Medicine and Health Sciences Commons^™

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 …

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 …

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 …

A Rare Case Of Penile Mucosal Melanoma, Safiya-Hana Belbina, Sofia Gereta, Mia Rose Schmolze, James Mclain Bradford, Christopher Yang, Aaron A. Laviana

School of Medicine Publications and Presentations

No abstract provided.

Tumor Vasculature Changes Before Or During Treatment To Predict Response To Systemic Therapy, Avinash Ramkissoon, Faria Ali, Thomas Vander Woude, Stephen Brown, James Ewing, Lisa Rogers

Medical Student Research Symposium

A diagnosis of non-small cell lung cancer (NSCLC) carries a grim prognosis, with 5-year survival rates of 25%. 25-30% of NSCLC patients have brain metastases at initial presentation, which carries an even worse prognosis. New systemic therapies such as targeted-therapies and immuno-therapies have potential to provide better outcomes, but are not without challenges. First, efficacy is limited to a subset of patients. Second, the blood-brain barrier limits penetration, which varies among patients. Third, toxicities can be considerable. Current practice involves waiting 3-6 months to follow-up and assess tumor response; however, by then, it is later than ideal to try other …

Is Timing Of Steroid Exposure Prior To Immune Checkpoint Inhibitor Initiation Associated With Treatment Outcomes In Melanoma? A Population-Based Study, Nikita Nikita, Joshua Banks, Scott W. Keith, Andrew Song, Jennifer M. Johnson, Melissa Wilson, Swapnil Sharma, Grace Lu-Yao

Department of Medical Oncology Faculty Papers

Immune checkpoint inhibitors (ICIs) harness the immune system and are the therapy of choice for multiple cancers. Although immunosuppressive agents such as steroids are also used in many cancers, it is unknown how their timing affects treatment outcomes. Thus, we investigated the relationship between the timing of steroid exposure preceding ICI administration and subsequent treatment outcomes in melanoma. This population-based study utilized the SEER-Medicare-linked database to identify patients diagnosed with melanoma between 1991 and 2015 and receiving ICIs between 2010 and 2016, examining last steroid exposure in the 12 months preceding ICI. The main outcome was all-cause mortality (ACM) after …

Targeting Angiogenesis In Squamous Cell Carcinoma Of The Head And Neck: Opportunities In The Immunotherapy Era, Nabil Saba, Pooja Vijayvargiya, Jan Vermorken, Juan Rodrigo, Stefan Willems, Nina Zidar, Remco De Bree, Antti Mäkitie, Greg Wolf, Athanassios Argiris, Yong Teng, Alfio Ferlito

Department of Medical Oncology Faculty Papers

Despite the lack of approved anti-angiogenic therapies in squamous cell carcinoma of the head and neck (SCCHN), preclinical and more recent clinical evidence support the role of targeting the vascular endothelial growth factor (VEGF) in this disease. Targeting VEGF has gained even greater interest following the recent evidence supporting the role of immunotherapy in the management of advanced SCCHN. Preclinical evidence strongly suggests that VEGF plays a role in promoting the growth and progression of SCCHN, and clinical evidence exists as to the value of combining this strategy with immunotherapeutic agents. Close to 90% of SCCHNs express VEGF, which has …

Challenges And Opportunities For Immunotherapeutic Intervention Against Myeloid Immunosuppression In Glioblastoma, Mark A Exley, Samantha Garcia, Amelia Zellander, Jenny Zilberberg, David W. Andrews

Department of Neurosurgery Faculty Papers

Glioblastoma multiforme (GBM), the most common and deadly brain cancer, exemplifies the paradigm that cancers grow with help from an immunosuppressive tumor microenvironment (TME). In general, TME includes a large contribution from various myeloid lineage-derived cell types, including (in the brain) altered pathogenic microglia as well as monocyte-macrophages (Macs), myeloid-derived suppressor cells (MDSC) and dendritic cell (DC) populations. Each can have protective roles, but has, by definition, been coopted by the tumor in patients with progressive disease. However, evidence demonstrates that myeloid immunosuppressive activities can be reversed in different ways, leading to enthusiasm for this therapeutic approach, both alone and …

Targeting Gastrointestinal Cancers With Chimeric Antigen Receptor (Car)-T Cell Therapy, Ross E Staudt, Robert D Carlson, Adam E. Snook

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The immune system is capable of remarkably potent and specific efficacy against infectious diseases. For decades, investigators sought to leverage those characteristics to create immune-based therapies (immunotherapy) that might be far more effective and less toxic than conventional chemotherapy and radiation therapy for cancer. Those studies revealed many factors and mechanisms underlying the success or failure of cancer immunotherapy, leading to synthetic biology approaches, including CAR-T cell therapy. In this approach, patient T cells are genetically modified to express a chimeric antigen receptor (CAR) that converts T cells of any specificity into tumor-specific T cells that can be expanded to …