ICOS costimulation at the tumor site in combination with CTLA-4 blockade therapy elicits strong tumor immunity

Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) blockade therapy is able to induce long-lasting antitumor responses in a fraction of cancer patients. Nonetheless, there is still room for improvement in the quest for new therapeutic combinations. ICOS costimulation has been underscored as a possible target to include with CTLA-4 blocking treatment. Herein, we describe an ICOS agonistic aptamer that potentiates T cell activation and induces stronger antitumor responses when locally injected at the tumor site in combination with anti-CTLA-4 antibody in different tumor models. Furthermore, ICOS agonistic aptamer was engineered as a bi-specific tumor-targeting aptamer to reach any disseminated tumor lesions after systemic injection. Treatment with the bi-specific aptamer in combination with CTLA-4 blockade showed strong antitumor immunity, even in a melanoma tumor model where CTLA-4 treatment alone did not display any significant therapeutic benefit. Thus, this work provides strong support for the development of combinatorial therapies involving anti-CTLA-4 blockade and ICOS agonist tumor-targeting agents

Non-Selective Beta-Adrenergic Blocker Propranolol: A Life Saving Drug for Hospitalized Patient with Traumatic Brain Injury in Intensive Care Unit

Background: Traumatic Brain Injury (TBI) is the most common cause of death under the age of forty. This in turn results in intracranial injury in about 90% of the cases from least-income countries. The majority of patients admitted to the Intensive care Unit (ICU) had trauma which is managed by preventive strategies and to combat the secondary hit stimulated by the primary hit International guidelines have formed a protocol to be applied in patients with TBI for the better outcome and to increase the survival rate. Objectives: The aim of this study was to determine the importance of beta-adrenergic blocker propranolol in patients admitted with TBI. Methodology: The literature search was conducted to find recent articles related to the aim of the study to analyze the significance of beta-blocking agent propranolol in TBI. Results: Paroxysmal Sympathetic Hyperactivity (PSH) occurs within 24 hours of TBI in patients with Glasgow Coma Scale (GCS ≤ 8). In patients who are agitated or in restlessness propranolol is the drug of choice to reduce hyperactivity. Several studies reported that using beta-adrenergic blocking agents decreases the mortality rate and current studies started focusing on the primary initiation of propranolol and also reported side-effects associated in TBI. Conclusion: Early administration of Non-selective beta-adrenergic blocker propranolol will continue to be the standard prophylactic pharmacotherapeutic method as it limits the risk of sympathetic storming in high-risk patients with TBI. Keywords: Traumatic Brain Injury (TBI), Propranolol, Beta-adrenergic blocker, Paroxysmal Sympathetic Hyperactivity (PSH)

The New Outlook of Monoclonal Antibodies in Neutralizing Target Cells in COVID-19

Background: The deadly arrival of novel coronavirus (COVID-19) in late December 2019, caused by the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has emerged worldwide causing a pandemic. The World Health Organization (WHO) has proved ineffectiveness against existing medications this influenced the prompt identification of Monoclonal antibodies (mAbs) which plays a vital role as the prophylactic application that helps in developing new interventions. Objectives: To study the effect of mAbs in high-risk individuals in treating COVID-19. Methodology: The recent studies related to the aim of the review were undertaken through a literature search to analyze the importance of mAbs in combating SARS-CoV-2. Results:  In several countries even though vaccines have reached the Emergency Use Authorization (EUA) people still rely on traditional medications. Besides repurposed drugs, recently many mAbs targeting S-protein of SARS-CoV-2 have been signed up for clinical trials. Currently, no specific neutralizing mAbs have been reported for SARS-CoV-2 and it may take several years for such antibodies to be readily available. The development of mAbs for preventing the SARS-CoV 2 infection is challenged by the threat of antibody-dependent enhancement, antibody-resistant against SARS-CoV-2 variants, acute respiratory infections, clinical trials and risk assessment, and inexplicable. The clinical trial data proved that there is no life-threatening Adverse Drug Reactions (ADR) occurred during mAbs therapy for COVID-19 patients. Conclusion: Establishing monoclonal antibodies will continue to be the best prophylactic application as it minimizes the risk of hospitalization in the high-risk individuals affected by SARS-CoV-2 infection. Keywords: COVID-19, Monoclonal antibodies (mAbs), Emergency Use Authorization (EUA), Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2

Aptamer-iRNAs as Therapeutics for Cancer Treatment

Aptamers are single-stranded oligonucleotides (ssDNA or ssRNA) that bind and recognize their targets with high affinity and specificity due to their complex tertiary structure. Aptamers are selected by a method called SELEX (Systematic Evolution of Ligands by EXponential enrichment). This method has allowed the selection of aptamers to different types of molecules. Since then, many aptamers have been described for the potential treatment of several diseases including cancer. It has been described over the last few years that aptamers represent a very useful tool as therapeutics, especially for cancer therapy. Aptamers, thanks to their intrinsic oligonucleotide nature, present inherent advantages over other molecules, such as cell-based products. Owing to their higher tissue penetrability, safer profile, and targeting capacity, aptamers are likely to become a novel platform for the delivery of many different types of therapeutic cargos. Here we focus the review on interfering RNAs (iRNAs) as aptamer-based targeting delivered agents. We have gathered the most reliable information on aptamers as targeting and carrier agents for the specific delivery of siRNAs, shRNA, microRNAs, and antisense oligonucleotides (ASOs) published in the last few years in the context of cancer therapy

ICOS costimulation at the tumor site in combination with CTLA-4 blockade therapy elicits strong tumor immunity

Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) blockade therapy is able to induce long-lasting antitumor responses in a fraction of cancer patients. Nonetheless, there is still room for improvement in the quest for new therapeutic combinations. ICOS costimulation has been underscored as a possible target to include with CTLA-4 blocking treatment. Herein, we describe an ICOS agonistic aptamer that potentiates T cell activation and induces stronger antitumor responses when locally injected at the tumor site in combination with anti-CTLA-4 antibody in different tumor models. Furthermore, ICOS agonistic aptamer was engineered as a bi-specific tumor-targeting aptamer to reach any disseminated tumor lesions after systemic injection. Treatment with the bi-specific aptamer in combination with CTLA-4 blockade showed strong antitumor immunity, even in a melanoma tumor model where CTLA-4 treatment alone did not display any significant therapeutic benefit. Thus, this work provides strong support for the development of combinatorial therapies involving anti-CTLA-4 blockade and ICOS agonist tumor-targeting agents