Editors Choice: The Emergence of Immune-checkpoint Inhibitors in Colorectal Cancer Therapy

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Abstract:

Immunotherapy has revolutionized the treatment landscape in a number of solid tumors. In colorectal cancer, evidence suggests that microsatellite high (MSI-H) tumors are the most responsive to immune checkpoint blockade due to increased neo-antigen load and a favorable tumor microenvironment. Indeed, Pembrolizumab now represents a first-line option in such patients. However, MSI-H tumors represent the minority and a proportion of patients’ progress despite initially responding. Trials are investigating different immunotherapy combinatorial strategies to enhance immune response in less immunogenic colorectal tumors. Such strategies include dual immune checkpoint blockade, combining immune checkpoint inhibitors with other treatment modalities such as radiotherapy, chemotherapy or other biological or targeted agents. Moreover, there is an increasing drive to identify biomarkers to better select patients most likely to respond to immunotherapy and understand intrinsic and acquired resistance mechanisms. Apart from MSI-H tumors, there is a strong rationale to suggest that tumors with alterations in DNA polymerase epsilon and DNA polymerase delta are also likely to respond to immunotherapy and trials in this subpopulation are underway. Other strategies such as priming O6-methylguanineDNA methyltransferase silenced tumors with alkylating agents to make them receptive to immune checkpoint blockade are also being investigated. Here we discuss different colorectal subpopulations together with their likelihood of response to immune checkpoint blockade and strategies to overcome barriers to a successful clinical outcome. We summarize evidence from published clinical trials and provide an overview of trials in progress whilst discussing newer immunotherapy strategies such as adoptive cell therapies and cancer vaccines. Read more here: https://www.eurekaselect.com/191176/article

Abstracts Ahead of Print | Safety Profiles and Pharmacovigilance Considerations for Recently Patented Anticancer Drugs: Lung Cancer

Journal Name: Recent Patents on Anti-Cancer Drug Discovery

Author(s): Alessandra Bearz, Sara Cecco, Sara Francescon, Francesco Lo Re, Giuseppe Corona, Paolo Baldo*.

 

 

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Background: Lung cancer is the most frequent cause of cancer-related death. In the last decades, the introduction of targeted therapies and more recently, of immunotherapy, has led to significant improvements in different outcomes of this malignant neoplasm.

Objective: The present review provides a balanced overview of most recent targeted therapies and immunotherapies patented for the treatment of lung cancer.

Method: An extensive scientific literature and patent databases search were performed to identify peer-reviewed studies containing information on recently patented drugs for the treatment of lung cancer, with a particular focus on their safety data and recently patented combinations.

Results: The development of therapies directed to different pathways involved in the tumor angiogenesis, proliferation, and metastasis has transformed the clinical practice of lung malignancies. Several clinical trials have shown an improvement in terms of progression-free survival and overall survival in patients with advanced/metastatic lung cancer. Safety data, extracted from clinical trials and from the WHO global database of adverse drug reactions (VigiAccessTM database), show that recently patented drugs for the treatment of lung cancer are well- tolerated and most of the adverse events reported are mild to moderate.

Conclusion: Currently, a consistent number of new drugs and combinations have been introduced for the treatment of patients with advanced-stage lung cancer. Safety data remain essential to better assess the long-term risk/benefit ratio of these valuable emerging therapies. The new patents’ development could provide further significant improvements for lung cancer treatment. To read full abstract, please visit: http://www.eurekaselect.com/173895/article

Abstracts Ahead of Print | Safety Profiles and Pharmacovigilance Considerations for Recently Patented Anticancer Drugs: Cutaneous Melanoma

Author(s): Debora Basile, Camilla Lisanti, Maria A. Pizzichetta, Paolo Baldo*, Giulia Fornasier, Francesco Lo Re, Giuseppe Corona, Fabio Puglisi.

 

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Background: Malignant melanoma is a skin cancer responsible of 90% of cutaneous cancer related deaths. In recent years, breakthroughs in treatment strategy have revolutionized the prognosis both of early and advanced melanoma patients. In particular, treatment with monoclonal antibodies targeting co-inhibitory checkpoints or specific molecular pathways are pawing the way for a new era of promising options, by prolonging survival time of these patients.

Moreover, unlike the chemotherapy that was used until some time ago, these new drugs have a good and more manageable toxicity profile. However, because of the recent introduction in clinical practice of the new agents, there is a learning curve among physicians regarding early recognition and management of the associated side effects.

Objectives: The analysis of the toxicity profiles of the different agents currently studied for the treatment of early and advanced melanoma, and the description of several relevant recent patents in this field, are the aims of this review.

Methods: A systematically conducted review, based on current clinical guidelines and on international Pharmacovigilance databases (AERS-Eudravigilance – WHO Vigibase).

Results: Our systematic analysis outlines a comprehensive overview about the pharmacology, clinical application and safety of recent anticancer drugs to treat melanoma, which can be an essential instrument for health professionals and researchers.

Conclusion: The new oncological therapies against melanoma are based on increasingly specific biological and immunological targets. For this reason, the potential toxicities that are expected from patients would be less relevant than the systemic “classical” chemotherapy. However, the new therapies are not free from the risk of causing adverse reactions, some of which must be managed promptly and appropriately; moreover the multiplicity of the metabolic pathways exposes the new target therapies to relevant potential interactions. This review can help to understand how important it is not to underestimate potential adverse drug reactions related to new targeted therapies. To read the full abstract, please visit: http://www.eurekaselect.com/173896/article

Most Accessed Articles – CAR T-cell Therapy: A New Era in Cancer Immunotherapy

Journal Name: Current Pharmaceutical Biotechnology

Author(s): Miliotou N. Androulla, Papadopoulou C. Lefkothea*.

 

 

 

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Abstract:

Background: Cancer is one of the leading causes of death worldwide. Over the years, a number of conventional cytotoxic approaches for neoplastic diseases has been developed. However, due to their limited effectiveness in accordance with the heterogeneity of cancer cells, there is a constant search for therapeutic approaches with improved outcome, such as immunotherapy that utilizes and enhances the normal capacity of the patient’s immune system.

Methods: Chimeric Antigen Receptor (CAR) T-cell therapy involves genetic modification of patient’s autologous T-cells to express a CAR specific for a tumor antigen, following by ex vivo cell expansion and re-infusion back to the patient. CARs are fusion proteins of a selected single-chain fragment variable from a specific monoclonal antibody and one or more T-cell receptor intracellular signaling domains. This T-cell genetic modification may occur either via viral-based gene transfer methods or nonviral methods, such as DNA-based transposons, CRISPR/Cas9 technology or direct transfer of in vitro transcribed-mRNA by electroporation.

Results: Clinical trials have shown very promising results in end-stage patients with a full recovery of up to 92% in Acute Lymphocytic Leukemia. Despite such results in hematological cancers, the effective translation of CAR T-cell therapy to solid tumors and the corresponding clinical experience is limited due to therapeutic barriers, like CAR T-cell expansion, persistence, trafficking, and fate within tumors.

Conclusion: In this review, the basic design of CARs, the main genetic modification strategies, the safety matters as well as the initial clinical experience with CAR T-cells are described.

 

For more details, please visit: http://www.eurekaselect.com/161365

EDITOR’S CHOICE – Immunotheraphy in Allergic Diseases

Journal: Current Pharmaceutical Design

Author(s): Albert Roger, Maria Basagana, Aina Teniente-Serra, Nathalie Depreux, Yanina Jurgens , Clara Padro, Sira Miquel, Carolina Elduque, Eva M. Martinez-Caceres*.

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Abstract:

The prevalence of allergic diseases is increasing worldwide. It is estimated that more than 30% of the world population is now affected by one or more allergic conditions and a high proportion of this increase is in young people. The diagnosis of allergy is dependent on a history of symptoms on exposure to an allergen together with the detection of allergen-specific IgE. Accurate diagnosis of allergies opens up therapeutic options. Allergen specific immunotherapy is the only successful disease-modifying therapy for IgE-mediated allergic diseases. New therapeutic strategies have been developed or are currently under clinical trials. Besides new routes of administration, new types of allergens are being developed. The use of adjuvants may amplify the immune response towards tolerance to the antigens. In this review, we analyze different antigen-specific immunotherapies according to administration route, type of antigens and adjuvants, and we address the special case of food allergy.

 

Read more here:  http://www.eurekaselect.com/159081/article

EDITOR’S CHOICE – Oncolytic Tanapoxvirus Expressing Interleukin-2 is Capable of Inducing the Regression of Human Melanoma Tumors in the Absence of T Cells

Journal: Current Cancer Drug Targets

Author(s): Tiantian Zhang, Dennis H. Kordish, Yogesh R. Suryawanshi, Rob R. Eversole, Steven Kohler,Charles D. Mackenzie, Karim Essani*.

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Abstract:

Background: Oncolytic viruses (OVs), which preferentially infect cancer cells and induce host anti-tumor immune responses, have emerged as an effective melanoma therapy. Tanapoxvirus (TANV), which possesses a large genome and causes mild self-limiting disease in humans, is potentially an ideal OV candidate. Interleukin-2 (IL-2), a T-cell growth factor, plays a critical role in activating T cells, natural killer (NK) cells and macrophages in both the innate and adaptive immune system.

Objective: We aimed to develop a recombinant TANV expressing mouse IL-2 (TANVΔ66R/mIL- 2), replacing the viral thymidine kinase (TK) gene (66R) with the mouse (m) mIL-2 transgene resulting in TANVΔ66R/mIL-2.

Methods: Human melanoma tumors were induced in female athymic nude mice by injecting SKMEL- 3 cells subcutaneously. Mice were treated with an intratumoral injection of viruses when the tumor volumes reached 45 ± 4.5 mm3.

Results: In cell culture, expression of IL-2 attenuated virus replication of not only TANVΔ66R/ mIL-2, but also TANVGFP. It was demonstrated that IL-2 inhibited virus replication through intracellular components and without activating the interferon-signaling pathway. Introduction of mIL-2 into TANV remarkably increased its anti-tumor activity, resulting in a more significant regression than with wild-type (wt) TANV and TANVΔ66R. Histopathological studies showed that extensive cell degeneration with a significantly increased peri-tumor accumulation of mononuclear cells in the tumors treated with TANVΔ66R/mIL-2, compared to wtTANV or TANVΔ66R.

Conclusion: We conclude that TANVΔ66R/mIL-2 is potentially therapeutic for human melanomas

 

Read more here: http://www.eurekaselect.com/153638/article

 

MOST ACCESSED ARTICLE – Advances in the Delivery of Cancer Therapeutics – Current Drug Delivery

Journal: Current Drug Delivery

Author(s): Gunjan Jeswani*, Swarnali Das Paul, Arvind Kumar Jha

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Abstract:

Background: The effects of various chemotherapeutic agents have been assessed for their capacity to inhibit the cell replication in variety of cancer cases. At present there are more than hundred chemotherapeutic agents capturing worth 42 billion dollar of drug market. The major obstacle in the successful treatment of cancer is the obnoxious side effects of chemotherapeutics and multi drug resistance, which deteriorates the quality of life of cancer patient.

Objective: This article attempts to summarize different novel chemotherapeutic delivery systems which aim to circumvent these unwanted effects.

Areas Covered: Outcomes of different tumor directed carrier systems have been discussed with special emphasis on nanocarriers systems, drug polymer conjugation, directly implantable matrices and others. In addition, combination therapy and immunotherapy are also discussed as a revolutionary alternative.

Conclusion: Even though significant contributions have been made in the development of carrier systems for the chemotherapeutic agents, merits and demerits of all the avenues should be critically examined. Potential of all novel strategies should be exploited by critically evaluating their strength, weakness, opportunities and threats. Further, clinical trials based on revised and critically scrutinized frameworks and protocols are needed so that the efficiency and safe action of these new systems can be guaranteed in cancer patients.

Read more here: http://www.eurekaselect.com/154483/article

 

Podcast: Oncolytic Tanapoxvirus Expressing Interleukin-2 Is Capable Of Inducing The Regression Of Human Melanoma Tumors In The Absence Of T Cells by Dr. Zhang

Author(s): Tiantian Zhang, Dennis H Kordish, Yogesh R Suryawanshi, Rob R Eversole, Steven Kohler, Charles D Mackenzie, Karim Essani

For article details, visit: http://www.eurekaselect.com/153638/article

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Highlighted Article – Glioblastoma Multiforme, Diagnosis and Treatment– Current Medicinal Chemistry

CMC-Articles_24-42-Noam Asna

http://www.eurekaselect.com/152454/article

New Chemotherapy and Immunotherapy for Tuberculosis!

On World Tuberculosis Day 2016, read our research article on tuberculosis from the journal Current Respiratory Medicine Reviews

Abstract: Tuberculosis (TB) has been a widespread infectious disease since ancient times and remains a worldwide major health problem. TB morbidity with 8 to 9 million active cases per year and 1.3 deaths annually represent the largest number of incidences and of human deaths attributable to a single bacterial agent. Its causal agent Mycobacterium tuberculosis is able to survive in a latent state in infected individuals, thereby serving as a reservoir, waiting for the reactivation that usually occurs in immune-suppressed individuals, such as HIV patients. According to World Health Organization estimation, 2 billion people, almost one-third of the world’s population, are believed to be latently infected. An additional significant factor is the continued emergence of new multidrug resistant strains often associated to poor compliance due to the long, complex, toxic and expensive treatment. Thus, new anti-TB drugs and better therapeutic strategies are urgently needed. New drug candidates should short the standard regimens and being effective against drug resistant strains. In recent years, an emphasized research activity in the development of new TB drugs has being produced. Some compounds are presently in clinical development, while others are being investigated pre-clinically. The immune system is a critical factor for containment and cure of mycobacterial infection. Augmentation of protective immunity or decreasing the immune modulatory responses during late disease can be of value in the TB treatment. Thus, the use of immunotherapy with cytokines or bacterial derivatives as an adjunct to drug treatment may improve success rates for treatment of MDR-TB and shorten treatment time for drug-sensitive TB.

The present review concentrates to describe the most promising new drugs against TB which are now in clinical trials, as well as the immunotherapeutic assays performed in humans.

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