The application, safety, and future of ex vivo immune cell therapies and prognosis in different malignancies.

Introduction: Immunotherapy has revolutionized how cancer is treated. Many of these immunotherapies rely on ex vivo expansion of immune cells, classically T cells. Still, several immunological obstacles remain, including tumor impermeability by immune cells and the immunosuppressive nature of the tumor microenvironment (TME). Logistically, high costs of treatment and variable clinical responses have also plagued traditional T cell-based immunotherapies. Methods: To review the existing literature on cellular immunotherapy, the PubMed database was searched for publications using variations of the phrases "cancer immunotherapy", "ex vivo expansion", and "adoptive cell therapy". The Clinicaltrials.gov database was searched for clinical trials related to ex vivo cellular therapies using the same phrases. The National Comprehensive Cancer Network guidelines for cancer treatment were also referenced. Results: To circumvent the challenges of traditional T cell-based immunotherapies, researchers have developed newer therapies including tumor infiltrating lymphocyte (TIL), chimeric antigen receptor (CAR), T cell receptor (TCR) modified T cell, and antibody-armed T cell therapies. Additionally, newer immunotherapeutic strategies have used other immune cells, including natural killer (NK) and dendritic cells (DC), to modulate the T cell immune response to cancers. From a prognostic perspective, circulating tumor cells (CTC) have been used to predict cancer morbidity and mortality. Conclusion: This review highlights the mechanism and clinical utility of various types of ex vivo cellular therapies in the treatment of cancer. Comparing these therapies or using them in combination may lead to more individualized and less toxic chemotherapeutics.

Emerging Immunotherapeutic and Diagnostic Modalities in Carcinoid Tumors.

Evasion of innate immunity represents a frequently employed method by which tumor cells survive and thrive. Previously, the development of immunotherapeutic agents capable of overcoming this evasion has realized pronounced clinical utility across a variety of cancer types. More recently, immunological strategies have been investigated as potentially viable therapeutic and diagnostic modalities in the management of carcinoid tumors. Classic treatment options for carcinoid tumors rely upon surgical resection or non-immune pharmacology. Though surgical intervention can be curative, tumor characteristics, such as size, location, and spread, heavily limit success. Non-immune pharmacologic treatments can be similarly limited, and many demonstrate problematic side effects. Immunotherapy may be able to overcome these limitations and further improve clinical outcomes. Similarly, emerging immunologic carcinoid biomarkers may improve diagnostic capabilities. Recent developments in immunotherapeutic and diagnostic modalities of carcinoid management are summarized here.

Folate Receptor as a Biomarker and Therapeutic Target in Solid Tumors.

Folate is a B vitamin necessary for basic biological functions, including rapid cell turnover occurring in cancer cell proliferation. Though the role of folate as a causative versus protective agent in carcinogenesis is debated, several studies have indicated that the folate receptor (FR), notably subtype folate receptor alpha (FRα), could be a viable biomarker for diagnosis, progression, and prognosis. Several cancers, including gastrointestinal, gynecological, breast, lung, and squamous cell head and neck cancers overexpress FR and are currently under investigation to correlate receptor status to disease state. Traditional chemotherapies have included antifolate medications, such as methotrexate and pemetrexed, which generate anticancer activity during the synthesis phase of the cell cycle. Increasingly, the repertoire of pharmacotherapies is expanding to include FR as a target, with a heterogenous pool of directed therapies. Here we discuss the FR, expression and effect in cancer biology, and relevant pharmacologic inhibitors.

Subcellular partitioning of protein kinase activity revealed by functional kinome profiling.

Protein kinases and their substrates form signaling networks partitioned across subcellular compartments to facilitate critical biological processes. While the subcellular roles of many individual kinases have been elucidated, a comprehensive assessment of the synaptic subkinome is lacking. Further, most studies of kinases focus on transcript, protein, and/or phospho-protein expression levels, providing an indirect measure of protein kinase activity. Prior work suggests that gene expression levels are not a good predictor of protein function. Thus, we assessed global serine/threonine protein kinase activity profiles in synaptosomal, nuclear, and cytosolic fractions from rat frontal cortex homogenate using peptide arrays. Comparisons made between fractions demonstrated differences in overall protein kinase activity. Upstream kinase analysis revealed a list of cognate kinases that were enriched in the synaptosomal fraction compared to the nuclear fraction. We identified many kinases in the synaptic fraction previously implicated in this compartment, while also identifying other kinases with little or no evidence for synaptic localization. Our results show the feasibility of assessing subcellular fractions with peptide activity arrays, as well as suggesting compartment specific activity profiles associated with established and novel kinases.

Homologous recombination proficiency in ovarian and breast cancer patients.

Homologous recombination and DNA repair are important for genome maintenance. Genetic variations in essential homologous recombination genes, including BRCA1 and BRCA2 results in homologous recombination deficiency (HRD) and can be a target for therapeutic strategies including poly (ADP-ribose) polymerase inhibitors (PARPi). However, response is limited in patients who are not HRD, highlighting the need for reliable and robust HRD testing. This manuscript will review BRCA1/2 function and homologous recombination proficiency in respect to breast and ovarian cancer. The current standard testing methods for HRD will be discussed as well as trials leading to approval of PARPi's. Finally, standard of care treatment and synthetic lethality will be reviewed.

SSRIs: Applications in inflammatory lung disease and implications for COVID-19.

Selective serotonin reuptake inhibitors (SSRIs) have anti-inflammatory properties that may have clinical utility in treating severe pulmonary manifestations of COVID-19. SSRIs exert anti-inflammatory effects at three mechanistic levels: (a) inhibition of proinflammatory transcription factor activity, including NF-κB and STAT3; (b) downregulation of lung tissue damage and proinflammatory cell recruitment via inhibition of cytokines, including IL-6, IL-8, TNF-α, and IL-1ß; and (c) direct suppression inflammatory cells, including T cells, macrophages, and platelets. These pathways are implicated in the pathogenesis of COVID-19. In this review, we will compare the pathogenesis of lung inflammation in pulmonary diseases including COVID-19, ARDS, and chronic obstructive pulmonary disease (COPD), describe the anti-inflammatory properties of SSRIs, and discuss the applications of SSRIS in treating COVID-19-associated inflammatory lung disease.

Fluoxetine as an anti-inflammatory therapy in SARS-CoV-2 infection.

Hyperinflammatory response caused by infections such as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) increases organ failure, intensive care unit admission, and mortality. Cytokine storm in patients with Coronavirus Disease 2019 (COVID-19) drives this pattern of poor clinical outcomes and is dependent upon the activity of the transcription factor complex nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and its downstream target gene interleukin 6 (IL6) which interacts with IL6 receptor (IL6R) and the IL6 signal transduction protein (IL6ST or gp130) to regulate intracellular inflammatory pathways. In this study, we compare transcriptomic signatures from a variety of drug-treated or genetically suppressed (i.e. knockdown) cell lines in order to identify a mechanism by which antidepressants such as fluoxetine demonstrate non-serotonergic, anti-inflammatory effects. Our results demonstrate a critical role for IL6ST and NF-kappaB Subunit 1 (NFKB1) in fluoxetine's ability to act as a potential therapy for hyperinflammatory states such as asthma, sepsis, and COVID-19.

Identification of candidate repurposable drugs to combat COVID-19 using a signature-based approach.

The COVID-19 pandemic caused by the novel SARS-CoV-2 is more contagious than other coronaviruses and has higher rates of mortality than influenza. Identification of effective therapeutics is a crucial tool to treat those infected with SARS-CoV-2 and limit the spread of this novel disease globally. We deployed a bioinformatics workflow to identify candidate drugs for the treatment of COVID-19. Using an "omics" repository, the Library of Integrated Network-Based Cellular Signatures (LINCS), we simultaneously probed transcriptomic signatures of putative COVID-19 drugs and publicly available SARS-CoV-2 infected cell lines to identify novel therapeutics. We identified a shortlist of 20 candidate drugs: 8 are already under trial for the treatment of COVID-19, the remaining 12 have antiviral properties and 6 have antiviral efficacy against coronaviruses specifically, in vitro. All candidate drugs are either FDA approved or are under investigation. Our candidate drug findings are discordant with (i.e., reverse) SARS-CoV-2 transcriptome signatures generated in vitro, and a subset are also identified in transcriptome signatures generated from COVID-19 patient samples, like the MEK inhibitor selumetinib. Overall, our findings provide additional support for drugs that are already being explored as therapeutic agents for the treatment of COVID-19 and identify promising novel targets that are worthy of further investigation.

Molecular mechanisms underlying rheumatoid arthritis and cancer development and treatment.

Given recent advances in cancer immune therapy, specifically use of checkpoint inhibitors, understanding the link between autoimmunity and cancer is essential. Rheumatoid arthritis (RA) affects about 1% of the population, and early diagnosis is key to prevent joint damage. Management consists of disease-modifying antirheumatic drugs that alter normal immunologic pathways, which could affect malignancy growth and survival. Prolonged immune dysregulation and the resulting inflammatory response associated with development of RA may also lead to increased cancer development risk. RA has long been associated with increased risk of non-Hodgkin's lymphoma [1] and further evidence supports relationship to lung cancer [2]. This review will address the mechanisms behind cancer development and progression in RA patients, biomarkers and assess cancer risk and early detection.