Medicine and Health Sciences Commons^™

Biological Insights From Plasma Proteomics Of Non-Small Cell Lung Cancer Patients Treated With Immunotherapy, Jair Bar, Raya Leibowitz, Niels Reinmuth, Astrid Ammendola, Eyal Jacob, Mor Moskovitz, Adva Levy-Barda, Michal Lotem, Rivka Katsenelson, Abed Agbarya, Mahmoud Abu-Amna, Maya Gottfried, Tatiana Harkovsky, Ido Wolf, Ella Tepper, Gil Loewenthal, Ben Yellin, Yehuda Brody, Nili Dahan, Maya Yanko, Coren Lahav, Michal Harel, Shani Raveh Shoval, Yehonatan Elon, Itamar Sela, Adam Dicker, Yuval Shaked

Department of Radiation Oncology Faculty Papers

INTRODUCTION: Immune checkpoint inhibitors have made a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). However, clinical response varies widely and robust predictive biomarkers for patient stratification are lacking. Here, we characterize early on-treatment proteomic changes in blood plasma to gain a better understanding of treatment response and resistance.

METHODS: Pre-treatment (T0) and on-treatment (T1) plasma samples were collected from 225 NSCLC patients receiving PD-1/PD-L1 inhibitor-based regimens. Plasma was profiled using aptamer-based technology to quantify approximately 7000 plasma proteins per sample. Proteins displaying significant fold changes (T1:T0) were analyzed further to identify associations with clinical outcomes using …

Determining Effective Treatment Regimens For Breast Cancer Using Combined Immunotherapy And Chemotherapy In Vivo, Akhila Kunuthuru

AUCTUS: The Journal of Undergraduate Research and Creative Scholarship

Breast cancer has the highest incidence rate of all cancers globally in women, and those of African descent, especially West African females, face higher rates of triple-negative breast cancer (TNBC), a more aggressive form of breast cancer. Immunotherapy for breast cancer is a relatively new treatment option, and research is ongoing to identify the best combination treatments for increasing survival of those diagnosed with TNBC. Eganelisib (IPI-549: a PI3K-gamma inhibitor that works to shift M2 macrophages to M1 to augment T cell function) with other combinatory treatments has shown promising results in reducing tumor growth and increasing survival in mice. …

Treatment Response Of Gingival Squamous-Cell Carcinoma To Palliative Intent Immunotherapy, Natalia Trehan, Angelina Debbas, Mykaihla Sternick, Jennifer Johnson, James Gates

Department of Medical Oncology Faculty Papers

The use of PD-1 immune checkpoint inhibitor medications has become a common practice in the treatment of recurrent and metastatic head and neck squamous-cell carcinomas. Success in this setting has led to the investigation of their efficacy in locally advanced cases as a part of first-line therapy. In this report, we detail the treatment response to palliative intent immunotherapy of three geriatric patients with mandibular gingival squamous-cell carcinoma who decided against surgical intervention. Patient #1 was treated with pembrolizumab, a PD-1 inhibitor, and displayed complete clinical and radiologic response of the gingival mass after three months of treatment, which is …

Xaluritamig, A Steap1 × Cd3 Xmab 2+1 Immune Therapy For Metastatic Castration-Resistant Prostate Cancer: Results From Dose Exploration In A First-In-Human Study, William K. Kelly, Daniel C. Danila, Chia-Chi Lin, Jae-Lyun Lee, Nobuaki Matsubara, Patrick J. Ward, Andrew J. Armstrong, David Pook, Miso Kim, Tanya B. Dorff, Stefanie Fischer, Yung-Chang Lin, Lisa G. Horvath, Christopher Sumey, Zhao Yang, Gabor Jurida, Kristen M. Smith, Jamie N. Connarn, Hweixian L. Penny, Julia Stieglmaier, Leonard J. Appleman

Kimmel Cancer Center Faculty Papers

ABSTRACT : Xaluritamig (AMG 509) is a six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-targeted T-cell engager designed to facilitate lysis of STEAP1-expressing cancer cells, such as those in advanced prostate cancer. This first-in-human study reports monotherapy dose exploration for patients with metastatic castration-resistant prostate cancer (mCRPC), primarily taxane pretreated. Ninety-seven patients received ≥1 intravenous dose ranging from 0.001 to 2.0 mg weekly or every 2 weeks. MTD was identified as 1.5 mg i.v. weekly via a 3-step dose. The most common treatment-related adverse events were cytokine release syndrome (CRS; 72%), fatigue (45%), and myalgia (34%). CRS occurred primarily during …

Extracellular Vesicles In Triple–Negative Breast Cancer: Immune Regulation, Biomarkers, And Immunotherapeutic Potential, Kaushik Das, Subhojit Paul, Arnab Ghosh, Saurabh Gupta, Tanmoy Mukherjee, Prem Shankar, Anshul Sharma, Shiva Keshava, Subhash C. Chauhan, Vivek Kumar Kashyap

School of Medicine Publications and Presentations

Triple–negative breast cancer (TNBC) is an aggressive subtype accounting for ~10–20% of all human BC and is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) amplification. Owing to its unique molecular profile and limited targeted therapies, TNBC treatment poses significant challenges. Unlike other BC subtypes, TNBC lacks specific molecular targets, rendering endocrine therapies and HER2–targeted treatments ineffective. The chemotherapeutic regimen is the predominant systemic treatment modality for TNBC in current clinical practice. However, the efficacy of chemotherapy in TNBC is variable, with response rates varying between a wide range …

International Consensus Statement On Allergy And Rhinology: Sinonasal Tumors, Edward C. Kuan, Eric W. Wang, Nithin D. Adappa, Daniel M. Beswick, Nyall R. London, Shirley Y. Su, Marilene B. Wang, Waleed M. Abuzeid, Borislav Alexiev, Jeremiah A. Alt, Paolo Antognoni, Michelle Alonso-Basanta, Pete S. Batra, Mihir Bhayani, Diana Bell, Manuel Bernal-Sprekelsen, Christian S. Betz, Jean Yves Blay, Benjamin S. Bleier, Juliana Bonilla-Velez, Claudio Callejas, Ricardo L. Carrau, Roy R. Casiano, Paolo Castelnuovo, Rakesh K. Chandra, Vasileios Chatzinakis, Simon B. Chen, Alexander G. Chiu, Stephen C. Hernandez, Et Al

School of Medicine Faculty Publications

Background; Sinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represent a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology; Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and presents 48 thematic and histopathology-based topics spanning the field. Methods; In accordance with prior International Consensus Statement on Allergy and Rhinology documents, ICSNT assigned each topic as an Evidence-Based Review with Recommendations, Evidence-Based Review, and Literature Review based on the level of evidence. An international group of multidisciplinary author teams were assembled for the …

T-Cell Receptor Beta Variable Gene Polymorphism Predicts Immune-Related Adverse Events During Checkpoint Blockade Immunotherapy, Bettzy Stephen, Joud Hajjar, Shrutii Sarda, Dzifa Yawa Duose, Jeffrey M Conroy, Carl Morrison, Anas Alshawa, Mingxuan Xu, Abdulrazzak Zarifa, Sapna P Patel, Ying Yuan, Evan Kwiatkowski, Linghua Wang, Jordi Rodon Ahnert, Siqing Fu, Funda Meric-Bernstam, Geoffrey M Lowman, Timothy Looney, Aung Naing

Journal Articles

BACKGROUND: Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have been implicated in autoimmune disease and may be mechanistically linked to irAEs. However, the repetitive nature of the TCRB locus and incomplete genome assembly has hampered the evaluation of TRBV polymorphisms in the …

The Gpcr-Gαs-Pka Signaling Axis Promotes T Cell Dysfunction And Cancer Immunotherapy Failure, Victoria H Wu, Bryan S Yung, Farhoud Faraji, Robert Saddawi-Konefka, Zhiyong Wang, Alexander T Wenzel, Miranda J Song, Meghana S Pagadala, Lauren M Clubb, Joshua Chiou, Sanju Sinha, Marin Matic, Francesco Raimondi, Thomas S Hoang, Rebecca Berdeaux, Dario A A Vignali, Ramiro Iglesias-Bartolome, Hannah Carter, Eytan Ruppin, Jill P Mesirov, J Silvio Gutkind

Journal Articles

Immune checkpoint blockade (ICB) targeting PD-1 and CTLA-4 has revolutionized cancer treatment. However, many cancers do not respond to ICB, prompting the search for additional strategies to achieve durable responses. G-protein-coupled receptors (GPCRs) are the most intensively studied drug targets but are underexplored in immuno-oncology. Here, we cross-integrated large singe-cell RNA-sequencing datasets from CD8+ T cells covering 19 distinct cancer types and identified an enrichment of Gαs-coupled GPCRs on exhausted CD8+ T cells. These include EP2, EP4, A2AR, β1AR and β2AR, all of which promote T cell dysfunction. We also developed transgenic mice expressing a chemogenetic CD8-restricted Gαs–DREADD to activate …

Editorial: Targeting Dna Damage Response To Enhance Antitumor Innate Immunity In Radiotherapy, Victoria Valvo, Emanuele Vitale, Marco Tigano, Rachel Evans, Meredith A. Morgan, Qiang Zhang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

No abstract provided.

Physician Views On The Provision Of Information On Immune Checkpoint Inhibitor Therapy To Patients With Cancer And Pre-Existing Autoimmune Disease: A Qualitative Study, Maria A Lopez-Olivo, Gabrielle F Duhon, Juan I Ruiz, Mehmet Altan, Hussein Tawbi, Adi Diab, Clifton O Bingham, Cassandra Calabrese, Natalia I Heredia, Robert J Volk, Maria E Suarez-Almazor

Journal Articles

Immune checkpoint inhibitors (ICIs) have improved cancer outcomes but can cause severe immune-related adverse events (irAEs) and flares of autoimmune conditions in cancer patients with pre-existing autoimmune disease. The objective of this study was to identify the information physicians perceived as most useful for these patients when discussing treatment initiation with ICIs. Twenty physicians at a cancer institution with experience in the treatment of irAEs were interviewed. Qualitative thematic analysis was performed to organize and interpret data. The physicians were 11 medical oncologists and 9 non-oncology specialists. The following themes were identified: (1) current methods used by physicians to provide …

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 …

Cd73-Dependent Adenosine Signaling Through Adora2b Drives Immunosuppression In Ductal Pancreatic Cancer, Erika Y Faraoni, Kanchan Singh, Vidhi Chandra, Olivereen Le Roux, Yulin Dai, Ismet Sahin, Baylee J O'Brien, Lincoln N Strickland, Le Li, Emily Vucic, Amanda N Warner, Melissa Pruski, Trent Clark, George Van Buren, Nirav C Thosani, John S Bynon, Curtis J Wray, Dafna Bar-Sagi, Kyle L Poulsen, Lana A Vornik, Michelle I Savage, Shizuko Sei, Altaf Mohammed, Zhongming Zhao, Powel H Brown, Tingting Mills, Holger K Eltzschig, Florencia Mcallister, Jennifer M Bailey-Lundberg

Journal Articles

UNLABELLED: The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing targets for effective prevention and therapy. Here, we interrogated differential molecular mechanisms dependent on cell of origin and subtype that promote immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell-of-origin-dependent epithelial gene signatures revealed that Nt5e/CD73, a cell-surface enzyme required for extracellular adenosine generation, is one of the top 10% of genes overexpressed in murine tumors arising from the ductal pancreatic epithelium as opposed to those rising from acinar …

Association Of Computed Tomography Measures Of Muscle And Adipose Tissue And Progressive Changes Throughout Treatment With Clinical Endpoints In Patients With Advanced Lung Cancer Treated With Immune Checkpoint Inhibitors, Azim Khan, Christopher J. Welman, Afaf Abed, Susan O’Hanlon, Andrew Redfern, Sara Azim, Pedro Lopez, Favil Singh, Adnan Khattak

Research outputs 2022 to 2026

To investigate the association between skeletal muscle mass and adiposity measures with disease-free progression (DFS) and overall survival (OS) in patients with advanced lung cancer receiving immunotherapy, we retrospectively analysed 97 patients (age: 67.5 ± 10.2 years) with lung cancer who were treated with immunotherapy between March 2014 and June 2019. From computed tomography scans, we assessed the radiological measures of skeletal muscle mass, and intramuscular, subcutaneous and visceral adipose tissue at the third lumbar vertebra. Patients were divided into two groups based on specific or median values at baseline and changes throughout treatment. A total number of 96 patients …

Bispecific T-Cell Engagers Therapies In Solid Tumors: Focusing On Prostate Cancer, Diana C Simão, Kevin K Zarrabi, José L Mendes, Ricardo Luz, Jorge A Garcia, William Kevin Kelly, Pedro C Barata

Department of Medical Oncology Faculty Papers

Over the past decade, immunotherapy has demonstrated an impressive improvement in treatment outcomes for multiple cancers. Following the landmark approvals for use of immune checkpoint inhibitors, new challenges emerged in various clinical settings. Not all tumor types harbor immunogenic characteristics capable of triggering responses. Similarly, many tumors' immune microenvironment allows them to become evasive, leading to resistance and, thus, limiting the durability of responses. To overcome this limitation, new T-cell redirecting strategies such as bispecific T-cell engager (BiTE) have become attractive and promising immunotherapies. Our review provides a comprehensive perspective of the current evidence of BiTE therapies in solid tumors. …

Predicting Survival Of Nsclc Patients Treated With Immune Checkpoint Inhibitors: Impact And Timing Of Immune-Related Adverse Events And Prior Tyrosine Kinase Inhibitor Therapy, Michael R. Sayer, Isa Mambetsariev, Kun-Han Lu, Chi Wah Wong, Ashley Duche, Richard Beuttler, Jeremy Fricke, Rebecca Pharaon, Leonidas Arvanitis, Zahra Eftekhari, Arya Amini, Marianna Koczywas, Erminia Massarelli, Moom Rahman Roosan, Ravi Salgia

Pharmacy Faculty Articles and Research

Introduction: Immune checkpoint inhibitors (ICIs) produce a broad spectrum of immune-related adverse events (irAEs) affecting various organ systems. While ICIs are established as a therapeutic option in non-small cell lung cancer (NSCLC) treatment, most patients receiving ICI relapse. Additionally, the role of ICIs on survival in patients receiving prior targeted tyrosine kinase inhibitor (TKI) therapy has not been well-defined.

Objective: To investigate the impact of irAEs, the relative time of occurrence, and prior TKI therapy to predict clinical outcomes in NSCLC patients treated with ICIs.

Methods: A single center retrospective cohort study identified 354 adult patients with NSCLC receiving ICI …

Immunotherapeutic Targets In Non-Small Cell Lung Cancer, Habib Sadeghirad, Tayyeb Bahrami, Sepideh M. Layeghi, Hassan Yousefi, Meysam Rezaei, Seyed R. Hosseini-Fard, Payar Radfar, Majid E. Warkiani, Ken O'Byrne, Arutha Kulasinghe

School of Medicine Faculty Publications

Non-small cell lung cancer (NSCLC) is one of the most common types of cancer in the world and has a 5-year survival rate of ~20%. Immunotherapies have shown promising results leading to durable responses, however, they are only effective for a subset of patients. To determine the best therapeutic approach, a thorough and in-depth profiling of the tumour microenvironment (TME) is required. The TME is a complex network of cell types that form an interconnected network, promoting tumour cell initiation, growth and dissemination. The stroma, immune cells and endothelial cells that comprise the TME generate a plethora of cytotoxic or …

Age-Induced Changes In Anti-Tumor Immunity Alter The Tumor Immune Infiltrate And Impact Response To Immuno-Oncology Treatments, Suzanne I Sitnikova, Jennifer A Walker, Laura B Prickett, Michelle Morrow, Viia E Valge-Archer, Matthew J Robinson, Robert W Wilkinson, Simon J Dovedi

Journal Articles

INTRODUCTION: Immuno-oncology (IO) research relies heavily on murine syngeneic tumor models. However, whilst the average age for a cancer diagnosis is 60 years or older, for practical purposes the majority of preclinical studies are conducted in young mice, despite the fact that ageing has been shown to have a significant impact on the immune response.

METHODS: Using aged (60-72 weeks old) mice bearing CT26 tumors, we investigated the impact of ageing on tumor growth as well as the immune composition of the tumor and peripheral lymphoid organs.

RESULTS: We found many differences in the immune cell composition of both the …

Systemic Treatment Of Advanced And Metastatic Urothelial Cancer: The Landscape In Australia, Howard Gurney, Timothy D. Clay, Niara Oliveira, Shirley Wong, Ben Tran, Carole Harris

Research outputs 2022 to 2026

The 5-year survival rate of metastatic urothelial carcinoma (mUC) is estimated to be as low as 5%. Currently, systemic platinum-based chemotherapy followed by avelumab maintenance therapy is the only first-line treatment for mUC that has an overall survival benefit. Cisplatin-based chemotherapy (usually in combination with gemcitabine) is the preferred treatment but carboplatin is substituted where contraindications to cisplatin exist. Treatment with immune checkpoint inhibitors, antibody-drug conjugates, and kinase inhibitors has not yet demonstrated superiority to chemotherapy as first-line therapy and remains investigational in this setting. A recent media release indicates that chemotherapy plus nivolumab gives an OS advantage as first-line …

The Resurgence Of The Adora2b Receptor As An Immunotherapeutic Target In Pancreatic Cancer, Lincoln N Strickland, Erika Y Faraoni, Wei Ruan, Xiaoyi Yuan, Holger K Eltzschig, Jennifer M Bailey-Lundberg

Journal Articles

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense desmoplastic stroma that impedes drug delivery, reduces parenchymal blood flow, and suppresses the anti-tumor immune response. The extracellular matrix and abundance of stromal cells result in severe hypoxia within the tumor microenvironment (TME), and emerging publications evaluating PDAC tumorigenesis have shown the adenosine signaling pathway promotes an immunosuppressive TME and contributes to the overall low survival rate. Hypoxia increases many elements of the adenosine signaling pathway, resulting in higher adenosine levels in the TME, further contributing to immune suppression. Extracellular adenosine signals through 4 adenosine receptors (Adora1, Adora2a, Adora2b, Adora3). Of …

Plasma Growth Hormone Is A Potential Biomarker Of Response To Atezolizumab And Bevacizumab In Advanced Hepatocellular Carcinoma Patients, Yehia I Mohamed, Dan G Duda, Muhammad O Awiwi, Sunyoung S Lee, Lina Altameemi, Lianchun Xiao, Jeffrey S Morris, Robert A Wolff, Khaled M Elsayes, Rikita I Hatia, Aliya Qayyum, Shadi M Chamseddine, Asif Rashid, James C Yao, Armeen Mahvash, Manal M Hassan, Hesham M Amin, Ahmed Omar Kaseb

Journal Articles

INTRODUCTION: Hepatocellular carcinoma (HCC) has limited systemic therapy options when discovered at an advanced stage. Thus, there is a need for accessible and minimally invasive biomarkers of response to guide the selection of patients for treatment. This study investigated the biomarker value of plasma growth hormone (GH) level as a potential biomarker to predict outcome in unresectable HCC patients treated with current standard therapy, atezolizumab plus bevacizumab (Atezo/Bev).

MATERIALS AND METHODS: Study included unresectable HCC patients scheduled to receive Atezo/Bev. Patients were followed to determine progression-free survival (PFS) and overall survival (OS). Plasma GH levels were measured by ELISA and …

Efficacy And Safety Of Lifileucel, A One-Time Autologous Tumor-Infiltrating Lymphocyte (Til) Cell Therapy, In Patients With Advanced Melanoma After Progression On Immune Checkpoint Inhibitors And Targeted Therapies: Pooled Analysis Of Consecutive Cohorts Of The C-144-01 Study, Jason Chesney, Karl D Lewis, Harriet Kluger, Omid Hamid, Eric Whitman, Sajeve Thomas, Martin Wermke, Mike Cusnir, Evidio Domingo-Musibay, Giao Q Phan, John M Kirkwood, Jessica C Hassel, Marlana Orloff, James Larkin, Jeffrey Weber, Andrew J S Furness, Nikhil I Khushalani, Theresa Medina, Michael E Egger, Friedrich Graf Finckenstein, Madan Jagasia, Parameswaran Hari, Giri Sulur, Wen Shi, Xiao Wu, Amod Sarnaik

Department of Medical Oncology Faculty Papers

Background: Patients with advanced melanoma have limited treatment options after progression on immune checkpoint inhibitors (ICI). Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, demonstrated an investigator-assessed objective response rate (ORR) of 36% in 66 patients who progressed after ICI and targeted therapy. Herein, we report independent review committee (IRC)-assessed outcomes of 153 patients treated with lifileucel in a large multicenter Phase 2 cell therapy trial in melanoma.

Methods: Eligible patients had advanced melanoma that progressed after ICI and targeted therapy, where appropriate. Melanoma lesions were resected (resected tumor diameter ≥1.5 cm) and shipped to a central good manufacturing …

Idiopathic Pulmonary Fibrosis And Lung Cancer: Future Directions And Challenges, Ahmad Abu Qubo, Jamil Numan, Juan Snijder, Maria Padilla, John H.M. Austin, Kathleen M. Capaccione, Monica Pernia, Jean Bustamante, Timothy O’Connor, Mary M. Salvatore

Einstein Health Papers

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of pulmonary scarring. New treatments slow disease progression and allow pulmonary fibrosis patients to live longer. Persistent pulmonary fibrosis increases a patient’s risk of developing lung cancer. Lung cancer in patients with IPF differs from cancers that develop in the non-fibrotic lung. Peripherally located adenocarcinoma is the most frequent cell type in smokers who develop lung cancer, while squamous cell carcinoma is the most frequent in pulmonary fibrosis. Increased fibroblast foci in IPF are associated with more aggressive cancer behaviour and shorter doubling times. Treatment of lung cancer in fibrosis is challenging …

Adjuvant Pembrolizumab Versus Placebo In Resected High-Risk Stage Ii Melanoma: Health-Related Quality Of Life From The Randomized Phase 3 Keynote-716 Study, Muhammad A. Khattak, Jason J. Luke, Georgina V. Long, Paolo A. Ascierto, Piotr Rutkowski, Dirk Schadendorf, Caroline Robert, Jean-Jacques Grob, Luis De La Cruz Merino, Michele Del Vecchio, Francesco Spagnolo, Jacek Mackiewicz, Vanna Chiarion-Sileni, Matteo S. Carlino, Peter Mohr, Federica De Galitiis, Merrick I. Ross, Zeynep Eroglu, Ke Chen, Ruixuan Jiang, Mizuho Fukunaga-Kalabis, Clemens Krepler, Alexander M. M. Eggermont, John M. Kirkwood

Research outputs 2022 to 2026

Background: Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) versus placebo in resected stage IIB and IIC melanoma in the phase 3 KEYNOTE-716 study. Health-related quality of life (HRQoL) results are reported. Methods: Patients were randomly assigned 1:1 to pembrolizumab 200 mg (2 mg/kg, patients ≥ 12 to < 18 years) Q3W or placebo for ≤ 17 cycles or until disease recurrence, unacceptable toxicity, or withdrawal. Change from baseline in EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) was a prespecified exploratory end point. Change in EORTC QLQ-C30 functioning, symptom, and single-item scales, and EQ-5D-5L visual analog scale (VAS) were also summarized. Primary analyses were performed at week 48 to ensure adequate completion/compliance. The HRQoL population comprised patients who received ≥ 1 dose of treatment and completed ≥ 1 assessment. Results: The HRQoL population included 969 patients (pembrolizumab, n = 483; placebo, n = 486). Compliance at week 48 was ≥ 80 % for both instruments. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores were stable from baseline to week 48 in both arms, with no clinically meaningful decline observed. Scores did not differ significantly between pembrolizumab and placebo. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores remained stable through week 96 in both arms. Conclusions: HRQoL was stable with adjuvant pembrolizumab, with no clinically meaningful decline observed. Change from baseline in HRQoL was similar between arms. These results, in conjunction with the improved RFS and manageable safety previously reported, support the use of adjuvant pembrolizumab for high-risk stage II melanoma.

Keynote - D36: Personalized Immunotherapy With A Neoepitope Vaccine, Evx-01 And Pembrolizumab In Advanced Melanoma, Georgina V. Long, Pier Francesco Ferrucci, Adnan Khattak, Tarek M. Meniawy, Patrick Alexander Ott, Michael Chisamore, Thomas Trolle, Agon Hyseni, Erik Heegaard

Research outputs 2022 to 2026

Despite improvements made with checkpoint inhibitor (CPI) therapy, a need for new approaches to improve outcomes for patients with unresectable or metastatic melanoma remains. EVX-01, a personalized neoepitope vaccine, combined with pembrolizumab treatment, holds the potential to fulfill this need. Here we present the rationale and novel design behind the KEYNOTE - D36 trial: an open label, single arm, phase II trial aiming to establish the clinical proof of concept and evaluate the safety of EVX-01 in combination with pembrolizumab in CPI naive patients with unresectable or metastatic melanoma. The primary objective is to evaluate if EVX-01 improves best overall …

Determining Front-Line Therapeutic Strategy For Metastatic Clear Cell Renal Cell Carcinoma, Kevin K Zarrabi, Oladimeji Lanade, Daniel M Geynisman

Department of Medical Oncology Faculty Papers

The therapeutic landscape for metastatic renal cell carcinoma has rapidly evolved over the years, and we are now in an era of combination therapy strategies employing immune checkpoint blockade and anti-angiogenesis targeted therapy. Since 2018, we have gained regulatory approval for four distinct combination therapies, all with survival benefits, and with guideline recommendation for use in the front-line setting. As such, treatment selection has become increasingly complex with a myriad of treatment choices but little high-level head-to-head data to guide treatment selection. Heterogeneity in tumor biology further complicates treatment selection as tumors vary in behavior and treatment responsiveness. Ongoing development …

Overcoming The Cardiac Toxicities Of Cancer Therapy Immune Checkpoint Inhibitors, Omoruyi Credit Irabor, Nicolas Nelson, Yash Shah, Muneeb Khan Niazi, Spencer Poiset, Eugene Storozynsky, Dinender K Singla, D. Craig Hooper, Bo Lu

Division of Cardiology Faculty Papers

Immune checkpoint inhibitors (ICIs) have led recent advances in the field of cancer immunotherapy improving overall survival in multiple malignancies with abysmal prognoses prior to their introduction. The remarkable efficacy of ICIs is however limited by their potential for systemic and organ specific immune-related adverse events (irAEs), most of which present with mild to moderate symptoms that can resolve spontaneously, with discontinuation of therapy or glucocorticoid therapy. Cardiac irAEs however are potentially fatal. The understanding of autoimmune cardiotoxicity remains limited due to its rareness. In this paper, we provide an updated review of the literature on the pathologic mechanisms, diagnosis, …

Human Leucocyte Antigen Genotype Association With The Development Of Immune-Related Adverse Events In Patients With Non-Small Cell Lung Cancer Treated With Single Agent Immunotherapy, Afaf Abed, Ngie Law, Leslie Calapre, Johnny Lo, Vikas Bhat, Samantha Bowyer, Michael Millward, Elin S. Gray

Research outputs 2022 to 2026

Introduction: Biomarkers that predict the risk of immune-mediated adverse events (irAEs) among patients with non-small cell lung cancer (NSCLC) may reduce morbidity and mortality associated with these treatments. Methods: We carried out high resolution human leucocyte antigen (HLA)-I typing on 179 patients with NSCLC treated with anti-program death (PD)-1/program death ligand (PDL)-1. Toxicity data were collected and graded as per common terminology criteria for adverse event (CTCAE) v5.0. We used 14.8-week for landmark analysis to address lead-time bias to investigate the correlation between HLA-I/II zygosity, supertypes and alleles with irAE. Furthermore, we assessed the association for irAE with clinical benefit …

Steap1-4 (Six-Transmembrane Epithelial Antigen Of The Prostate 1-4) And Their Clinical Implications For Prostate Cancer, Michael Xu, Latese Evans, Candice L Bizzaro, Fabio Quaglia, Cecilia E Verrillo, Li Li, Julia Stieglmaier, M J Schiewer, Lucia R Languino, William Kevin Kelly

Department of Urology Faculty Papers

Six-Transmembrane Epithelial Antigen of the Prostate 1-4 (STEAP1-4) compose a family of metalloproteinases involved in iron and copper homeostasis and other cellular processes. Thus far, five homologs are known: STEAP1, STEAP1B, STEAP2, STEAP3, and STEAP4. In prostate cancer, STEAP1, STEAP2, and STEAP4 are overexpressed, while STEAP3 expression is downregulated. Although the metalloreductase activities of STEAP1-4 are well documented, their other biological functions are not. Furthermore, the properties and expression levels of STEAP heterotrimers, homotrimers, heterodimers, and homodimers are not well understood. Nevertheless, studies over the last few decades have provided sufficient impetus to investigate STEAP1-4 as potential biomarkers and therapeutic …

Artificial Intelligence In The Radiomic Analysis Of Glioblastomas: A Review, Taxonomy, And Perspective, Ming Zhu, Sijia Li, Yu Kuang, Virigina B. Hill, Amy B. Heimberger, Lijie Zhai, Shenjie Zhai

Electrical & Computer Engineering Faculty Research

Radiological imaging techniques, including magnetic resonance imaging (MRI) and positron emission tomography (PET), are the standard-of-care non-invasive diagnostic approaches widely applied in neuro-oncology. Unfortunately, accurate interpretation of radiological imaging data is constantly challenged by the indistinguishable radiological image features shared by different pathological changes associated with tumor progression and/or various therapeutic interventions. In recent years, machine learning (ML)-based artificial intelligence (AI) technology has been widely applied in medical image processing and bioinformatics due to its advantages in implicit image feature extraction and integrative data analysis. Despite its recent rapid development, ML technology still faces many hurdles for its broader applications …

A Retrospective Study For Prognostic Significance Of Type Ii Diabetes Mellitus And Hemoglobin A1c Levels In Non-Small Cell Lung Cancer Patients Treated With Pembrolizumab, Yinchen Shen, Jiaqi Li, Huiping Qiang, Yuqiong Lei, Qing Chang, Runbo Zhong, Giulia Maria Stella, Francesco Gelsomino, Yeon Wook Kim, Afaf Abed, Jialin Qian, Tianqing Chu

Research outputs 2022 to 2026

Background:

Diabetes mellitus (DM) is common and recognized as a risk factor for developing non-small cell lung cancer (NSCLC) while the prognostic evaluation is still controversial. As immunotherapy is widely used in clinical practice, its efficacy and survival should be investigated in patients with DM.

Methods:

We retrospectively recruited 266 locally advanced and metastatic NSCLC patients who received pembrolizumab alone or in combination with chemotherapy. Patients' clinicopathological data, including age, history of DM, hemoglobin A1c (HbA1c), genetic tumor profiling, and survival data were collected. Associations between clinical characteristics and survival were evaluated by univariate and multivariate analyses.

Results:

In this …