Issue on Ovarian Cancer Immunology Immunotherapy, I would like to include certain brief comments on the current state of the field and to introduce the Special Issue. Ovarian carcinoma and malignant melanoma are the first human tumors where immune responses, primarily restricted to autologous tumor cells, were first demonstrated. T-cell lines and clones developed in recombinant interleukin-2 (rIL-2) from tumor-infiltrating lymphocytes (TIL) from these tumors exhibited cytotoxicity and/or cytokine production, primarily restricted to autologous tumor cells. The T-cell receptor (TCR) and the CD3 differentiation antigen on effector T cells and HLA on …

New Therapies, New Challenges: Cystic Lung Disease After Cancer Immunotherapy, Ananya Venkatesh, David Camacho, Ross Summer, Michael Dong

Division of Internal Medicine Faculty Papers & Presentations

Immunotherapies have reduced reliance on cytotoxic strategies with their associated high toxicity levels, revolutionizing cancer care. However, these targeted therapies have also increased prevalence of previously rare sequelae, impacting patients experiencing longer survival. We describe a case of endometrial adenocarcinoma with lung metastases, in which tumor resolution following immunotherapy created cystic airspaces, leading to a pneumothorax complication. A 49-year-old female with advanced stage endometrial adenocarcinoma and lung metastasis developed cystic lung lesions in areas of previous metastatic lesions after treatment with Pembrolizumab and Bevacizumab. She developed a pneumothorax secondary to the rupture of one of the large lung cysts, leading …

A Unique Protein Adjuvant For Precision Immunotherapy To Prevent Recurrence Of Surgically Resected Colorectal Cancer, Yasuhiro Suzuki, Rajesh Mani, B. Mark Evers

Markey Cancer Center Faculty Publications

Effectively activating protective CD8⁺ T cell immunity specifically against cancer antigens is an important pathway to prevent the growth of various types of cancers. A major obstacle in this approach is variations in cancer antigens among patients. A valuable material to overcome the antigen variation among cancer patients is the use of each individual’s own cancer cells for immunization. In colorectal cancer (CRC), approximately one-third of the patients who receive curative surgical resection have a recurrence of cancer. Therefore, the use of surgically resected CRC for immunotherapy to specifically activate the protective CD8⁺ T cells against their own …

Survival Outcomes Of First-Line Therapy In De Novo Metastatic Urothelial Carcinoma With Histologic Subtypes: A National Cancer Database Analysis, Zin W. Myint, Feitong Lei, Bin Huang

Markey Cancer Center Faculty Publications

Background: Urothelial carcinoma with histologic subtypes represent an aggressive and understudied population frequently excluded from prospective clinical trials. Evidence guiding optimal first-line systemic therapy in de novo metastatic disease with histologic subtypes remains limited.

Method: Patients with de novo stage IV urothelial carcinoma with histologic subtypes diagnosed between 2016 and 2021 were identified from the National Cancer Database (NCDB). Eligible patients received first-line chemotherapy, immunotherapy, or concurrent chemoimmunotherapy (both modalities initiated within 30 days). Overall survival (OS) was compared across groups using Kaplan–Meier methods and compared using log-rank tests and multivariable Cox regression. Result: Among 800 patients, 596 (74.5%) received …

Eef2k Promotes Immune Evasion In Melanoma Via Cyclin D1–Mediated Stabilization Of Pd-L1, Yijie Ren, Darby J. Ballard, Anil Kumar, Andy F. Song, Mitiksha Gupta, Xiaofang Xiong, Xingcong Ren, Jugal Kishore Das, Jin-Ming Yang, Jianxun Song

Markey Cancer Center Faculty Publications

Eukaryotic elongation factor 2 kinase (eEF2K) is a stress-responsive regulator of protein synthesis implicated in melanoma progression, but its role in tumor immune evasion remains poorly defined. We investigated how eEF2K influences programmed death ligand 1 (PD-L1) expression through modulation of Cyclin D1. We analyzed gene expression and dependency datasets from The Cancer Genome Atlas and the Cancer Dependency Map. Protein–protein interactions were assessed by co-immunoprecipitation. Cyclin D1 was inhibited pharmacologically with palbociclib. Immune responses were evaluated in murine B16-OVA and human A2058 melanoma models using flow cytometry and immunohistochemistry after genetic or pharmacologic modulation of eEF2K and Cyclin D1. …

Immune-Mediated Diarrhea And Colitis With Normal Biochemical, Endoscopic And Histologic Findings: A Retrospective Study, Malek Shatila, Sharada Wali, Carolina Colli Cruz, Kei Takigawa, Andres Caleb Urias Rivera, Kian Abdul-Baki, Tanvi Gupta, Elliot Baerman, Linfeng Lu, Irene Jeong-Ah Lee, Raakhi Menon, Hamza Salim, Andrew Sullivan, Varun Vemulapalli, Cristina Natha, Ayesha Khan, Krishnavathana Varatharajalu, Stephane Champiat, Kerry L Reynolds, Lucy B Kennedy, Katy Tsai, Anusha Shirwaiker Thomas, Yinghong Wang

Faculty, Staff and Students Publications

Background: Immune-mediated diarrhea and colitis (IMDC) due to checkpoint inhibition infrequently presents with normal stool biomarkers and no endoscopic or histologic evidence of inflammation. Little is known about the treatment needs and outcomes of this subset of patients. We aimed to describe this entity and clarify the role of immunosuppressive treatments in its management.

Method: This was a single-center, retrospective study of patients treated with immune checkpoint inhibitors who developed clinical symptoms of IMDC, with no evidence of inflammation based on fecal calprotectin or endoscopic/histologic evaluation, between January 2010 and February 2024.

Results: Of 1151 patients with IMDC, 131 (11.4%) …

Outcomes Of Patients With Melanoma Brain Metastases Treated With Ipilimumab And Nivolumab With Or Without Upfront Comprehensive Stereotactic Radiosurgery, Troy J Kleber, Denái R Milton, Subhiksha Srinivasan, Bikash Panthi, Warren Floyd, Eric A Goethe, Michael A Davies, Hussein A Tawbi, Isabella C Glitza Oliva, Diana Kaya, Jing Li, Todd A Swanson, Subha Perni, Martin C Tom, Chenyang Wang, Sujit Prabhu, Jeffrey S Weinberg, Ian E Mccutcheon, Caroline Chung, Sherise D Ferguson, Thomas H Beckham

Faculty, Staff and Student Publications

Background: The efficacy of ipilimumab and nivolumab (ipi/nivo) for melanoma brain metastases (MBMs) has been previously reported, leading to uncertainty regarding the optimal role of comprehensive stereotactic radiosurgery (cSRS). We therefore conducted a single-institution retrospective study to compare outcomes of upfront versus deferred cSRS for MBM treated with ipi/nivo.

Methods: We identified patients who started ipi/nivo for newly diagnosed MBMs between 2018 and 2023, with or without upfront cSRS. Patients with >15 MBMs, leptomeningeal disease, or whole-brain radiotherapy at baseline were excluded. Outcomes were compared using multivariable regression and reported as adjusted hazard ratios (aHRs) with 95% CIs.

Results: Of …

Integrative Multi-Omics Profiling Identifies Infiltrative Hepatocellular Carcinoma As An Immunotherapy-Resistant Subtype With Distinct Molecular Features, Won Suk Lee, Seonjeong Woo, Sung Hwan Lee, Gae Hoon Jo, Ilhwan Kim, Hyeyeong Kim, Chansik An, Sanghoon Jung, Gwangil Kim, Haeyoun Kang, Beodeul Kang, Jung Sun Kim, Ho Yeong Lim, Incheon Kang, Hannah Yang, So Jung Kong, Dahyeon Son, Dong Jun Shin, Woo Young Kwon, Da-Yeon Lee, Ju-Seog Lee, Junho Park, Youngsoo Kim, Sohyun Hwang, Chan Kim, Hong Jae Chon

Faculty, Staff and Student Publications

Background/aims: Hepatocellular carcinoma (HCC) exhibits substantial morphological and biological heterogeneity. Clinical and molecular relevance of the infiltrative subtype remains poorly defined in the context of cancer immunotherapy. We aimed to evaluate the prognostic impact and molecular features of infiltrative HCC in patients treated with first-line atezolizumab plus bevacizumab (Ate/Bev).

Methods: We included 307 patients with advanced HCC treated with Ate/Bev and classified them into four gross morphological types based on imaging. Multi-omics profiling was conducted on tumor samples. Type IV infiltrative signature was derived and externally validated using five independent HCC cohorts, including IMbrave150.

Results: Infiltrative morphology, encompassing pure and …

Functional, Pharmacogenomic, And Immune Landscapes Of Long Non-Coding Rnas In Cancer, Runhao Wang, Mei Luo, Yuan Liu, Jingwen Yang, Yamei Chen, Chengxuan Chen, Lifei Ma, Stephanie Ding, James Wengler, Yong Zang, Bora Lim, Wenbo Li, Liuqing Yang, Chunru Lin, Lixia Diao, Leng Han

Faculty, Staff and Student Publications

Long non-coding RNAs (lncRNAs) are emerging as key regulators in cancer, with significant potential as diagnostic, prognostic, and therapeutic targets. Here, this work systematically analyzes lncRNA associations with targeted therapies and immunotherapies across 33 cancer types using The Cancer Genome Atlas (TCGA) and real-world datasets. This work identifies 53,173 lncRNA-pathway associations, millions of lncRNA-drug response associations (via CancerRxTissue and VAEN), and extensive correlations with immune checkpoints and infiltration. This work further identifies 69 lncRNAs associated with immunotherapy response and 2,611 differentially expressed lncRNAs between low and high objective response rate (ORR) groups. Additionally, two lncRNAs are correlated with immune-related adverse …

Intratumoral Bacteria Are Immunosuppressive And Promote Immunotherapy Resistance In Head And Neck Squamous Cell Carcinoma, Natalie L Silver, Jin Dai, Travis D Kerr, Jessica Altemus, Rekha Garg, Hannah Simmons, Tyler Alban, Laura Noel-Romas, Vladimir Makarov, David J H Shih, Shwetha V Kumar, Akeem Santos, Rehan Akbani, Adam Burgener, Mohammed Dwidar, Neil Gross, Andrew G Sikora, Elias J Sayour, Apollo Stacy, Christian Jobin, Timothy A Chan, Renata Ferrarotto, Daniel J Mcgrail

Faculty, Staff and Student Publications

Despite the promise of immune checkpoint blockade (ICB) in head and neck squamous cell carcinoma (HNSCC), mediators of response are poorly understood. To address this, here we analyzed oropharyngeal HNSCCs treated with neoadjuvant durvalumab (anti-PDL1) alone or in combination with tremelimumab (anti-CTLA4) from the CIAO clinical trial ( NCT03144778 ). We found that only the total abundance of intratumoral bacteria predicted ICB response, which was validated in multiple independent cohorts. High intratumoral bacteria abundance was associated with an immunosuppressive tumor microenvironment, characterized by an accumulation of neutrophils coupled with depletion of T cells and other adaptive immune cells. Experimental elevation …

Adjuvant Pembrolizumab For Stage Iib Or Iic Melanoma: A Secondary Analysis Of A Randomized Clinical Trial, Sancy A. Leachman, Jason J. Luke, Paolo A. Ascierto, Georgina V. Long, Muhammad Khattak, Piotr Rutkowski, Zhi Jin Xu, Mizuho Fukunaga-Kalabis, Clemens Krepler, Alexander M.M. Eggermont, Dirk Schadendorf

Research outputs 2022 to 2026

Importance Patients with melanoma are at risk of developing subsequent cutaneous malignant neoplasms, and the effect of prior immunotherapy is unknown. Objective To analyze new skin cancers in participants with high-risk stage II melanoma treated with adjuvant pembrolizumab or placebo. Design, Setting, and Participants The multicenter double-blind, phase 3 KEYNOTE-716 randomized clinical trial enrolled 976 participants 12 years or older with completely resected stage IIB or IIC cutaneous melanoma between September 23, 2018, and November 4, 2020. Follow-up was completed on February 16, 2024. This analysis was not prespecified in the trial protocol. Interventions Participants were randomly assigned to receive …