National Center for Cancer Care and Research

The tumor microenvironment represents a complex network, in which tumor cells not only communicate with each other but also with stromal and immune cells. Current research has demonstrated the vital role of the tumor microenvironment in supporting tumor phenotype via a sophisticated system of intercellular communication through direct cell-to-cell contact or by classical paracrine signaling loops of cytokines or growth factors. Recently, extracellular vesicles have emerged as an important mechanism of cellular interchange of bioactive molecules. Extracellular vesicles isolated from tumor and stromal cells have been implicated in various steps of tumor progression, such as proliferation, angiogenesis, metastasis, and drug resistance. Inhibition of extracellular vesicles secretion, and thus of the transfer of oncogenic molecules, holds promise for preventing tumor growth and drug resistance. This review focuses on the role of extracellular vesicles in modulating the tumor microenvironment by addressing different aspects of the bidirectional interactions among tumor and tumor-associated cells. The contribution of extracellular vesicles to drug resistance will also be discussed as well as therapeutic strategies targeting extracellular vesicles production for the treatment of cancer.

In the last decade, Chimeric Antigen Receptor (CAR)-T cell therapy has emerged as a promising immunotherapeutic approach to fight cancers. This approach consists of genetically engineered immune cells expressing a surface receptor, called CAR, that specifically targets antigens expressed on the surface of tumor cells. In hematological malignancies like leukemias, myeloma, and non-Hodgkin B-cell lymphomas, adoptive CAR-T cell therapy has shown efficacy in treating chemotherapy refractory patients. However, the value of this therapy remains inconclusive in the context of solid tumors and is restrained by several obstacles including limited tumor trafficking and infiltration, the presence of an immunosuppressive tumor microenvironment, as well as adverse events associated with such therapy. Recently, CAR-Natural Killer (CAR-NK) and CAR-macrophages (CAR-M) were introduced as a complement/alternative to CAR-T cell therapy for solid tumors. CAR-NK cells could be a favorable substitute for CAR-T cells since they do not require HLA compatibility and have limited toxicity. Additionally, CAR-NK cells might be generated in large scale from several sources which would suggest them as promising off-the-shelf product. CAR-M immunotherapy with its capabilities of phagocytosis, tumor-antigen presentation, and broad tumor infiltration, is currently being investigated. Here, we discuss the emerging role of CAR-T, CAR-NK, and CAR-M cells in solid tumors. We also highlight the advantages and drawbacks of CAR-NK and CAR-M cells compared to CAR-T cells. Finally, we suggest prospective solutions such as potential combination therapies to enhance the efficacy of CAR-cells immunotherapy.

During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.

The emergence of novel and evolving variants of SARS-CoV-2 has fostered the need for change in the form of newer and more adaptive diagnostic methods for the detection of SARS-CoV-2 infections. On the other hand, developing rapid and sensitive diagnostic technologies is now more challenging due to emerging variants and varying symptoms exhibited among the infected individuals. In addition to this, vaccines remain the major mainstay of prevention and protection against infection. Novel vaccines and drugs are constantly being developed to unleash an immune response for the robust targeting of SARS-CoV-2 and its associated variants. In this review, we provide an updated perspective on the current challenges posed by the emergence of novel SARS-CoV-2 mutants/variants and the evolution of diagnostic techniques to enable their detection. In addition, we also discuss the development, formulation, working mechanisms, advantages, and drawbacks of some of the most used vaccines/therapeutic drugs and their subsequent immunological impact.Key messageThe emergence of novel variants of the SARS-CoV-2 in the past couple of months, highlights one of the primary challenges in the diagnostics, treatment, as well as vaccine development against the virus.Advancements in SARS-CoV-2 detection include nucleic acid based, antigen and immuno- assay-based and antibody-based detection methodologies for efficient, robust, and quick testing; while advancements in COVID-19 preventive and therapeutic strategies include novel antiviral and immunomodulatory drugs and SARS-CoV-2 targeted vaccines.The varied COVID-19 vaccine platforms and the immune responses induced by each one of them as well as their ability to battle post-vaccination infections have all been discussed in this review.

Iron is a critical metal for several vital biological processes. Most of the body's iron is bound to hemoglobin in erythrocytes. Iron from senescent red blood cells is recycled by macrophages in the spleen, liver and bone marrow. Dietary iron is taken up by the divalent metal transporter 1 (DMT1) in enterocytes and transported to portal blood via ferroportin (FPN), where it is bound to transferrin and taken up by hepatocytes, macrophages and bone marrow cells via transferrin receptor 1 (TfR1). While most of the physiologically active iron is bound hemoglobin, the major storage of most iron occurs in the liver in a ferritin-bound fashion. In response to an increased iron load, hepatocytes secrete the peptide hormone hepcidin, which binds to and induces internalization and degradation of the iron transporter FPN, thus controlling the amount of iron released from the cells into the blood. This review summarizes the key mechanisms and players involved in cellular and systemic iron regulation.

NY-ESO-1 or New York esophageal squamous cell carcinoma 1 is a well-known cancer-testis antigen (CTAs) with re-expression in numerous cancer types. Its ability to elicit spontaneous humoral and cellular immune responses, together with its restricted expression pattern, have rendered it a good candidate target for cancer immunotherapy. In this review, we provide background information on NY-ESO-1 expression and function in normal and cancerous tissues. Furthermore, NY-ESO-1-specific immune responses have been observed in various cancer types; however, their utility as biomarkers are not well determined. Finally, we describe the immune-based therapeutic options targeting NY-ESO-1 that are currently in clinical trial. We will highlight the recent advancements made in NY-ESO-1 cancer vaccines, adoptive T cell therapy, and combinatorial treatment with checkpoint inhibitors and will discuss the current trends for future NY-ESO-1 based immunotherapy. Cancer treatment has been revolutionized over the last few decades with immunotherapy emerging at the forefront. Immune-based interventions have shown promising results, providing a new treatment avenue for durable clinical responses in various cancer types. The majority of successful immunotherapy studies have been reported in liquid cancers, whereas these approaches have met many challenges in solid cancers. Effective immunotherapy in solid cancers is hampered by the complex, dynamic tumor microenvironment that modulates the extent and phenotype of the antitumor immune response. Furthermore, many solid tumor-associated antigens are not private but can be found in normal somatic tissues, resulting in minor to detrimental off-target toxicities. Therefore, there is an ongoing effort to identify tumor-specific antigens to target using various immune-based modalities. CTAs are considered good candidate targets for immunotherapy as they are characterized by a restricted expression in normal somatic tissues concomitant with a re-expression in solid epithelial cancers. Moreover, several CTAs have been found to induce a spontaneous immune response, NY-ESO-1 being the most immunogenic among the family members. Hence, this review will focus on NY-ESO-1 and discuss the past and current NY-ESO-1 targeted immunotherapeutic strategies.

BACKGROUND: Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality. METHODS: The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020. RESULTS: The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March-May 2020) and the second wave (October-December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value < 0.0001). In the multivariable analysis, age, active malignancy, chronic cardiac disease, liver disease, renal impairment, smoking history, and ICU stay correlated with mortality. Acute myeloid leukemia was a higher mortality risk than lymphoproliferative diseases. CONCLUSIONS: This survey confirms that COVID-19 patients with HM are at high risk of lethal complications. However, improved COVID-19 prevention has reduced mortality despite an increase in the number of reported cases.

Angiogenesis is defined as the physiological process by which new blood vessels develop from pre-existing vessels; either by sprouting or intussusception. Inhibition of angiogenesis is one of the most encouraging strategies to manage the growth and metastasis of cancers. The functional and proliferative status of blood vessels is regulated by the balance between various key molecules that either stimulate or inhibit angiogenesis. During quiescence, the "angiogenic switch" is "off". However, during tumour development pro-angiogenic factors such as vascular endothelial growth factor (VEGF), basic and acidic fibroblast growth factor, tumour necrosis factor-α and interleukin-1 are pathologically enhanced. Persistent growth of tumour directed capillary networks creates a favourable microenvironment, promoting cancer growth, progression and metastasis. VEGF, particularly VEGF-A, is a key angiogenic factor. Targeting VEGF, its receptors and the downstream signaling cascade, is a viable strategy to prevent tumour growth and metastasis. The present review discusses the role of VEGF in tumour angiogenesis and the current understanding of anti-VEGF therapies as well as refractoriness of anti-angiogenesis cancer therapy.

Traditional cancer treatments use nonspecific drugs and monoclonal antibodies to target tumor cells. Chimeric antigen receptor (CAR)-T cell therapy, however, leverages the immune system's T-cells to recognize and attack tumor cells. T-cells are isolated from patients and modified to target tumor-associated antigens. CAR-T therapy has achieved FDA approval for treating blood cancers like B-cell acute lymphoblastic leukemia, large B-cell lymphoma, and multiple myeloma by targeting CD-19 and B-cell maturation antigens. Bi-specific chimeric antigen receptors may contribute to mitigating tumor antigen escape, but their efficacy could be limited in cases where certain tumor cells do not express the targeted antigens. Despite success in blood cancers, CAR-T technology faces challenges in solid tumors, including lack of reliable tumor-associated antigens, hypoxic cores, immunosuppressive tumor environments, enhanced reactive oxygen species, and decreased T-cell infiltration. To overcome these challenges, current research aims to identify reliable tumor-associated antigens and develop cost-effective, tumor microenvironment-specific CAR-T cells. This review covers the evolution of CAR-T therapy against various tumors, including hematological and solid tumors, highlights challenges faced by CAR-T cell therapy, and suggests strategies to overcome these obstacles, such as utilizing single-cell RNA sequencing and artificial intelligence to optimize clinical-grade CAR-T cells.

Background: Intravenous (IV) acetaminophen is increasingly used around the world for pain control for a variety of indications. However, it is unclear whether IV administration offers advantages over oral administration.Objective: To identify, summarize, and critically evaluate the literature comparing analgesic efficacy, safety, and pharmacokinetics for IV and oral dosage forms of acetaminophen.Data Sources: A literature search of the PubMed, Embase, and International Pharmaceutical Abstracts databases was supplemented with keyword searches of Science Direct, Wiley Library Online, and Springer Link databases for the period 1948 to November 2014. The reference lists of identified studies were searched manually. Study Selection and Data Extraction: Randomized controlled trials comparing IV and oral dosage forms of acetaminophen were included if they assessed an efficacy, safety, or pharmacokinetic outcome. For each study, 2 investigators independently extracted data (study design, population, interventions, follow-up, efficacy outcomes, safety outcomes, pharmacokinetic outcomes, and any other pertinent information) and completed risk-of-bias assessments.Data Synthesis: Six randomized clinical trials were included. Three of the studies reported outcomes pertaining to efficacy, 4 to safety, and 4 to pharmacokinetics. No clinically significant differences in efficacy were found between the 2 dosage forms. Safety outcomes were not reported consistently enough to allow adequate assessment. No evidence was found to suggest that increased bioavailability of the IV formulation enhances efficacy outcomes. For studies reporting clinical outcomes, the results of risk-of-bias assessments were largely unclear.Conclusions: For patients who can take an oral dosage form, no clear indication exists for preferential prescribing of IV acetaminophen. Decision-making must take into account the known adverse effects of each dosage form and other considerations such as convenience and cost. Future studies should assess multiple-dose regimens over longer periods for patients with common pain indications such as cancer, trauma, and surgery.RÉSUMÉContexte : L’administration intraveineuse d’acétaminophène est de plus en plus employée partout dans le monde pour combattre la douleur due à toute une gamme de causes. Cependant, on ignore si elle offre des avantages comparativement à l’administration d’acétaminophène par voie orale.Objectif : Relever, résumer et faire une évaluation critique de la littérature qui compare l’efficacité analgésique, la sécurité et le comportement pharmacocinétique des formes pharmaceutiques intraveineuse et orale d’acétaminophène.Sources des données : Une recherche documentaire dans les bases de données de PubMed, Embase et International Pharmaceutical Abstracts a été complétée à l’aide de recherches de mots clés dans les bases de données de Science Direct, Wiley Library Online et Springer Link entre 1948 et novembre 2014. Un examen des bibliographies des études retenues a été réalisé manuellement.Sélection des études et extraction des données : Les essais cliniques à répartition aléatoire comparant les formes pharmaceutiques intraveineuse et orale d’acétaminophène ont été inclus lorsqu’ils évaluaient des résultats sur l’efficacité, la sécurité ou la pharmacocinétique. Pour chaque étude, deux chercheurs travaillant de façon indépendante ont extrait des données (sur le plan de l’étude, la population, les interventions, le suivi, l’efficacité, la sécurité, la pharmacocinétique et sur toute autre information pertinente) et ils ont rempli des évaluations du risque de biais.Synthèse des données : Au total, six essais cliniques à répartition aléatoire ont été retenus aux fins de l’analyse. Parmi ceux-ci, trois présentaient des résultats sur l’efficacité, quatre sur la sécurité et quatre sur la pharmacocinétique. Aucune différence cliniquement significative quant à l’efficacité n’a été relevée entre les deux formes pharmaceutiques. Les résultats sur la sécurité n’étaient pas présentés assez systématiquement pour permettre une évaluation pertinente. Aucune donnée n’a été trouvée permettant de croire que la biodisponibilité accrue de la préparation intraveineuse augmente l’efficacité. Pour les études présentant des résultats cliniques, le bilan des évaluations du risque de biais était en grande partie équivoque.Conclusions : Il n’y a pas d’indication claire favorisant la prescription d’acétaminophène par voie intraveineuse chez les patients en mesure de prendre la forme pharmaceutique orale. Tout choix doit tenir compte des effets indésirables propres à chaque forme pharmaceutique ainsi que d’autres facteurs, notamment la commodité et le coût. Des études ultérieures devraient évaluer les schémas à dose multiples sur une plus longue période chez les patients souffrant de douleurs courantes telles que celles causées par un cancer, un trauma ou une chirurgie.

Background: We conducted a meta-analysis to evaluate the efficacy of anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) monotherapy or immunotherapy combined with chemotherapy and further estimated the value of PD-L1 expression in predicting the response from anti-PD-1/PD-L1 treatments as monotherapy or in combination with chemotherapy. Methods: Clinical trial data were searched from electronic databases, which evaluated PD-1/PD-L1 inhibitors in non-small cell lung cancer (NSCLC) and correlated with PD-L1 expression levels. Results: Fifteen randomized-controlled trials involving 10,074 patients were identified. Comparing anti-PD-1/PD-L1 monotherapy to chemotherapy, the pooled HR for overall survival (OS) was 0.77 (95% CI: 0.69–0.85, P<0.00001). Subgroup analyses revealed that patients had longer OS at ≥1%, ≥5%, ≥10% and ≥50% PD-L1 expression levels. Patients with higher PD-L1 expression may get increased benefit from PD-1/PD-L1 inhibitors. Moreover, patients with PD-L1 ≥50% had an objective response rate (ORR) improvement from anti-PD-1/PD-L1 therapy (RR =1.87, 95% CI: 1.27–2.75, P=0.001), but no ORR benefits were observed in patients with PD-L1 expression <1% (RR =0.82, 95% CI: 0.56–1.22, P=0.33) or 1–49% (RR =0.80, 95% CI: 0.64–0.98, P=0.03). OS was significantly better in patients receiving second-or-third line treatments (P<0.00001) with PD-L1 ≥1%. The efficacy of PD-1 inhibitors was similar to that of PD-L1 inhibitors, with no significant difference (P=0.63, I2=0%). Furthermore, immunotherapy combined with chemotherapy had better OS (HR =0.64, 95% CI: 0.48–0.84, P=0.001) than chemotherapy alone. Subgroup analyses showed that patients benefited from the combined chemo-IO treatment in the first-line setting regardless of PD-L1 expression level. Conclusions: PD-L1 expression may be a valuable predictor of the efficacy of anti-PD-1/PD-L1 monotherapy in certain NSCLC patients. However, the combination of chemotherapy plus immunotherapy significantly improved survival regardless of the PD-L1 expression level in the first-line treatment of NSCLC.

Myeloproliferative neoplasms are clonal disorders characterized by the presence of several gene mutations associated with particular hematologic parameters, clinical evolution, and prognosis. Few therapeutic options are available, among which interferon α (IFNα) presents interesting properties like the ability to induce hematologic responses (HRs) and molecular responses (MRs) in patients with JAK2 mutation. We report on the response to IFNα therapy in a cohort of 31 essential thrombocythemia (ET) patients with CALR mutations (mean follow-up of 11.8 years). HR was achieved in all patients. Median CALR mutant allelic burden (%CALR) significantly decreased from 41% at baseline to 26% after treatment, and 2 patients even achieved complete MR. In contrast, %CALR was not significantly modified in ET patients treated with hydroxyurea or aspirin only. Next-generation sequencing identified additional mutations in 6 patients (affecting TET2, ASXL1, IDH2, and TP53 genes). The presence of additional mutations was associated with poorer MR on CALR mutant clones, with only minor or no MRs in this subset of patients. Analysis of the evolution of the different variant allele frequencies showed that the mutated clones had a differential sensitivity to IFNα in a given patient, but no new mutation emerged during treatment. In all, this study shows that IFNα induces high rates of HRs and MRs in CALR-mutated ET, and that the presence of additional nondriver mutations may influence the MR to therapy.

BACKGROUND: The authors assessed the use of herbal medicine by Middle Eastern patients with cancer, as reported by their oncology health care professionals (HCPs). Herbal products identified by the study HCPs were evaluated for potential negative effects. METHODS: Oncology HCPs from 16 Middle Eastern countries received a 17-item questionnaire asking them to list 5 herbal products in use by their patients with cancer. A literature search (PubMed, Micromedex, AltMedDex, and the Natural Medicine Comprehensive Database) was conducted to identify safety-related concerns associated with the products listed. RESULTS: A total of 339 HCPs completed the study questionnaire (response rate of 80.3%), identifying 44 herbal and 3 nonherbal nutritional supplements. Safety-related concerns were associated with 29 products, including herb-drug interactions with altered pharmacodynamics (15 herbs), direct toxic effects (18 herbs), and increased in vitro response of cancer cells to chemotherapy (7 herbs). CONCLUSIONS: Herbal medicine use, which is prevalent in Middle Eastern countries, has several potentially negative effects that include direct toxic effects, negative interactions with anticancer drugs, and increased chemosensitivity of cancer cells, requiring a reduction in dose-density. Oncology HCPs working in countries in which herbal medicine use is prevalent need to better understand the implications of this practice. The presence of integrative physicians with training in complementary and traditional medicine can help patients and their HCPs reach an informed decision regarding the safety and effective use of these products.

Colorectal cancer (CRC) is one of the most common cancers worldwide. The diagnosis, prognosis and therapeutic monitoring of CRC depends largely on tissue biopsy. However, due to tumor heterogeneity and limitations such as invasiveness, high cost and limited applicability in longitudinal monitoring, liquid biopsy has gathered immense attention in CRC. Liquid biopsy has several advantages over tissue biopsy including ease of sampling, effective monitoring, and longitudinal assessment of treatment dynamics. Furthermore, the importance of liquid biopsy is signified by approval of several liquid biopsy assays by regulatory bodies indicating the powerful approach of liquid biopsy for comprehensive CRC screening, diagnostic and prognostics. Several liquid biopsy biomarkers such as novel components of the microbiome, non-coding RNAs, extracellular vesicles and circulating tumor DNA are extensively being researched for their role in CRC management. Majority of these components have shown promising results on their clinical application in CRC including early detection, observe tumor heterogeneity for treatment and response, prediction of metastases and relapse and detection of minimal residual disease. Therefore, in this review, we aim to provide updated information on various novel liquid biopsy markers such as a) oral microbiota related bacterial network b) gut microbiome-associated serum metabolites c) PIWI-interacting RNAs (piRNAs), microRNA(miRNAs), Long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and d) circulating tumor DNAs (ctDNA) and circulating tumor cells (CTC) for their role in disease diagnosis, prognosis, treatment monitoring and their applicability for personalized management of CRC.

BACKGROUND: Modern radiotherapy techniques enable delivery of high doses to the target volume without escalating dose to organs at risk, offering the possibility of better local control while preserving good quality of life. Uncertainties in target volume delineation have been demonstrated for most tumour sites, and various studies indicate that inconsistencies in target volume delineation may be larger than errors in all other steps of the treatment planning and delivery process. The aim of this paper is to summarize the degree of delineation uncertainties for different tumour sites reported in the literature and review the effect of strategies to minimize them. CONCLUSIONS: Our review confirmed that interobserver variability in target volume contouring represents the largest uncertainty in the process for most tumour sites, potentially resulting in a systematic error in dose delivery, which could influence local control in individual patients. For most tumour sites the optimal combination of imaging modalities for target delineation still needs to be determined. Strict use of delineation guidelines and protocols is advisable both in every day clinical practice and in clinical studies to diminish interobserver variability. Continuing medical education of radiation oncologists cannot be overemphasized, intensive formal training on interpretation of sectional imaging should be included in the program for radiation oncology residents.

Whereas preclinical investigations and clinical studies have established that CD8+ T cells can profoundly affect cancer progression, the underlying mechanisms are still elusive. Challenging the prevalent view that the beneficial effect of CD8+ T cells in cancer is solely attributable to their cytotoxic activity, several reports have indicated that the ability of CD8+ T cells to promote tumor regression is dependent on their cytokine secretion profile and their ability to self-renew. Evidence has also shown that the tumor microenvironment can disarm CD8+ T cell immunity, leading to the emergence of dysfunctional CD8+ T cells. The existence of different types of CD8+ T cells in cancer calls for a more precise definition of the CD8+ T cell immune phenotypes in cancer and the abandonment of the generic terms “pro-tumor” and “antitumor.” Based on recent studies investigating the functions of CD8+ T cells in cancer, we here propose some guidelines to precisely define the functional states of CD8+ T cells in cancer.

Tyrosine kinases belong to a family of enzymes that mediate the movement of the phosphate group to tyrosine residues of target protein, thus transmitting signals from the cell surface to cytoplasmic proteins and the nucleus to regulate physiological processes. Non-receptor tyrosine kinases (NRTK) are a sub-group of tyrosine kinases, which can relay intracellular signals originating from extracellular receptor. NRTKs can regulate a huge array of cellular functions such as cell survival, division/propagation and adhesion, gene expression, immune response, etc. NRTKs exhibit considerable variability in their structural make up, having a shared kinase domain and commonly possessing many other domains such as SH2, SH3 which are protein-protein interacting domains. Recent studies show that NRTKs are mutated in several hematological malignancies, including lymphomas, leukemias and myelomas, leading to aberrant activation. It can be due to point mutations which are intragenic changes or by fusion of genes leading to chromosome translocation. Mutations that lead to constitutive kinase activity result in the formation of oncogenes, such as Abl, Fes, Src, etc. Therefore, specific kinase inhibitors have been sought after to target mutated kinases. A number of compounds have since been discovered, which have shown to inhibit the activity of NRTKs, which are remarkably well tolerated. This review covers the role of various NRTKs in the development of hematological cancers, including their deregulation, genetic alterations, aberrant activation and associated mutations. In addition, it also looks at the recent advances in the development of novel natural compounds that can target NRTKs and perhaps in combination with other forms of therapy can show great promise for the treatment of hematological malignancies.

Abstract Active immunotherapy of cancer aims to treat the disease by inducing effective cellular and humoral immune responses. Virus‐like particle‐based vaccines have evolved dramatically over the last few decades, greatly reducing morbidity and mortality of several infectious diseases and expectedly preventing cervical cancer caused by human papilloma virus. In contrast to these broad successes of disease prevention, therapeutic cancer vaccines remain to demonstrate clinical benefit. Yet, several preclinical and clinical trials have revealed promising results and are paving the way for medical breakthroughs. This study reviews and discusses the recent preclinical development and clinical trials in this field. This article is categorized under: Biology‐Inspired Nanomaterials &gt; Protein and Virus‐Based Structures Nanotechnology Approaches to Biology &gt; Nanoscale Systems in Biology

The global burden of breast cancer (BC) is increasing significantly. This trend is caused by several factors such as late diagnosis, limited treatment options for certain BC subtypes, drug resistance which all lead to poor clinical outcomes. Recent research has reported the role of epigenetic alterations in the mechanism of BC pathogenesis and its hallmarks include drug resistance and stemness features. The understanding of these modifications and their significance in the management of BC carcinogenesis is challenging and requires further attention. Nevertheless, it promises to provide novel insight needed for utilizing these alterations as potential diagnostic, prognostic markers, predict treatment efficacy, as well as therapeutic agents. This highlights the importance of continuing research development to further advance the existing knowledge on epigenetics and BC carcinogenesis to overcome the current challenges. Hence, this review aims to shed light and discuss the current state of epigenetics research in the diagnosis and management of BC.

INTRODUCTION: Cancer Immunotherapy has recently emerged as a promising and effective modality to treat different malignancies. Antigenic profiling of cancer tissues and determination of any pre-existing immune responses to cancer antigens may help predict responses to immune intervention in cancer. NY-ESO-1, a cancer testis antigen is the most immunogenic antigen to date. The promise of NY-ESO-1 as a candidate for specific immune recognition of cancer comes from its restricted expression in normal adult tissue but frequent occurrence in multiple tumors including melanoma and carcinomas of lung, esophageal, liver, gastric, prostrate, ovarian, and bladder. MAIN BODY: This review summarizes current knowledge of NY-ESO-1 as efficient biomarker and target of immunotherapy. It also addresses limitations and challenges preventing a robust immune response to NY-ESO-1 expressing cancers, and describes pre-clinical and clinical observations relevant to NY-ESO-1 immunity, holding potential therapeutic relevance for cancer treatment. CONCLUSION: NY-ESO-1 induces strong immune responses in cancer patients but has limited objective clinical responses to NY-ESO-1 expressing tumors due to effect of competitive negative signaling from immune-checkpoints and immune-suppressive tumor microenvironment. We propose that combination therapy to increase the efficacy of NY-ESO-1 specific immunotherapeutic interventions should be explored to unleash the immune response against NY-ESO-1 expressing tumors.