Medicine and Health Sciences Commons^™

Immunotherapy Resistance In Solid Tumors: Mechanisms And Potential Solutions, Daniel Lefler, Steven Manobianco, Babar Bashir

Kimmel Cancer Center Faculty Papers

While the emergence of immunotherapies has fundamentally altered the management of solid tumors, cancers exploit many complex biological mechanisms that result in resistance to these agents. These encompass a broad range of cellular activities - from modification of traditional paradigms of immunity via antigen presentation and immunoregulation to metabolic modifications and manipulation of the tumor microenvironment. Intervening on these intricate processes may provide clinical benefit in patients with solid tumors by overcoming resistance to immunotherapies, which is why it has become an area of tremendous research interest with practice-changing implications. This review details the major ways cancers avoid both natural …

Phi-1, An Endogenous Inhibitor Protein For Protein Phosphatase-1 And A Pan-Cancer Marker, Regulates Raf-1 Proteostasis, Jason Kirkbride, Garbo Nilsson, Jee In Kim, Kosuke Takeya, Yoshinori Tanaka, Hiroshi Tokumitsu, Futoshi Suizu, Masumi Eto

Kimmel Cancer Center Faculty Papers

Raf-1, a multifunctional kinase, regulates various cellular processes, including cell proliferation, apoptosis, and migration, by phosphorylating MAPK/ERK kinase and interacting with specific kinases. Cellular Raf-1 activity is intricately regulated through pathways involving the binding of regulatory proteins, direct phosphorylation, and the ubiquitin-proteasome axis. In this study, we demonstrate that PHI-1, an endogenous inhibitor of protein phosphatase-1 (PP1), plays a pivotal role in modulating Raf-1 proteostasis within cells. Knocking down endogenous PHI-1 in HEK293 cells using siRNA resulted in increased cell proliferation and reduced apoptosis. This heightened cell proliferation was accompanied by a 15-fold increase in ERK1/2 phosphorylation. Importantly, the observed …

Preclinical Evaluation Of Anti-Cd38 Therapy In Mature T-Cell Neoplasms, Colleen Isabelle, William Johnson, Kathleen Mcconnell, Ashley Vogel, Jonathan Brammer, Amy Boles, Robyn Keller, Paola Sindaco, Liam Nisenfeld, Guldeep Uppal, Neda Nikbakht, Bruno Calabretta, Patrizia Porazzi, Jerald Gong, Nitin Chakravarti, Pierluigi Porcu, Anjali Mishra

Kimmel Cancer Center Faculty Papers

No abstract provided.

The Role Of Interleukin-15 In The Development And Treatment Of Hematological Malignancies, Paola Sindaco, Hritisha Pandey, Colleen Isabelle, Nitin Chakravarti, Jonathan Edward Brammer, Pierluigi Porcu, Anjali Mishra

Kimmel Cancer Center Faculty Papers

Cytokines are a vital component of the immune system that controls the activation and growth of blood cells. However, chronic overexpression of cytokines can trigger cellular events leading to malignant transformation. The cytokine interleukin-15 (IL-15) is of particular interest, which has been shown to contribute to the development and progression of various hematological malignancies. This review will provide an overview of the impact of the immunopathogenic function of IL-15 by studying its role in cell survival, proliferation, inflammation, and treatment resistance. We will also review therapeutic approaches for inhibiting IL-15 in blood cancers.

Assessing The Coverage Of Us Cancer Center Primary Catchment Areas., Amy E Leader, Christopher Mcnair, Christina Yurick, Matthew Huesser, Elizabeth Schade, Emily E Stimmel, Caryn Lerman, Karen E Knudsen

Kimmel Cancer Center Faculty Papers

Background: Cancer centers are expected to engage communities and reduce the burden of cancer in their catchment areas. However, the extent to which cancer centers adequately reach the entire US population is unknown. Methods: We surveyed all members of the Association of American Cancer Institutes (N ¼ 102 cancer centers) to document and map each cancer center’s primary catchment area. Catchment area descriptions were aggregated to the county level. Catchment area coverage scores were calculated for each county and choropleths generated representing coverage across the US. Similar analyses were used to overlay US population density, cancer incidence, and cancer-related mortality …

Assessment Of Regional Variability In Covid-19 Outcomes Among Patients With Cancer In The United States., Jessica E Hawley, Tianyi Sun, David D Chism, Narjust Duma, Julie C Fu, Na Tosha N Gatson, Sanjay Mishra, Ryan H Nguyen, Sonya A Reid, Oscar K Serrano, Sunny R K Singh, Neeta K Venepalli, Ziad Bakouny, Babar Bashir, Mehmet A Bilen, Paolo F Caimi, Toni K Choueiri, Scott J Dawsey, Leslie A Fecher, Daniel B Flora, Christopher R Friese, Michael J Glover, Cyndi J Gonzalez, Sharad Goyal, Thorvardur R Halfdanarson, Dawn L Hershman, Hina Khan, Chris Labaki, Mark A Lewis, Rana R Mckay, Ian Messing, Nathan A Pennell, Matthew Puc, Deepak Ravindranathan, Terence D Rhodes, Andrea V Rivera, John Roller, Gary K Schwartz, Sumit A Shah, Justin A Shaya, Mitrianna Streckfuss, Michael A Thompson, Elizabeth M Wulff-Burchfield, Zhuoer Xie, Peter Paul Yu, Jeremy L Warner, Dimpy P Shah, Benjamin French, Clara Hwang

Kimmel Cancer Center Faculty Papers

Importance: The COVID-19 pandemic has had a distinct spatiotemporal pattern in the United States. Patients with cancer are at higher risk of severe complications from COVID-19, but it is not well known whether COVID-19 outcomes in this patient population were associated with geography.

Objective: To quantify spatiotemporal variation in COVID-19 outcomes among patients with cancer.

Design, Setting, and Participants: This registry-based retrospective cohort study included patients with a historical diagnosis of invasive malignant neoplasm and laboratory-confirmed SARS-CoV-2 infection between March and November 2020. Data were collected from cancer care delivery centers in the United States.

Exposures: Patient residence was categorized …

Returning To Sport: Female Athletes Living With And Beyond Cancer., Anna L. Schwartz, Christopher Terry

Kimmel Cancer Center Faculty Papers

Many athletes living with and beyond cancer can continue to train and, in some cases, compete during treatment. Following cancer treatment, athletes can return to competitive sport but need to learn to adapt their physical strength and training to the lingering effects of cancer. It is critical for oncology healthcare providers to use the principles of assess, refer and advise to exercise oncology programs that are appropriate for the individual. Managing side effects of treatment is key to being able to train during and immediately following cancer treatment. Keen attention to fatigue is important at any point in the cancer …

Digital Literacy At An Urban Cancer Center: Implications For Technology Use And Vulnerable Patients, Amy Leader, Lisa M. Capparella, L. Waldman, Ba, Rebecca Cammy, Alison Petok, Rebecca Dean, Ayako Shimada, Liana Yocavitch, Kristin L. Rising, Gregory Garber, Brooke Worster, Adam Dicker

Kimmel Cancer Center Faculty Papers

PURPOSE: eHealth literacy, or the ability to seek, find, understand, and appraise health information from electronic sources, has become increasingly relevant in the era of COVID-19, when so many aspects of patient care became dependent on technology. We aimed to understand eHealth literacy among a diverse sample of patients with cancer and discuss ways for health systems and cancer centers to ensure that all patients have access to high-quality care.

METHODS: A cross-sectional survey of patients with cancer and caregivers was conducted at an NCI-designated cancer center to assess access to the Internet, smartphone ownership, use of mobile apps, willingness …

Health Insurance Coverage Disruptions And Cancer Care And Outcomes: Systematic Review Of Published Research, K Robin Yabroff, Katherine Reeder-Hayes, Jingxuan Zhao, Michael T Halpern, Ana Maria Lopez, Leon Bernal-Mizrachi, Anderson B Collier, Joan Neuner, Jonathan Phillips, William Blackstock, Manali Patel

Kimmel Cancer Center Faculty Papers

BACKGROUND: Lack of health insurance coverage is associated with poor access and receipt of cancer care and survival in the United States. Disruptions in coverage are common among low-income populations, but little is known about associations of disruptions with cancer care, including prevention, screening, and treatment, as well as outcomes of stage at diagnosis and survival.

METHODS: We conducted a systematic review of studies of health insurance coverage disruptions and cancer care and outcomes published between 1980 and 2019. We used the PubMed, EMBASE, Scopus, and CINAHL databases and identified 29 observational studies. Study characteristics and key findings were abstracted …

A Phase 1b Study Of Humanized Ks-Interleukin-2 (Huks-Il2) Immunocytokine With Cyclophosphamide In Patients With Epcam-Positive Advanced Solid Tumors., Joseph P Connor, Mihaela C Cristea, Nancy L Lewis, Lionel D Lewis, Philip B Komarnitsky, Maria R Mattiacci, Mildred Felder, Sarah Stewart, Josephine Harter, Jean Henslee-Downey, Daniel Kramer, Roland Neugebauer, Roger Stupp

Kimmel Cancer Center Faculty Papers

BACKGROUND: Humanized KS-interleukin-2 (huKS-IL2), an immunocytokine with specificity for epithelial cell adhesion molecule (EpCAM), has demonstrated favorable tolerability and immunologic activity as a single agent.

METHODS: Phase 1b study in patients with EpCAM-positive advanced solid tumors to determine the maximum tolerated dose (MTD) and safety profile of huKS-IL2 in combination with low-dose cyclophosphamide. Treatment consisted of cyclophosphamide (300 mg/m2 on day 1), and escalating doses of huKS-IL2 (0.5-4.0 mg/m2 IV continuous infusion over 4 hours) on days 2, 3, and 4 of each 21-day cycle. Safety, pharmacokinetic profile, immunogenicity, anti-tumor and biologic activity were evaluated.

RESULTS: Twenty-seven patients were treated …

Biological Rationale For The Use Of Dna Methyltransferase Inhibitors As New Strategy For Modulation Of Tumor Response To Chemotherapy And Radiation., Giovanni L Gravina, Claudio Festuccia, Francesco Marampon, Vladimir M Popov, Richard G Pestell, Bianca M Zani, Vincenzo Tombolini

Kimmel Cancer Center Faculty Papers

Epigenetic modifications play a key role in the patho-physiology of many tumors and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research. DNA methyltransferase (DNMT) inhibitors represent a promising class of epigenetic modulators. Research performed yielded promising anti-tumorigenic activity for these agents in vitro and in vivo against a variety of hematologic and solid tumors. These epigenetic modulators cause cell cycle and growth arrest, differentiation and apoptosis. Rationale for combining these agents with cytotoxic therapy or radiation is straightforward since the use of DNMT inhibitor offers greatly improved access for cytotoxic …

Physiologically Based Pharmacokinetics Of Molecular Imaging Nanoparticles For Mrna Detection Determined In Tumor-Bearing Mice., Armin W Opitz, Eric Wickstrom, Mathew L Thakur, Norman J Wagner

Kimmel Cancer Center Faculty Papers

Disease detection and management might benefit from external imaging of disease gene mRNAs. Previously we designed molecular imaging nanoparticles (MINs) based on peptide nucleic acids complementary to cancer gene mRNAs. The MINs included contrast agents and analogs of insulin-like growth factor 1 (IGF-1). Analysis of MIN tumor uptake data showed stronger binding in tumors than in surrounding tissues. We hypothesized that MINs with an IGF-1 analog stay in circulation by binding to IGF-binding proteins. To test that hypothesis, we fit the tissue distribution results of several MINs in xenograft-bearing mice to a physiological pharmacokinetics model. Fitting experimental tissue distribution data …