Advances in Targeting Cutaneous Melanoma

To date, the skin remains the most common cancer site among Caucasians in the western world. The complex, layered structure of human skin harbors a heterogenous population of specialized cells. Each cell type residing in the skin potentially gives rise to a variety of cancers, including non-melanoma skin cancer, sarcoma, and cutaneous melanoma. Cutaneous melanoma is known to exacerbate and metastasize if not detected at an early stage, with mutant melanomas tending to acquire treatment resistance over time. The intricacy of melanoma thus necessitates diverse and patient-centered targeted treatment options. In addition to classical treatment through surgical intervention and radio- or chemotherapy, several systemic and intratumoral immunomodulators, pharmacological agents (e.g., targeted therapies), and oncolytic viruses are trialed or have been recently approved. Moreover, utilizing combinations of immune checkpoint blockade with targeted, oncolytic, or anti-angiogenic approaches for patients with advanced disease progression are promising approaches currently under pre-clinical and clinical investigation. In this review, we summarize the current ‘state-of-the-art’ as well as discuss emerging agents and regimens in cutaneous melanoma treatment.

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The Present Status of Immuno-Oncolytic Viruses in the Treatment of Pancreatic Cancer

Viruses ◽

10.3390/v12111318 ◽

2020 ◽

Vol 12 (11) ◽

pp. 1318

Author(s):

Scott D. Haller ◽

Michael L. Monaco ◽

Karim Essani

Keyword(s):

United States ◽

Pancreatic Cancer ◽

Surgical Resection ◽

Clinical Investigation ◽

Treatment Options ◽

Late Phase ◽

The United States ◽

Oncolytic Viruses ◽

Ductal Adenocarcinoma ◽

Treatment Regimens

Pancreatic ductal adenocarcinoma (PDAC) is the fifth leading cause of cancer-related death in Western countries. The incidence of PDAC has increased over the last 40 years and is projected to be the second leading cause of cancer death by 2030. Despite aggressive treatment regimens, prognosis for patients diagnosed with PDAC is very poor; PDAC has the lowest 5-year survival rate for any form of cancer in the United States (US). PDAC is very rarely detected in early stages when surgical resection can be performed. Only 20% of cases are suitable for surgical resection; this remains the only curative treatment when combined with adjuvant chemotherapy. Treatment regimens excluding surgical intervention such as chemotherapeutic treatments are associated with adverse effects and genetherapy strategies also struggle with lack of specificity and/or efficacy. The lack of effective treatments for this disease highlights the necessity for innovation in treatment options for patients diagnosed with early- to late-phase PDAC and immuno-oncolytic viruses (OVs) have been of particular interest since 2006 when the first oncolytic virus was approved as a therapy for nasopharyngeal cancers in China. Interest resurged in 2015 when T-Vec, an oncolytic herpes simplex virus, was approved in the United States for treatment of advanced melanoma. While many vectors have been explored, few show promise as treatment for pancreatic cancer, and fewer still have progressed to clinical trial evaluation. This review outlines recent strategies in the development of OVs targeting treatment of PDAC, current state of preclinical and clinical investigation and application.

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Immunotherapy for Colorectal Cancer: Mechanisms and Predictive Biomarkers

10.20944/preprints202112.0525.v1 ◽

2021 ◽

Author(s):

Lindsey Carlsen ◽

Kelsey E. Huntington ◽

Wafik S. El-Deiry

Keyword(s):

Colorectal Cancer ◽

Immune System ◽

Cancer Cells ◽

Mismatch Repair ◽

Early Stage ◽

Adoptive Cell Therapy ◽

Acquired Resistance ◽

Predictive Biomarkers ◽

Immune Checkpoint Blockade ◽

Oncolytic Viruses

Though early-stage colorectal cancer has a high 5-year survival rate of 65-92% depending on the specific stage, this probability drops to 13% after the cancer metastasizes. Frontline treatments for colorectal cancer such as chemotherapy and radiation often produce dose-limiting toxicities in patients and acquired resistance in cancer cells. Additional targeted treatments are needed to improve patient outcomes and quality of life. Immunotherapy involves treatment with peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer cells. Preclinical and clinical investigations of immunotherapy for treatment of colorectal cancer including immune checkpoint blockade, adoptive cell therapy, monoclonal antibodies, oncolytic viruses, anti-cancer vaccines, and immune system modulators have been promising, but demonstrate limitations for patients with proficient mismatch repair enzymes. In this review, we discuss preclinical and clinical studies investigating immunotherapy for treatment of colorectal cancer and predictive biomarkers for response to these treatments. We also consider open questions including optimal combination treatments to maximize efficacy, minimize toxicity, and prevent acquired resistance and approaches to sensitize mismatch repair proficient patients to immunotherapy.

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Introduction to immunotherapy for brain tumor patients: challenges and future perspectives

Neuro-Oncology Practice ◽

10.1093/nop/npaa007 ◽

2020 ◽

Vol 7 (5) ◽

pp. 465-476 ◽

Cited By ~ 1

Author(s):

Megan L Montoya ◽

Noriyuki Kasahara ◽

Hideho Okada

Keyword(s):

Treatment Options ◽

Malignant Gliomas ◽

Standard Of Care ◽

Immune Checkpoint Blockade ◽

Oncolytic Viruses ◽

Current Status ◽

Current Standard ◽

T Cell Therapy ◽

Sensitive Organ ◽

Cancer Types

Abstract Malignant gliomas, including glioblastoma (GBM) as the most aggressive type of adult CNS tumors, are notoriously resistant to current standard of care treatments, including surgery, systemic chemotherapy, and radiation therapy (RT). This lack of effective treatment options highlights the urgent need for novel therapies, including immunotherapies. The overarching goal of immunotherapy is to stimulate and activate the patient’s immune system in a targeted manner to kill tumor cells. The success of immunotherapeutic interventions in other cancer types has led to interest in and evaluation of various experimental immunotherapies in patients with malignant gliomas. However, these primary malignant brain tumors present a challenge because they exist in a vital and sensitive organ with a unique immune environment. The challenges and current status of experimental immunotherapeutic approaches, including vaccines, immune-checkpoint blockade, chimeric antigen receptor T-cell therapy, and oncolytic viruses will be discussed, as well as the potential for combinatorial therapies.

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Tumor-Associated Mast Cells in Urothelial Bladder Cancer: Optimizing Immuno-Oncology

Biomedicines ◽

10.3390/biomedicines9111500 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1500

Author(s):

Hae Woong Choi ◽

Manisha Naskar ◽

Ho Kyung Seo ◽

Hye Won Lee

Keyword(s):

Bladder Cancer ◽

Mast Cells ◽

Tumor Progression ◽

Early Stage ◽

Treatment Resistance ◽

Resistance Mechanisms ◽

Immune Checkpoint Blockade ◽

Tumor Type ◽

Urothelial Bladder Cancer ◽

Urothelial Bladder

Urothelial bladder cancer (UBC) is one of the most prevalent and aggressive malignancies. Recent evidence indicates that the tumor microenvironment (TME), including a variety of immune cells, is a critical modulator of tumor initiation, progression, evolution, and treatment resistance. Mast cells (MCs) in UBC are possibly involved in tumor angiogenesis, tissue remodeling, and immunomodulation. Moreover, tumor-infiltration by MCs has been reported in early-stage UBC patients. This infiltration is linked with a favorable or unfavorable prognosis depending on the tumor type and location. Despite the discrepancy of MC function in tumor progression, MCs can modify the TME to regulate the immunity and infiltration of tumors by producing an array of mediators. Nonetheless, the precise role of MCs in UBC tumor progression and evolution remains unknown. Thus, this review discusses some critical roles of MCs in UBC. Patients with UBC are treated at both early and late stages by immunotherapeutic methods, including intravenous bacillus Calmette–Guérin instillation and immune checkpoint blockade. An understanding of the patient response and resistance mechanisms in UBC is required to unlock the complete potential of immunotherapy. Since MCs are pivotal to understand the underlying processes and predictors of therapeutic responses in UBC, our review also focuses on possible immunotherapeutic treatments that involve MCs.

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The APAC Score: A Novel and Highly Performant Serological Tool for Early Diagnosis of Hepatocellular Carcinoma in Patients with Liver Cirrhosis

Journal of Clinical Medicine ◽

10.3390/jcm10153392 ◽

2021 ◽

Vol 10 (15) ◽

pp. 3392

Author(s):

Joeri Lambrecht ◽

Mustafa Porsch-Özçürümez ◽

Jan Best ◽

Fabian Jost-Brinkmann ◽

Christoph Roderburg ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

At Risk ◽

Liver Cirrhosis ◽

Early Stage ◽

Treatment Options ◽

Growth Factor Receptor ◽

Serum Samples ◽

Disease Etiology ◽

Risk Patients ◽

Scoring Tool

(1) Background: Surveillance of at-risk patients for hepatocellular carcinoma (HCC) is highly necessary, as curative treatment options are only feasible in early disease stages. However, to date, screening of patients with liver cirrhosis for HCC mostly relies on suboptimal ultrasound-mediated evaluation and α-fetoprotein (AFP) measurement. Therefore, we sought to develop a novel and blood-based scoring tool for the identification of early-stage HCC. (2) Methods: Serum samples from 267 patients with liver cirrhosis, including 122 patients with HCC and 145 without, were collected. Expression levels of soluble platelet-derived growth factor receptor beta (sPDGFRβ) and routine clinical parameters were evaluated, and then utilized in logistic regression analysis. (3) Results: We developed a novel serological scoring tool, the APAC score, consisting of the parameters age, sPDGFRβ, AFP, and creatinine, which identified patients with HCC in a cirrhotic population with an AUC of 0.9503, which was significantly better than the GALAD score (AUC: 0.9000, p = 0.0031). Moreover, the diagnostic accuracy of the APAC score was independent of disease etiology, including alcohol (AUC: 0.9317), viral infection (AUC: 0.9561), and NAFLD (AUC: 0.9545). For the detection of patients with (very) early (BCLC 0/A) HCC stage or within Milan criteria, the APAC score achieved an AUC of 0.9317 (sensitivity: 85.2%, specificity: 89.2%) and 0.9488 (sensitivity: 91.1%, specificity 85.3%), respectively. (4) Conclusions: The APAC score is a novel and highly accurate serological tool for the identification of HCC, especially for early stages. It is superior to the currently proposed blood-based algorithms, and has the potential to improve surveillance of the at-risk population.

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Prospects of immune checkpoint blockade and vaccine-based immunotherapy for glioblastoma

Innovative Surgical Sciences ◽

10.1515/iss-2020-0034 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Stefanie Tietze ◽

Susanne Michen ◽

Gabriele Schackert ◽

Achim Temme

Keyword(s):

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Primary Brain Tumor ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Oncolytic Viruses ◽

Therapeutic Vaccines ◽

Dismal Prognosis ◽

Tumor Parenchyma ◽

Immunosuppressive Microenvironment

Abstract Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor endowed with a dismal prognosis. Nowadays, immunotherapy in a particular immune checkpoint blockade and therapeutic vaccines are being extensively pursued. Yet, several characteristics of GBM may impact such immunotherapeutic approaches. This includes tumor heterogeneity, the relatively low mutational load of primary GBM, insufficient delivery of antibodies to tumor parenchyma and the unique immunosuppressive microenvironment of GBM. Moreover, standard treatment of GBM, comprising temozolomide chemotherapy, radiotherapy and in most instances the application of glucocorticoids for management of brain edema, results in a further increased immunosuppression. This review will provide a brief introduction to the principles of vaccine-based immunotherapy and give an overview of the current clinical studies, which employed immune checkpoint inhibitors, oncolytic viruses-based vaccination, cell-based and peptide-based vaccines. Recent experiences as well as the latest developments are reviewed. Overcoming obstacles, which limit the induction and long-term immune response against GBM when using vaccination approaches, are necessary for the implementation of effective immunotherapy of GBM.

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Medication of Hydroxychloroquine, Remdesivir and Convalescent Plasma during the COVID-19 Pandemic in Germany—An Ethical Analysis

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18115685 ◽

2021 ◽

Vol 18 (11) ◽

pp. 5685

Author(s):

Katja Voit ◽

Cristian Timmermann ◽

Florian Steger

Keyword(s):

Early Stage ◽

Treatment Options ◽

Drug Distribution ◽

Experimental Treatment ◽

Ethical Analysis ◽

Ethical Principles ◽

Ethical Challenges ◽

Ethical Guidelines ◽

Negative Effects ◽

Experimental Drug

This paper aims to analyze the ethical challenges in experimental drug use during the early stage of the COVID-19 pandemic, using Germany as a case study. In Germany uniform ethical guidelines were available early on nationwide, which was considered as desirable by other states to reduce uncertainties and convey a message of unity. The purpose of this ethical analysis is to assist the preparation of future guidelines on the use of medicines during public health emergencies. The use of hydroxychloroquine, remdesivir and COVID-19 convalescent plasma in clinical settings was analyzed from the perspective of the ethical principles of beneficence, non-maleficence, justice and autonomy. We observed that drug safety and drug distribution during the pandemic affects all four ethical principles. We therefore recommend to establish ethical guidelines (i) to discuss experimental treatment options with patients from all population groups who are in urgent need, (ii) to facilitate the recording of patient reactions to drugs in off-label use, (iii) to expand inclusion criteria for clinical studies to avoid missing potentially negative effects on excluded groups, and (iv) to maintain sufficient access to repurposed drugs for patients with prior conditions.

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Lomeguatrib Increases the Radiosensitivity of MGMT Unmethylated Human Glioblastoma Multiforme Cell Lines

International Journal of Molecular Sciences ◽

10.3390/ijms22136781 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6781

Author(s):

Anna Kirstein ◽

Daniela Schilling ◽

Stephanie E. Combs ◽

Thomas E. Schmid

Keyword(s):

Glioblastoma Multiforme ◽

Cell Lines ◽

Dna Methyltransferase ◽

Treatment Options ◽

Treatment Resistance ◽

Cell Cycle Distribution ◽

Human Glioblastoma ◽

Human Glioblastoma Multiforme ◽

Mgmt Protein

Background: Treatment resistance of glioblastoma multiforme to chemo- and radiotherapy remains a challenge yet to overcome. In particular, the O6-methylguanine-DNA-methyltransferase (MGMT) promoter unmethylated patients have only little benefit from chemotherapy treatment using temozolomide since MGMT counteracts its therapeutic efficacy. Therefore, new treatment options in radiotherapy need to be developed to inhibit MGMT and increase radiotherapy response. Methods: Lomeguatrib, a highly specific MGMT inhibitor, was used to inactivate MGMT protein in vitro. Radiosensitivity of established human glioblastoma multiforme cell lines in combination with lomeguatrib was investigated using the clonogenic survival assay. Inhibition of MGMT was analyzed using Western Blot. Cell cycle distribution and apoptosis were investigated to determine the effects of lomeguatrib alone as well as in combination with ionizing radiation. Results: Lomeguatrib significantly decreased MGMT protein and reduced radiation-induced G2/M arrest. A radiosensitizing effect of lomeguatrib was observed when administered at 1 µM and increased radioresistance at 20 µM. Conclusion: Low concentrations of lomeguatrib elicit radiosensitization, while high concentrations mediate a radioprotective effect.

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The Emerging Factors and Treatment Options for NAFLD-Related Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers13153740 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3740

Author(s):

Chunye Zhang ◽

Ming Yang

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cancer ◽

Fatty Liver ◽

Early Stage ◽

Primary Liver Cancer ◽

Treatment Options ◽

Underlying Mechanism ◽

Diagnostic Methods ◽

T Cell Therapy ◽

Nonalcoholic Fatty Liver

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, followed by cholangiocarcinoma (CCA). HCC is the third most common cause of cancer death worldwide, and its incidence is rising, associated with an increased prevalence of obesity and nonalcoholic fatty liver disease (NAFLD). However, current treatment options are limited. Genetic factors and epigenetic factors, influenced by age and environment, significantly impact the initiation and progression of NAFLD-related HCC. In addition, both transcriptional factors and post-transcriptional modification are critically important for the development of HCC in the fatty liver under inflammatory and fibrotic conditions. The early diagnosis of liver cancer predicts curative treatment and longer survival. However, clinical HCC cases are commonly found in a very late stage due to the asymptomatic nature of the early stage of NAFLD-related HCC. The development of diagnostic methods and novel biomarkers, as well as the combined evaluation algorithm and artificial intelligence, support the early and precise diagnosis of NAFLD-related HCC, and timely monitoring during its progression. Treatment options for HCC and NAFLD-related HCC include immunotherapy, CAR T cell therapy, peptide treatment, bariatric surgery, anti-fibrotic treatment, and so on. Overall, the incidence of NAFLD-related HCC is increasing, and a better understanding of the underlying mechanism implicated in the progression of NAFLD-related HCC is essential for improving treatment and prognosis.

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Clostridial Spores for Cancer Therapy: Targeting Solid Tumour Microenvironment

Journal of Toxicology ◽

10.1155/2012/862764 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 14

Author(s):

Brittany Umer ◽

David Good ◽

Jozef Anné ◽

Wei Duan ◽

Ming Q. Wei

Keyword(s):

Cancer Therapy ◽

Solid Tumour ◽

Early Stage ◽

Treatment Options ◽

Anaerobic Bacteria ◽

Past Research ◽

Tumour Microenvironment ◽

The Body ◽

Solid Tumours ◽

Current Status

Solid tumour accounts for 90% of all cancers. The current treatment approach for most solid tumours is surgery, however it is limited to early stage tumours. Other treatment options such as chemotherapy and radiotherapy are non-selective, thus causing damage to both healthy and cancerous tissue. Past research has focused on understanding tumour cells themselves, and conventional wisdom has aimed at targeting these cells directly. Recent research has shifted towards understanding the tumour microenvironment and it’s differences from that of healthy cells/tissues in the body and then to exploit these differences for treatmeat of the tumour. One such approach is utilizing anaerobic bacteria. Several strains of bacteria have been shown to selectively colonize in solid tumours, making them valuable tools for selective tumour targeting and destruction. Amongst them, the anaerobicClostridiumhas shown great potential in penetration and colonization of the hypoxic and necrotic areas of the tumour microenvironment, causing significant oncolysis as well as enabling the delivery of therapeutics directly to the tumourin situ. Various strategies utilizingClostridiumare currently being investigated, and represent a novel area of emerging cancer therapy. This review provides an update review of tumour microenvironment as well as summary of the progresses and current status of Clostridial spore-based cancer therapies.

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