El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Background: Clinical trial completion is critical for new cancer therapies. Premature trial termination or withdrawal is common and impairs progress. We assessed factors of early terminated/withdrawn oncology trials focusing on trials with immune checkpoint inhibitors (ICI), hypothesizing that the latter may be associated with lower rates of premature discontinuation. Materials and Methods: We reviewed all adult, intervention, oncology trials registered in ClinicalTrials.gov (November 16, 2011, to April 16, 2015) to identify all terminated/withdrawn trials and reasons for termination. Logistics regression model was used to identify factors associated with early termination/withdrawal. Discontinuation rate was compared in trials with and without ICI. Results: We identified 12,875 trials (35% industry funded, 12% federal funded), of which 8.5% were prematurely terminated (5%) or withdrawn (3.5%); the main reasons were poor accrual (33%) and logistical (24%). ICI trials (n = 350) had a nonsignificant lower rate of termination or withdrawal compared with all other oncology trials (5.4% vs. 8.5%; p =.9) and were less likely to discontinue due to poor accrual (nonsignificant difference: 21% vs. 33%; p =.4). ICI trials were also less likely to discontinue compared with all other oncology drug trials (e.g., chemotherapy, targeted inhibitors, antiangiogenesis, biologics; 5.4% vs. 7.9%, respectively, nonsignificant difference). The 4-year cumulative incidence of failing to complete for reasons unrelated to toxicity or efficacy was 18% (95% confidence interval 16%–20%). There was no association between annual incidence across different tumor types or accrual goal and rate of trial termination. Conclusion: Poor accrual represents the main cause of early cancer trial termination. Premature termination/withdrawal rate was not significantly lower in ICI compared with other trials. Clinical trial completion remains a high priority and can be influenced by provider and patient factors. Implications for Practice: Clinical trial completion is critical for new cancer therapies. Premature trial termination or withdrawal is common and impairs progress. This study assessed factors of early terminated/withdrawn oncology trials, focusing on trials with immune checkpoint inhibitors (ICI), and found that poor accrual represents the main cause of early cancer trial termination. Premature termination/withdrawal rate was not significantly lower in immune checkpoint inhibitor trials compared to other trials. The discussion herein is focused on measures taken by the National Cancer Institute and other institutions to improve clinical trial accrual and prevent premature clinical trial discontinuation. / Revisión por pares

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Precision medicine has allowed for the development of monoclonal antibodies that unmask the anti-tumor immune response. These agents have provided some patients durable clinical benefit. However, PD-1 and PD-L1 inhibitor therapies are effective in a small group (10-20%) of non-small cell lung cancer (NSCLC) patients when used as single-agent therapy. The approved companion diagnostic is expression of the immune cell surface molecule, programmed death ligand 1 (PD-L1), on tumors measured by immunohistochemistry (IHC). Studies in tumor biology and immune surveillance dictate that PD-1 inhibitor efficacy should depend on the level of PD-L1 expression; however, the literature has not followed with convincing evidence. The limitations of this test include timing of tissue acquisition, tumor heterogeneity, and timing of therapy relative to the expression of PD-L1. In addition, the requirement of analyzing tumor tissue biopsy samples from a patient is cumbersome. Thus, a peripheral blood biomarker that predicts efficacy of PD-1/PD-L1 inhibition would be optimal for precise and cost-effective treatment. A history of chronic inflammatory diseases may be advantageous for a cancer patient who is treated with PD-1/PD-L1 inhibitors and may allow them to then mobilize a swift immune response to tumor cells. Specific biological components of this persistent inflammation may predict PD-1 inhibitor response. We have taken a novel approach to leverage national healthcare claims data that couples patient history with response to therapy. We have identified potential peripheral blood biomarkers of response to PD-1/PD-L1 inhibitors using a combination of healthcare outcomes and molecular markers that correlate with therapeutic efficacy.

Cancer is a leading cause of morbidity and mortality in the developed world. While much has been learned about these diseases in the last few decades, one of the main barriers to widespread advancement is the heterogeneity of cancer biology. A growing body of evidence supports the idea that certain protein receptors are overexpressed on the surface of tumor cells as compared to normal tissues. These extracellular biomarkers provide a unique opportunity to selectively target the tumor with both imaging and therapeutic modalities. The research in this dissertation focuses on targeting proteins on the tumor cell surface with peptidomimetic ligands. Following a description of various extracellular receptors, chapter one discusses targeting ligands designed to specifically and selectively bind these receptors. It reviews recent literature on targeted alpha-particle therapy and ends with an explanation of the advantages of peptide ligands. Three distinct approaches to imaging and therapeutic modalities are then discussed in subsequent chapters. First, a peptide ligand was designed to target radionuclides to malignant melanoma cells in an effort to develop companion radiotherapeutics and diagnostic imaging agents. The second research project describes the synthesis of a novel antagonist peptide ligand with conjugated near infrared dye, and its utility for real-time intraoperative guidance during pancreatic adenocarcinoma resection. Finally, the last chapter describes how the relatively new field of immunomodulatory effectors may be enhanced by their derivatization with peptide targeting ligands.

abstract: Immunotherapy has received great attention recently, as it has become a powerful tool in fighting certain types of cancer. Immunotherapeutic drugs strengthen the immune system's natural ability to identify and eradicate cancer cells. This work focuses on immune checkpoint inhibitor and oncolytic virus therapies. Immune checkpoint inhibitors act as blocking mechanisms against the binding partner proteins, enabling T-cell activation and stimulation of the immune response. Oncolytic virus therapy utilizes genetically engineered viruses that kill cancer cells upon lysing. To elucidate the interactions between a growing tumor and the employed drugs, mathematical modeling has proven instrumental. This dissertation introduces and analyzes three different ordinary differential equation models to investigate tumor immunotherapy dynamics. The first model considers a monotherapy employing the immune checkpoint inhibitor anti-PD-1. The dynamics both with and without anti-PD-1 are studied, and mathematical analysis is performed in the case when no anti-PD-1 is administrated. Simulations are carried out to explore the effects of continuous treatment versus intermittent treatment. The outcome of the simulations does not demonstrate elimination of the tumor, suggesting the need for a combination type of treatment. An extension of the aforementioned model is deployed to investigate the pairing of an immune checkpoint inhibitor anti-PD-L1 with an immunostimulant NHS-muIL12. Additionally, a generic drug-free model is developed to explore the dynamics of both exponential and logistic tumor growth functions. Experimental data are used for model fitting and parameter estimation in the monotherapy cases. The model is utilized to predict the outcome of combination therapy, and reveals a synergistic effect: Compared to the monotherapy case, only one-third of the dosage can successfully control the tumor in the combination case. Finally, the treatment impact of oncolytic virus therapy in a previously developed and fit model is explored. To determine if one can trust the predictive abilities of the model, a practical identifiability analysis is performed. Particularly, the profile likelihood curves demonstrate practical unidentifiability, when all parameters are simultaneously fit. This observation poses concerns about the predictive abilities of the model. Further investigation showed that if half of the model parameters can be measured through biological experimentation, practical identifiability is achieved. / Dissertation/Thesis / Doctoral Dissertation Applied Mathematics 2020

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal cancer, accounting for 3.2% of new cancer cases yearly but nearly 8% of all yearly cancer mortalities. Over the past twenty years, our understanding of cancer biology has greatly improved which has resulted in vastly improved prognoses for many cancers. However, the prognosis of pancreatic ductal adenocarcinoma has not improved despite the advance in cancer treatments. This is especially apparent with cancer immunotherapies, a newer therapeutic strategy that utilizes the innate defense mechanism of the body to target malignancies. Immune checkpoint inhibitors are a type of cancer immunotherapy that act by inhibiting the PD-1/PD-L1 and CTLA-4 immune checkpoint pathways and allowing T lymphocytes to proliferate and generate an antitumor response. They have greatly improved the prognosis for many types of malignancies, but clinical studies show that immune checkpoint inhibition has had a limited effect on the prognosis of PDAC. Recent studies have demonstrated that the immune microenvironment of PDAC is highly immunosuppressive, which is a probable factor in limiting the therapeutic efficacy of immune checkpoint inhibitors. Myeloid derived suppressor cells (MDSCs) are a main component of the immune microenvironment in PDAC. They are immature cells of myeloid origin that express CD11b+Gr-1+ on their surface, making them phenotypically distinct from mature dendritic cells. Their infiltration of the PDAC microenvironment early on in the course of the disease is promoted in a large part by the cytokine GM-CSF. MDSCs are believed to contribute to the limited efficacy of immune checkpoint inhibitor therapy both directly and indirectly. Indirect mechanisms are mediated by promoting the activity of other immunosuppressive cells in the PDAC microenvironment such as tumor associated macrophages and regulatory T lymphocytes. MDSCs induce the transformation of naïve CD4+ T lymphocytes into protumorigenic regulatory T lymphocytes. They also promote the polarization of macrophages to the tumor associated macrophage phenotype (IL-10high IL-12low) by secreting IL-10, which decreases IL-12 synthesis by macrophages present in the tumor microenvironment. On top of mediating immunosuppression through other cell types, MDSCs directly mediate immunosuppression by decreasing the amounts of amino acids necessary for anti-tumor immunity in the tumor microenvironment and disrupting the activity of antigen presenting cells and the signaling needed to initiate a cytotoxic T lymphocyte response. The decreased amount of arginine limits the ability of T cells to proliferate, resulting in a weaker cytotoxic response. These mechanisms limit the antitumor response against pancreatic ductal adenocarcinoma, resulting in the decreased response to immune checkpoint inhibitor therapy observed in clinical trials. Future attempts to strengthen the anti-tumor immune response must be combinatorial therapies that incorporate therapeutic strategies that seek to alleviate MDSC-mediated immunosuppression of T lymphocytes from the tumor microenvironment in addition to the more widely available immune checkpoint inhibitor therapy. Such therapeutics are currently being studied in murine models and have shown promising preliminary results but have yet to have been examined in clinical trials. These therapies are an ideal avenue to explore in a search for more effective therapy for this highly lethal disease.

The development and design of immune-based strategies have become an increasingly important topic during the last few years in acute myeloid leukemia (AML), based on successful immunotherapies in solid cancer. The spectrum ranges from antibody drug conjugates, immune checkpoint inhibitors blocking programmed cell death protein 1 (PD1), cytotoxic T lymphocyte antigen 4 (CTLA4) or T cell immunoglobulin and mucin domain containing-3 (TIM3), to T-cell based monoclonal and bispecific T-cell engager antibodies, chimeric antigen receptor-T-cell (CAR-T) approaches and leukemia vaccines. Currently, there are many substances in development and multiple phase I/II studies are ongoing. These trials will help us to deepen our understanding of the pathogenesis of AML and facilitate the best immunotherapeutic strategy in AML. We discuss here the mode of action of immune-based therapies and provide an overview of the available data.

Hintergrund: Das Nierenzellkarzinom (NZK) ist die dritthäufigste urologische Tumorerkrankung in Deutschland. Mit der Zulassung der Immun-Checkpoint-Inhibitoren (CPI) wurde die Therapie des metastasierten NZK (mNZK) revolutioniert und die Prognose für viele Patienten signifikant verbessert. Als Standard in der Erstlinie (1L) werden aktuell hauptsächlich CPI in Kombination mit Tyrosinkinase-Inhibitoren (TKI) oder anderen CPI sowie optional TKI-Monotherapien eingesetzt. Die Ansprechraten der CPI-basierten Therapie sind jedoch sehr variabel, was dazu führt, dass einige Patienten keinen Nutzen und nur die teilweise schwerwiegenden Nebenwirkungen der Therapie erfahren. Welche Patienten gut auf die Therapie ansprechen bzw. eine gute Prognose zeigen und welche besonders unter den Nebenwirkungen leiden, kann aktuell erst im langfristigen Therapieverlauf abgeschätzt werden. Fragestellung: Das Ziel dieser Arbeit war es daher, Biomarker zu identifizieren, die ein prognostisches Potential für mNZK-Patienten unter Systemtherapie, insbesondere CPI-basierter Therapie, besitzen. Diese potenziellen Biomarker sollten einfach zugänglich sein und keine zusätzliche Prozedur für die Patienten bedeuten, um eine einfache Anwendung im klinischen Alltag zu ermöglichen. Daher konzentrierte sich diese Arbeit auf Routine-Laborparameter, welche standardmäßig im peripheren Blut bei den Patientenvisiten bestimmt werden. Neben Parametern für Entzündung und Immunreaktion (CRP, NLR), Zellschädigung (LDH) und oxidativen Stress (GGT) wurden auch Leberwerte (ALAT, ASAT), Pankreasenzyme (Lipase, Amylase) und Schilddrüsenwerte (TSH, T3, T4) erfasst und hinsichtlich ihres prognostischen Potentials untersucht. Material und Methoden: Zunächst wurden 71 mNZK-Patienten retrospektiv identifiziert, die in der Klinik und Poliklinik für Urologie des Universitätsklinikums Dresden eine systemische 1L-Therapie (CPI+TKI, CPI+CPI, TKI) erhielten. Anhand des klinikinternen Patientendokumentationssystems wurden für diese Patienten die demographischen und klinisch-pathologischen Daten inklusive Therapie- und Krankheitsverlauf erfasst. Für die Standardlaborparameter wurden sowohl die prätherapeutischen Werte als auch die Verlaufswerte bis zu 12 Wochen nach 1L-Start dokumentiert. Anschließend wurden die Patienten anhand spezifischer Cut-Offs in Gruppen mit niedrigen und hohen Leveln (≤/> Cut-Off) der jeweiligen Laborparameter eingeteilt. Für CRP, LDH und GGT erfolgte zusätzlich eine Einteilung der Patienten in Abhängigkeit von der Zusammenfassung: Kinetik der Laborwerte in der Anfangsphase der Therapie in die Gruppen normal (prätherapeutisch ≤ Cut-Off), normalized (prätherapeutisch > Cut-Off & im Verlauf ≤ Cut-Off) und non-normalized (prätherapeutisch & im Verlauf > Cut-Off). Das prognostische Potential der erfassten Parameter wurde sowohl in der Gesamtkohorte von Patienten unter systemischer 1L-Therapie als auch in der Subkohorte von Patienten unter CPI-basierter Therapie anhand des progressionsfreien (PFS) und Gesamtüberlebens (OS) mittels Kaplan-Meier-Überlebensanalysen und Sterbetafeln sowie uni- und multivariater Cox-Regressionsanalysen evaluiert. Für die multivariaten Cox-Regressionsanalysen zur Identifizierung von prognostisch unabhängigen Faktoren wurde ein Basismodell aus Alter, vorheriger Nephrektomie und Metastasenanzahl verwendet, welchem dann die kategorisierten Laborparameter mit zuvor nachgewiesener PFS- bzw. OS-Assoziation einzeln hinzugefügt wurden. Ergebnisse: In der Gesamtkohorte zeigten Patienten mit einer normal- und normalized-CRP-Kinetik ein signifikant längeres PFS, während in der CPI-basierten Kohorte Patienten mit einer normal- und normalized-Kinetik für CRP und LDH nur ein per Trend längeres PFS aufwiesen. Anhand von multivariaten Cox-Regressionsanalysen konnte die CRP-Kinetik in der CPI-basierten Kohorte allerdings als unabhängiger prognostischer Parameter für das PFS identifiziert werden. In der Gesamtkohorte zeigten Patienten mit einem prätherapeutisch niedrigen CRP- (≤15 mg/l), LDH- (≤4 μmol/s*l), GGT- (≤0,8 μmol/s*l) und ASAT-Wert (≤0,5 μmol/s*l) sowie Patienten mit einer normal- und normalized-Kinetik für CRP und LDH und einer normal-GGT-Kinetik ein signfikant bzw. per Trend längeres OS. In der CPI-basierten Kohorte zeigten Patienten mit einem prätherapeutisch niedrigen LDH- (≤4 μmol/s*l), GGT- (≤0,8 μmol/s*l), ALAT- (≤0,4 μmol/s*l) und ASAT-Wert (≤0,5 μmol/s*l) sowie Patienten mit einer normal- und normalized-Kinetik für CRP und LDH und einer normal-GGT-Kinetik ein signfikant bzw. per Trend längeres OS. In der Gesamtkohorte konnten anhand von multivariaten Cox-Regressionsanalysen der prätherapeutische LDH-Wert und die LDH-Kinetik als unabhängige prognostische Parameter für das OS identifiziert werden, während der prätherapeutische GGT-Wert und die GGT-Kinetik nur per Trend unabhägige prognostische Parameter waren. In der CPI-basierten Kohorte konnten die prätherapeutischen LDH-, GGT-, ALAT- und ASAT- Werte sowie die LDH- und GGT-Kinetik signifikant bzw. per Trend als unabhängige prognostische Parameter für das OS identifiziert werden. Für die prätherapeutischen Werte von NLR, Amylase, Lipase und TSH konnte kein signifikanter Zusammenhang mit dem PFS und OS in beiden Patientenkohorten gezeigt werden. Zusammenfassung Schlussfolgerung Die beobachtete Assoziation zwischen sowohl prätherapeutischen CRP-, LDH- , GGT-, ALAT- und ASAT-Werten sowie der frühen Kinetik von CRP, LDH und GGT mit der Prognose von mNZK-Patienten unter systemischer, insbesondere CPI-basierter 1L-Therapie könnte zukünftig potentiell für die frühe Einschätzung der patientenspezifischen CPI-Wirksamkeit genutzt werden. Diese Laborparameter sind im klinischen Alltag leicht zugänglich, reproduzierbar und könnten ohne vermehrten Aufwand prätherapeutisch bestimmt werden, um die Prognose bzw. das Therapieansprechen vorherzusagen. Das Therapieansprechen wird aktuell 12 Wochen nach Beginn der Behandlung durch das radiologische Staging beurteilt. Eine zeitnahe Einschätzung des Ansprechens der Patienten auf die CPI-basierte Therapie anhand von prätherapeutischen Laborwerten bzw. ihrer frühen Kinetik könnte daher, falls erforderlich, zu einer früheren Bewertung des Krankheitsstadiums und zu entsprechenden Anpassungen in der Therapie führen.

Head and neck squamous cell carcinoma encompasses a complex and heterogeneous group of malignant diseases. Originally, this tumor type was associated with tobacco and alcohol consumption. However, a significantly expanding subset of tumors associated with oncogenic human papillomavirus infection arising in deep tonsillar crypts was identified within the last decades. Due to the essential role of the immune system in antiviral and anticancer immune response, the prognosis of patients is significantly influenced by the volume, composition and functional capacity of the immune infiltrate. The immunosuppressive landscape of head and neck cancer leads to unfavorable outcome of patients and decreased efficacy of immunotherapy. The response rate to standard treatment is high, however, standard therapy is accompanied by considerable toxicity influencing the quality of life. In 2016, the first immunotherapeutics for the treatment of patients with recurrent squamous cell carcinoma of the head and neck were approved - the anti-PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab. This type of therapy, based on mitigation of immunosuppression, shows strong efficacy and less toxicity in combination with other therapies. Therefore, anti-PD-1 immunotherapy was recently approved in the first-line...

Many studies show the ability of gut microbes to modulate the anti-tumour immune response by direct triggering the immune cells or by bacterial metabolites. Interestingly bacteria may even migrate to the tumour tissue and orchestrate the immune response on site. These anti-tumour effects can be improved by the administration of immune checkpoint inhibitors (ICI). Notably, some microbial effects occur only in the presence of ICI. On the contrary, microbiota may also promote tumour growth and negatively impact the effects of ICI therapy. We have disrupted the gut microbiota homeostasis by antibiotics (ATB) to study the effects of gut microbiota on the ICI. This disturbance led surprisingly to reduced tumour growth and enhanced pro-inflammatory immune response not only in the gut but also within the tumour tissue, where especially IFN-γ orchestrated the anti-tumour immune response. Importantly the anti-tumour immune response could be transferred through colonisation of germ-free mice by ATB-changed gut microbiota if concomitantly anti- programmed cell death protein 1 (αPD-1) monoclonal antibody was administrated. These mice had elevated levels of segmented filamentous bacteria (SFB), which induced systemic immune response with increased expression of IL-17 and elevated amounts of Th 17 cells,...