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Objective: Immunotherapeutic inhibition of PD-1 by systemically administered monoclonal antibodies is widely used in cancer treatment, but it may cause severe immune-related adverse events (irSAEs). Neoadjuvant PD-1 inhibition before surgery has shown promise in reducing recurrence by stimulating durable antitumor immunity. Local intratumoral (IT) immunotherapy is a potential strategy to minimize irSAEs, but antibodies have limited tumor penetration, making them less suitable for this approach. Therapeutic self-delivering RNAi (INTASYL) is an emerging modality well-suited for neoadjuvant immunotherapy. This study presents preclinical proof-of-concept for PH-762, an INTASYL designed to silence PD-1, currently in clinical development for advanced cutaneous malignancies (ClinicalTrials.gov#NCT06014086). Methods and analysis: PH-762 pharmacology was characterized in vitro , and in vivo antitumor efficacy was evaluated using a murine analogue (mPH-762) in syngeneic tumor models with varying PD-1 responsiveness. Bilateral Hepa1-6 models assessed abscopal effects of local treatment. Ex vivo analyses explored mechanisms of direct and abscopal efficacy. Results: PH-762 was rapidly internalized by human T cells, silencing PD-1 mRNA and decreasing PD-1 surface protein, enhancing TCR-stimulated IFN-γ and CXCL10 secretion. In vivo , IT mPH-762 provided robust antitumor efficacy, local and lymphatic biodistribution, and was well tolerated. Ex vivo analyses revealed that IT mPH-762 depleted PD-1 protein, promoted leukocyte and T cell infiltration, and correlated with tumor control. IT mPH-762 also demonstrated efficacy against untreated distal tumors (abscopal effect) by priming systemic antitumor immunity. Conclusion: These data support PH-762 as a promising candidate for neoadjuvant immunotherapy in clinical studies. [ABSTRACT FROM AUTHOR]

ObjectiveImmunotherapeutic inhibition of PD-1 by systemically administered monoclonal antibodies is widely used in cancer treatment, but it may cause severe immune-related adverse events (irSAEs). Neoadjuvant PD-1 inhibition before surgery has shown promise in reducing recurrence by stimulating durable antitumor immunity. Local intratumoral (IT) immunotherapy is a potential strategy to minimize irSAEs, but antibodies have limited tumor penetration, making them less suitable for this approach. Therapeutic self-delivering RNAi (INTASYL) is an emerging modality well-suited for neoadjuvant immunotherapy. This study presents preclinical proof-of-concept for PH-762, an INTASYL designed to silence PD-1, currently in clinical development for advanced cutaneous malignancies (ClinicalTrials.gov#NCT06014086).Methods and analysisPH-762 pharmacology was characterized in vitro, and in vivo antitumor efficacy was evaluated using a murine analogue (mPH-762) in syngeneic tumor models with varying PD-1 responsiveness. Bilateral Hepa1-6 models assessed abscopal effects of local treatment. Ex vivo analyses explored mechanisms of direct and abscopal efficacy.ResultsPH-762 was rapidly internalized by human T cells, silencing PD-1 mRNA and decreasing PD-1 surface protein, enhancing TCR-stimulated IFN-γ and CXCL10 secretion. In vivo, IT mPH-762 provided robust antitumor efficacy, local and lymphatic biodistribution, and was well tolerated. Ex vivo analyses revealed that IT mPH-762 depleted PD-1 protein, promoted leukocyte and T cell infiltration, and correlated with tumor control. IT mPH-762 also demonstrated efficacy against untreated distal tumors (abscopal effect) by priming systemic antitumor immunity.ConclusionThese data support PH-762 as a promising candidate for neoadjuvant immunotherapy in clinical studies.

Impressive advances have been seen in cancer immunotherapy during the last years. Although breast cancer (BC) has been long considered as non-immunogenic, immunotherapy for the treatment of BC is now emerging as a new promising therapeutic approach with considerable potential. This is supported by a plethora of completed and ongoing preclinical and clinical studies in various types of immunotherapies. However, a significant gap between clinical oncology and basic cancer research impairs the understanding of cancer immunology and immunotherapy, hampering cancer therapy research and development. To exploit the accumulating available data in an optimal way, both fundamental mechanisms at play in BC immunotherapy and its clinical pitfalls must be integrated. Then, clinical trials must be critically designed with appropriate combinations of conventional and immunotherapeutic strategies. While there is room for major improvement, this updated review details the immunotherapeutic tools available to date, from bench to bedside, in the hope that this will lead to rethinking and optimizing standards of care for BC patients. [ABSTRACT FROM AUTHOR]

From 19 to 21 November 2022, BioCanRx held its first post-pandemic in-person Summit for Cancer Immunotherapy in Montreal, Canada. The meeting was well attended by patients, trainees, researchers, clinicians, and industry professionals, who came together to discuss the current state and future of biotherapeutics for cancer in Canada and beyond. Three plenaries, three keynote speakers, a lively debate, and panel discussions, together with poster sessions and a social event, made the event memorable and productive. The current state of cellular therapies, cellular engineering, clinical trials, and the role of the cancer microbiome were discussed in plenary session, and the patient voice was welcomed and present throughout the meeting, in large part due to the Learning Institute, a BioCanRx initiative to include patient partners in research. In this meeting review, we highlight the platform presentations, keynote speakers, debate combatants, panellists, and the patient perspective on the annual meeting. [ABSTRACT FROM AUTHOR]

Simple Summary: The discovery of the involvement of the kynurenine pathway in carcinogenesis has prompted significant changes in pharmacotherapy strategies. One such approach involves the simultaneous targeting of an ongoing process in cancer cells and inhibiting the abovementioned pathway. Based on this approach, we investigated the anticancer effect of combining a 1,2,4-triazine derivative, MM-129, together with an inhibitor of the kynurenine pathway, indoximod, in a colon cancer model. The obtained results support the efficacy of this strategy, providing a basis for future in-depth analyses. (1) Background: The purpose of the given study was to examine the antitumor activity of the simultaneous administration of MM-129, a 1,2,4-triazine derivative, and indoximod (IND), the kynurenine pathway inhibitor, toward colon cancer. (2) Methods: The efficiency of the co-administration of the studied compounds was assessed in xenografted zebrafish embryos. Then, the effects of the combined administration of compounds on cellular processes such as cell viability, apoptosis, and intracellular signaling pathways were evaluated. In vitro studies were performed using two colorectal cancer cell lines, namely, DLD-1 and HT-29. (3) Results: The results indicated that the simultaneous application of MM-129 and indoximod induced a stronger inhibition of tumor growth in zebrafish xenografts. The combination of these compounds intensified the process of apoptosis by lowering the mitochondrial potential, enhancing the externalization of phosphatidylserine (PS) and activation of caspases. Additionally, the expression of protein kinase B (AKT) and indoleamine 2,3-dioxygenase-(1IDO1) was disrupted under the applied compound combination. (4) Conclusions: Simultaneous targeting of ongoing cell signaling that promotes tumor progression, along with inhibition of the kynurenine pathway enzyme IDO1, results in the enhancement of the antitumor effect of the tested compounds against the colon cancer cells. [ABSTRACT FROM AUTHOR]

DNA damage is one of the foremost mechanisms of irradiation at the biological level. After the first isolation of DNA by Friedrich Miescher in the 19th century, the structure of DNA was described by Watson and Crick. Several Nobel Prizes have been awarded for DNA-related discoveries. This review aims to describe the historical perspective of DNA in radiation biology. Over the decades, DNA damage has been identified and quantified after irradiation. Depending on the type of sensing, different proteins are involved in sensing DNA damage and repairing the damage, if possible. For double-strand breaks, the main repair mechanisms are non-homologous end joining and homologous recombination. Additional mechanisms are the Fanconi anaemia pathway and base excision repair. Different methods have been developed for the detection of DNA double-strand breaks. Several drugs have been developed that interfere with different DNA repair mechanisms, e.g., PARP inhibitors. These drugs have been established in the standard treatment of different tumour entities and are being applied in several clinical trials in combination with radiotherapy. Over the past decades, it has become apparent that DNA damage mechanisms are also directly linked to the immune response in tumours. For example, cytosolic DNA fragments activate the innate immune system via the cGAS STING pathway. [ABSTRACT FROM AUTHOR]

Impressive advances have been seen in cancer immunotherapy during the last years. Although breast cancer (BC) has been long considered as non-immunogenic, immunotherapy for the treatment of BC is now emerging as a new promising therapeutic approach with considerable potential. This is supported by a plethora of completed and ongoing preclinical and clinical studies in various types of immunotherapies. However, a significant gap between clinical oncology and basic cancer research impairs the understanding of cancer immunology and immunotherapy, hampering cancer therapy research and development. To exploit the accumulating available data in an optimal way, both fundamental mechanisms at play in BC immunotherapy and its clinical pitfalls must be integrated. Then, clinical trials must be critically designed with appropriate combinations of conventional and immunotherapeutic strategies. While there is room for major improvement, this updated review details the immunotherapeutic tools available to date, from bench to bedside, in the hope that this will lead to rethinking and optimizing standards of care for BC patients.

The article reviews the literature on adoptive T-cell therapy of malignancies. Adoptive T-cell transfer allows treatment of metastatic disease on the late stages of certain tumors. The method has a number of advantages before traditional antitumor therapy. The special attention is paid to the possibility of adoptive cells genetic programming, which increases the treatment effectiveness and safety in cancer patients. The article also discusses the method introduction into clinical practice.

Theranostics is a promising branch of nuclear medicine that uses radiopharmaceuticals for diagnosis and treatment of cancer, and immunotheranostics is a special area in it. The aim of the study was to summarise the potential of theranostics for visualisation of the tumour microenvironment and elimination of its immunosuppressive components. The article presents up-to-date information on the composition and interaction of various cell subpopulations in the tumour microenvironment, as well as on the role of cancer stem cells in its formation. It describes defects of signalling pathways and potential targets for theranostics of cancer stem cells. Also, the article provides a description of the mechanism of interaction between the tumour and the immune system in the process of carcinogenesis. The review offers a detailed analysis of approaches to assessing the type of tumour microenvironment in order to individualise treatment and develop a rational design of clinical studies of theranostic couples. The authors present their own data on the distribution of subpopulations of lymphocytes and myeloid-derived suppressor cells in patients with metastatic tumours. The authors have considered the nuances of creating and using various molecules for targeted delivery in the development of diagnostic and therapeutic radiopharmaceuticals. The most promising diagnostic and therapeutic isotopes are described from the point of view of assessing the microenvironment and the possibility of influencing it. The article highlights modern and promising methods of pre-targeting to reduce the toxicity and increase the effectiveness of theranostics. Furthermore, having compared the advantages and disadvantages of theranostics with those of other systemic treatment options for metastatic tumours, the authors outline possible ways to overcome the shortcomings of theranostics.

T cell bispecific antibodies (TCBs) are the focus of intense development for cancer immunotherapy. Recently, peptide-MHC (major histocompatibility complex)-targeted TCBs have emerged as a new class of biotherapeutics with improved specificity. These TCBs simultaneously bind to target peptides presented by the polymorphic, species-specific MHC encoded by the human leukocyte antigen (HLA) allele present on target cells and to the CD3 coreceptor expressed by human T lymphocytes. Unfortunately, traditional models for assessing their effects on human tissues often lack predictive capability, particularly for "on-target, off-tumor" interactions. Here, we report an immune-infiltrated, kidney organoid-on-chip model in which peripheral blood mononuclear cells (PBMCs) along with nontargeting (control) or targeting TCB-based tool compounds are circulated under flow. The target consists of the RMF peptide derived from the intracellular tumor antigen Wilms' tumor 1 (WT1) presented on HLA-A2 via a bivalent T cell receptor-like binding domain. Using our model, we measured TCB- mediated CD8+ T cell activation and killing of RMF-HLA-A2-presenting cells in the presence of PBMCs and multiple tool compounds. DP47, a non-pMHC-targeting TCB that only binds to CD3 (negative control), does not promote T cell activation and killing. Conversely, the nonspecific ESK1-like TCB (positive control) promotes CD8+ T cell expansion accompanied by dose-dependent T cell--mediated killing of multiple cell types, while WT1-TCB* recognizing the RMF-HLA-A2 complex with high specificity, leads solely to selective killing of WT1-expressing cells within kidney organoids under flow. Our 3D kidney organoid model offers a platform for preclinical testing of cancer immunotherapies and investigating tissue- immune system interactions. [ABSTRACT FROM AUTHOR]

Increased glutamine metabolism is a hallmark of many cancer types. In recent years, our understanding of the distinct and diverse metabolic pathways through which glutamine can be utilized has grown more refined. Additionally, the different metabolic requirements of the diverse array of cell types within the tumor microenvironment complicate the strategy of targeting any particular glutamine pathway as cancer therapy. In this Mini-Review, we discuss recent advances in further clarifying the cellular fate of glutamine through different metabolic pathways. We further discuss potential promising strategies which exploit the different requirements of cells in the tumor microenvironment as it pertains to glutamine metabolism in an attempt to suppress cancer growth and enhance anti-tumor immune responses. [ABSTRACT FROM AUTHOR]

NK cells have unique attributes to react towards cells undergoing malignant transformation or viral infection. This reactivity is regulated by activating or inhibitory germline encoded receptors. An impaired NK cell function may result from an aberrant expression of such receptors, a condition often seen in patients with hematological cancers. Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer worldwide and NK cells have emerged as crucial targets for developing immunotherapies. However, there are important gaps concerning the phenotype and behavior of NK cells during emergence of ALL. In this study we analyze the phenotype and function of NK cells from peripheral blood in pediatric patients with ALL at diagnosis. Our results showed that NK cells exhibited an altered phenotype highlighted by a significant reduction in the overall expression and percent representation of activating receptors compared to age-matched controls. No significant differences were found for the expression of inhibitory receptors. Moreover, NK cells with a concurrent reduced expression in various activating receptors, was the dominant phenotype among patients. An alteration in the relative frequencies of NK cells expressing NKG2A and CD57 within the mature NK cell pool was also observed. In addition, NK cells from patients displayed a significant reduction in the ability to sustain antibody-dependent cellular cytotoxicity (ADCC). Finally, an aberrant expression of activating receptors is associated with the phenomenon of leukemia during childhood.

Increased glutamine metabolism is a hallmark of many cancer types. In recent years, our understanding of the distinct and diverse metabolic pathways through which glutamine can be utilized has grown more refined. Additionally, the different metabolic requirements of the diverse array of cell types within the tumor microenvironment complicate the strategy of targeting any particular glutamine pathway as cancer therapy. In this Mini-Review, we discuss recent advances in further clarifying the cellular fate of glutamine through different metabolic pathways. We further discuss potential promising strategies which exploit the different requirements of cells in the tumor microenvironment as it pertains to glutamine metabolism in an attempt to suppress cancer growth and enhance anti-tumor immune responses.

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How cancers are characterized and treated has evolved over the past few decades. Major advances in genomics tools and techniques have revealed interlinked regulatory pathways of cancers with unprecedented detail. Early discoveries led to success with rationally targeted small molecules and more recently with immunomodulatory agents, setting the stage for precision oncology. However, drug resistance to every agent has thus far proven intractable, sending us back to fill the gaps in our rudimentary knowledge of tumor biology. Epigenetics is emerging as a fundamental process in every hallmark of cancer. Large-scale interrogation of the cancer epigenome continues to reveal new mechanisms of astounding complexity. In this review, I present selected experimental and clinical examples that have shaped our understanding of cancer at the molecular level. Translation of our collective erudition into revolutionary diagnostic and treatment strategies will advance the precision oncology paradigm.

The confluence of immunology and oncology has led to a lot of uncertainty and questions about relevant biomarkers. Despite the complexity of the tumour microenvironment, most clinical studies have relied on a single-parameter immunohistochemical assay to prospectively select patients for checkpoint inhibitor therapy; the results of this strategy have been highly variable and often less than optimal. While great efforts have been made to identify additional or alternative biomarkers, pathologists, drug developers, and clinicians alike have faced technical, logistical, and regulatory challenges on how to implement them successfully. In this review, we will discuss these challenges; we will also highlight recent advances in dissecting the functional diversity of immune cell populations within the tumour microenvironment and their potential for improved, biomarker-driven therapeutic strategies. The dynamic nature and cellular diversity of the tumour microenvironment may challenge past models of a single biomarker predicting patient response and clinical outcome. [ABSTRACT FROM AUTHOR]

Copyright of Der Pathologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Immunotheranostics will be an important development in the future of nuclear medicine and medical oncology. It describes the synergy of theranostic procedures in nuclear medicine and immune oncology (IO) treatment. In brief, it takes advantage of molecular imaging and subsequent targeted modulation of the—in most cases immunosuppressive—tumor microenvironment (TME) by diagnostic and therapeutic radioisotopes. This is of high importance since only a fraction of patients receiving IO is currently being cured by this exciting therapy option. We therefore envision the concept of immunotheranostics as a powerful mean to augment the success of IO treatment in the future and thus the urgent need to further develop the interaction and joint action of nuclear medicine and medical oncology for substantially improved therapy outcome for cancer patients. [ABSTRACT FROM AUTHOR]

Immunooncology is still a growing area in cancer therapy. Drugs within this therapeutic approach do not directly target/attack the tumor but interfere with immune checkpoints and target or reprogram key metabolic pathways critical for anti-cancer immune defense. Indolamine 2,3-dioxygenase 1 (IDO1) and the tryptophan (TRP)-kynurenine pathway were identified as critical mechanisms in cancer immune escape and their inhibition as an approach with promising therapeutic potential. Particularly, a multitude of IDO1 inhibiting tryptophan analogs are widely applied in several clinical trials. However, this therapy results in a variety of implications for the patient's physiology. This is not only due to the inhibition of an enzyme important in almost every organ and tissue in the body but also because of the general nature of the inhibitor as an analog of a proteinogenic amino acid as well as the initiation of cellular detoxification known to affect inflammatory pathways. In this review we provide a deeper insight into the physiological consequences of an IDO1 inhibiting therapy based on TRP related molecules. We discuss potential side and off-target effects that contribute to the interpretation of unexpected positive as well as negative results of ongoing or discontinued clinical studies while we also highlight the potential of these inhibitors independent of the IDO1 signaling pathway.

Oncology treatment has been revolutionized by the introduction of immune checkpoint inhibitor drugs, which enable 20–40% of patients to generate anti-tumor immune responses. Combination treatment approaches with chemotherapeutic drugs may enable responses in the remaining patient cohorts. In this regard, a handful of drugs are promising due to their ability to induce immunogenic cell death in target cells. However, these agents are systemically delivered and indiscriminately cytotoxic to proliferating cells. By contrast, antibody-drug conjugates can selectively deliver a cytotoxic payload to a tumor, sparing most healthy cells. The ability of antibody-drug conjugates to induce immunogenic cell death in target cells has not yet been determined, although preclinical in vivo studies suggest this possibility. Here, we describe for the first time production of the in vitro hallmarks of immunogenic cell death – ecto-calreticulin and secreted ATP and HMGB1 protein – by cells in response to treatment with antibody-drug conjugates bearing a maytansine payload.

Immunooncology is still a growing area in cancer therapy. Drugs within this therapeutic approach do not directly target/attack the tumor but interfere with immune checkpoints and target or reprogram key metabolic pathways critical for anti-cancer immune defense. Indolamine 2,3-dioxygenase 1 (IDO1) and the tryptophan (TRP)-kynurenine pathway were identified as critical mechanisms in cancer immune escape and their inhibition as an approach with promising therapeutic potential. Particularly, a multitude of IDO1 inhibiting tryptophan analogs are widely applied in several clinical trials. However, this therapy results in a variety of implications for the patient's physiology. This is not only due to the inhibition of an enzyme important in almost every organ and tissue in the body but also because of the general nature of the inhibitor as an analog of a proteinogenic amino acid as well as the initiation of cellular detoxification known to affect inflammatory pathways. In this review we provide a deeper insight into the physiological consequences of an IDO1 inhibiting therapy based on TRP related molecules. We discuss potential side and off-target effects that contribute to the interpretation of unexpected positive as well as negative results of ongoing or discontinued clinical studies while we also highlight the potential of these inhibitors independent of the IDO1 signaling pathway. [ABSTRACT FROM AUTHOR]

Metastatic melanoma remains a refractory disease. Great progress in therapy of metastatic melanoma patients has been made in the recent five years. Targeted immunotherapy – a selective effect on lymphocytes signal molecules - became a principally new trend in the drug therapy of tumors. Ipilimumab is the first drug of this class that demonstrated clinical effectiveness in metastatic melanoma patients. This article deals with a review of the latest data of internal studies and own clinical experience of ipilimumab application in metastatic melanoma patients.

Radiotherapy serves as a foundational pillar for the therapeutic management of diverse solid tumors through the generation of lethal DNA damage and induction of cell death. While the direct cytotoxic effects of radiation therapy remain a cornerstone for cancer management, in the era of immunooncology there is renewed and focused interest in exploiting the indirect bystander activities of radiation, termed abscopal effects. In radioimmunobiologic terms, abscopal effects describe the radiotherapy-induced regression of cancerous lesions distant from the primary site of radiation delivery and rely upon the induction of immunogenic cell death and consequent systemic anticancer immune activation. Despite the promise of radiation therapy for awaking potent anticancer immune responses, the purposeful harnessing of abscopal effects with radiotherapy remain clinically elusive. In part, failure to fully leverage and clinically implement the promise of radiation-induced abscopal effects stems from limitations associated with existing conventional tumor models which inadequately recapitulate the complexity of malignant transformation and the dynamic nature of tumor immune surveillance. To supplement this existing gap in modeling systems, pet dogs diagnosed with solid tumors including melanoma and osteosarcoma, which are both metastatic and immunogenic in nature, could potentially serve as unique resources for exploring the fundamental underpinnings required for maximizing radiation-induced abscopal effects. Given the spontaneous course of cancer development in the context of operative immune mechanisms, pet dogs treated with radiotherapy for metastatic solid tumors might be leveraged as valuable model systems for realizing the science and best clinical practices necessary to generate potent abscopal effects with anti-metastatic immune activities.

Vitamin D deficiency is frequently observed in human cancer patients and a prognostic relevance could be shown for some entities. Additionally, it is known that vitamin D can stimulate the patients’ antitumor immunity. However, valid epidemiological data for head and neck squamous cell carcinoma (HNSCC) patients are sparse and functional studies on a possible connection between vitamin D and the patients’ immune system are missing. 25-OH vitamin D serum levels were analyzed in 231 HNSCC patients and 232 healthy controls and correlated with clinical data and patient survival. Intra- and peritumoral infiltration with T-cell, NK-cell and macrophage populations was analyzed in 102 HNSCC patients by immunohistochemistry. In 11 HNSCC patients, NK-cells were isolated before and after vitamin D substitution and analyzed for their cytotoxic activity directed against a HNSCC cell line. Vitamin D serum levels were significantly lower in HNSCC patients compared with healthy controls. Low vitamin D levels were associated with lymphatic metastasis and a negative HPV status and were a significant predictor of poor overall survival. HNSCC patients with severe vitamin D deficiency showed significantly altered intra- and peritumoral immune cell infiltrate levels. After vitamin D substitution, the patients’ NK cells showed a significant rise in cytotoxic activity. Taken together, we could show that Vitamin D deficiency is highly prevalent in HNSCC patients and is a predictor of poor survival. Vitamin D substitution used as an adjuvant in immune therapies such as cetuximab and nivolumab treatment could support antitumorigenic immune responses, thus contributing to the improvement of the patients’ prognosis in the context of a multimodal therapy.

Radiotherapy serves as a foundational pillar for the therapeutic management of diverse solid tumors through the generation of lethal DNA damage and induction of cell death. While the direct cytotoxic effects of radiation therapy remain a cornerstone for cancer management, in the era of immunooncology there is renewed and focused interest in exploiting the indirect bystander activities of radiation, termed abscopal effects. In radioimmunobiologic terms, abscopal effects describe the radiotherapy-induced regression of cancerous lesions distant from the primary site of radiation delivery and rely upon the induction of immunogenic cell death and consequent systemic anticancer immune activation. Despite the promise of radiation therapy for awaking potent anticancer immune responses, the purposeful harnessing of abscopal effects with radiotherapy remain clinically elusive. In part, failure to fully leverage and clinically implement the promise of radiation-induced abscopal effects stems from limitations associated with existing conventional tumor models which inadequately recapitulate the complexity of malignant transformation and the dynamic nature of tumor immune surveillance. To supplement this existing gap in modeling systems, pet dogs diagnosed with solid tumors including melanoma and osteosarcoma, which are both metastatic and immunogenic in nature, could potentially serve as unique resources for exploring the fundamental underpinnings required for maximizing radiation-induced abscopal effects. Given the spontaneous course of cancer development in the context of operative immune mechanisms, pet dogs treated with radiotherapy for metastatic solid tumors might be leveraged as valuable model systems for realizing the science and best clinical practices necessary to generate potent abscopal effects with anti-metastatic immune activities. [ABSTRACT FROM AUTHOR]

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Abstract According to data from recent studies from Europe, a large percentage of patients have restricted access to innovative medicines for metastatic melanoma. Melanoma World Society and European Association of Dermato-oncology conducted a Web-based survey on access to first-line recommended treatments for metastatic melanoma by current guidelines (National Comprehensive Center Network, European Society for Medical Oncology [ESMO] and European Organization for Research and Treatment of Cancer/European Association of Dermato-oncology/European dermatology Forum) among melanoma experts from 27 European countries, USA, China, Australia, Argentina, Brazil, Chile and Mexico from September 1st, 2017 to July 1st, 2018. Data on licencing and reimbursement of medicines and the number of patient treated were correlated with the data on health expenditure per capita (HEPC), Mackenbach score of health policy performance, health technology assessment (HTA), ASCO and ESMO Magnitude of clinical benefit scale (ESMO MCBS) scores of clinical benefit and market price of medicines. Regression analysis for evaluation of correlation between the parameters was carried out using SPSS software. The estimated number of patients without access in surveyed countries was 13768. The recommended BRAFi + MEKi combination and anti-PD1 immunotherapy were fully reimbursed/covered in 19 of 34 (55.8%) and 17 of 34 (50%) countries, and combination anti-CTLA4+anti-PD1 in was fully covered in 6 of 34 (17.6%) countries. Median delay in reimbursement was 991 days, and it was in significant correlation with ESMO MCBS (p = 0.02), median market price (p = 0.001), HEPC and Mackenbach scores (p < 0.01). Price negotiations or managed entry agreements (MEAs) with national authorities were necessary for reimbursement. In conclusion, great discrepancy exists in metastatic melanoma treatment globally. Access to innovative medicines is in correlation with economic parameters as well as with healthcare system performance parameters. Patient-oriented drug development, market access and reimbursement pathways must be urgently found. Highlights • New therapies have dramatically improved the prognosis of metastatic melanoma, but disparities in access to these medicines exist worldwide. • BRAFi+MEKi combinations are fully reimbursed in 17 of 34 (50%) countries. • Anti-PD1 immunotherapies are fully reimbursed in 17 of 34 (50%) countries. • Combination immunotherapy (anti-CTLA4+anti-PD1) is reimbursed in 9 of 34 (26.4%) countries, in 3 countries with restrictions. • Patient-oriented research, development, market access and reimbursement mechanisms must be urgently developed. [ABSTRACT FROM AUTHOR]

The introduction of checkpoint inhibitors revolutionized immuno-oncology. The efficacy of traditional immunotherapeutics, like vaccines and immunostimulants was very limited due to persistent immune-escape strategies of cancer cells. Checkpoint inhibitors target these escape mechanisms and re-direct the immune system to anti-tumor toxicity. Phenomenal results have been reported in entities like melanoma, where no other therapy was able to demonstrate survival benefit, before the introduction of immunotherapeutics. The first experience in ovarian cancer (OC) was reported for nivolumab, a fully human antiprogrammed cell death protein 1 (PD1) antibody, in 2015. While the data are extraordinary for a mono-immunotherapeutic agent and very promising, they do not match up to the revolutionary results in entities like melanoma. The key to exceptional treatment response in OC, could be the identification of the most immunogenic patients. We hypothyse that BRCA mutation could be a predictor of improved response in OC. The underlying DNArepair- deficiancy should result in increased immunogenicity because of higher mutational load and more neoantigen presentation. This hypothesis was not tested to date and should be subject to future trials. The present article gives an overview of the immunologic background of checkpoint inhibition (CI). It presents current data on nivolumab and other checkpoint-inhibitors in solid tumors and OC specifically and depicts important topics in the management of this novel substance group, such as side effect control, diagnostic PD-1/programmed cell death-ligand 1 (PD-L1) expression assessment and management of pseudoprogression. [ABSTRACT FROM AUTHOR]

Recent successful results of a relatively new immunotherapeutic anti-cancer strategy based on the blockade of immune inhibitory pathways by monoclonal antibodies against checkpoint molecules can be considered as a medical breakthrough in clinical cancer immunotherapy. This type of immunotherapy became a standard part of systemic therapy protocols in the treatment of some metastatic solid tumors such as melanoma, non-small cell lung cancer, genitourinary cancers, Merkel-cell carcinoma, squamous-cell carcinoma of the head and neck, and solid tumors with DNA high microsatellite instability or DNA mismatch-repair deficiency. Recent progress in colorectal cancer genome analysis, and also supported by clinical observations, indicates that patients with DNA mismatch repair deficiency or microsatellite instability-high metastatic colorectal cancers are a distinct biomarker-defined population that might benefit from immunotherapy treatment with monoclonal antibodies against checkpoint molecules. This treatment has therefore become a new treatment option for this colorectal cancer subgroup of patients. However, besides tumor microsatellite instability or mismatch-repair deficiency status, other predictive biomarkers are also needed since not all these tumors respond to anti-check point immunotherapy treatment. This paper aims to present a basic overview of immunotherapy in mismatch repair deficient colorectal cancer patients. [ABSTRACT FROM AUTHOR]

Over the last forty years, recombinant antibodies have been transformed from an unproven experimental approach to a therapeutic modality with multiple success stories in the treatment of cancer, inflammation, infections and cardiometabolic diseases. Owing to their high affinity and selectivity for the target antigen, their multimodal tunable mode of action, their modular nature and long half-life, antibodies now hold prominent positions in the pipelines of major biopharmaceutical companies. In this brief report, I aim to highlight the themes that have shaped the therapeutic antibody engineering as it exists today and to offer a personal perspective on its future developments. Distinct antibody engineering history, developments and trends in Russian Federation will not be discussed since they are detailed elsewhere in this journal issue. [ABSTRACT FROM AUTHOR]

Oncoimmunology (or immunooncology) is a burgeoning specialty of precision (“personalized”) medicine designed to heighten the antitumor response of the immune system against molecules expressed excessively or only by tumor cells. This focus is necessary, as cancers are polyclonal tissues comprised of antigenically heterogeneous cells, the exact composition of which is shaped by the balance between antitumor immunity and tumor-promoting inflammation. Key targets include enhancing immune system (especially T cell) reactivity, inhibiting immune checkpoints, and promoting tumor cytolysis. Therapeutic modalities to address these targets include administering antibodies, cytokines, or small molecules that directly stimulate the immune system, attack tumor-associated antigens, or interfere with tumor–stroma interactions; adoptive transfer of autologous T cells following ex vivo selection/expansion/activation (typically after lymphoid-depleting regimens and in conjunction with immunostimulatory therapy); and vaccination (against tumor antigens). Pathology involvement in oncoimmunology product development is critical to assess expression of target molecules in tumor cells, stromal cells, and tumor-infiltrating leukocytes. [ABSTRACT FROM AUTHOR]

Background Despite the efficacy of innovative treatments for metastatic melanoma, their high costs has led to disparities in cancer care among different European countries. We analysed the availability of these innovative therapies in Europe and estimated the number of patients without access to first-line recommended treatment per current guidelines of professional entities such as the European Society for Medical Oncology (ESMO), the European Organisation for Research and Treatment of Cancer (EORTC), the European Association of Dermato-Oncology (EADO), and European Dermatology Forum (EDF). Materials and methods Web-based online survey was conducted in 30 European countries with questions about the treatment schedules from 1st May 2015 to 1st May 2016: number of metastatic melanoma patients, registration and reimbursement of innovative medicines (updated data, as of 1st October 2016), percentage of patients treated and availability of clinical studies and compassionate-use programmes. Results The recommended BRAF inhibitor (BRAFi) + MEK inhibitor (MEKi) combination was both registered and fully reimbursed in 9/30 (30%) countries, and in 13/30 (43%) (all from Eastern Europe) not reimbursed. First-line immunotherapy with anti-PD1 antibodies was registered and fully reimbursed in 14/30 (47%) countries, while in 13/30 (43%) (all from Eastern Europe) not reimbursed. It was estimated that in Europe 19,600 patients with metastatic melanoma are treated, and 5238 (27%) do not have access to recommended first-line therapy. Significant correlation was found between human development index (HDI, UNDP report 2015), (r = 0.662; p < 0.001), health expenditure per capita (r = 0.695; p < 0.001) and the Mackenbach score of health policy performance (r = 0.765; p < 0.001) with the percentage of patients treated with innovative medicines and a number of reimbursed medicines. Conclusions Great discrepancy exists in metastatic melanoma treatment across Europe. It is crucial to increase the awareness of national and European policymakers, oncological societies, melanoma patients' associations and pharma industry. [ABSTRACT FROM AUTHOR]

With the advent of targeted therapies, there has been a revolution in the treatment of cancer across multiple histologies. Immune checkpoint blockade has made it possible to take advantage of receptor-ligand interactions between immune and tumor cells in a wide spectrum of malignancies. Toxicity in healthy tissue, however, can limit our use of these agents. Immune checkpoint blockade has been approved in advanced melanoma, renal cell cancer, non-small cell lung cancer, relapsed refractory Hodgkin's lymphoma, and urothelial cancer. Though FDA-approved indications for use of some of these novel agents depend on current protein-based programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) assays, detection methods come with several caveats. Additional predictive tools must be interrogated to discern responders from non-responders. Some of these include measurement of microsatellite instability, PD-L1 amplification, cluster of differentiation 8 (CD8) infiltrate density, and tumor mutational burden. This review serves to synthesize biomarker detection at the DNA, RNA, and protein level to more accurately forecast benefit from these novel agents. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy is effective, but current biomarkers for patient selection have proven modest sensitivity. Here, we developed VIGex, an optimized gene signature based on the expression level of 12 genes involved in immune response with RNA sequencing., Methods: We implemented VIGex using the nCounter platform (Nanostring) on a large clinical cohort encompassing 909 tumor samples across 45 tumor types. VIGex was developed as a continuous variable, with cutoffs selected to detect three main categories (hot, intermediate-cold and cold) based on the different inflammatory status of the tumor microenvironment., Findings: Hot tumors had the highest VIGex scores and exhibited an increased abundance of tumor-infiltrating lymphocytes as compared with the intermediate-cold and cold. VIGex scores varied depending on tumor origin and anatomic site of metastases, with liver metastases showing an immunosuppressive tumor microenvironment. The predictive power of VIGex-Hot was observed in a cohort of 98 refractory solid tumor from patients treated in early-phase immunotherapy trials and its clinical performance was confirmed through an extensive metanalysis across 13 clinically annotated gene expression datasets from 877 patients treated with immunotherapy agents. Last, we generated a pan-cancer biomarker platform that integrates VIGex categories with the expression levels of immunotherapy targets under development in early-phase clinical trials., Conclusions: Our results support the clinical utility of VIGex as a tool to aid clinicians for patient selection and personalized immunotherapy interventions., Funding: BBVA Foundation; 202-2021 Division of Medical Oncology and Hematology Fellowship award; Princess Margaret Cancer Center., Competing Interests: Declaration of interests A.H.C. reports travel and accommodation expenses from Merk Serono and Kyowa Kirin International. I.B. reports research funding for the present manuscript from Incyte, Merck Sharp & Dohme (MSD), Cellex Foundation, La Caixa Foundation, BBVA Foundation Comprehensive Program of Cancer Immunotherapy and Immunology (CAIMI) - (grant 89/2017). Other research funding as principal investigator: Astrazeneca, Bicycle therapeutics, Boehringer Ingellheim, Bristol Myers Squibb, Celgene, Dragonfly, GlaxoSmithkline, Gliknik, Immutep, ISA Pharmaceuticals, Janssen Oncology, Kura, Merck Serono, Nanobiotics, Novartis, Northern Biologics, Orion Pharma, Odonate Therapeutics, Regeneron, Pfizer, Sanofi, Pharmamar, Seattle Genetics, Shattuck Labs, and VCN Biosciences. Consulting fees: Achilles Therapeutics, Bristol Myers Squibb, Cancer Expert Now, eTheRNA immunotherapies, Merck Serono, Merck Sharp & Dohme (MSD), Rakuten pharma, Boehringer Ingellheim, and PCI biotech. Payment or honoraria: Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme (MSD). Support for attending meetings and/or travel: Merck Sharp &Dohme (MSD) and Merck Serono. Leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid: ESMO Head and Neck track, EORTC Head and Neck group and Cancer Core Europe Clinical Taskforce. Other financial or non-financial interests: Bristol Myers Squibb educational grant. J.S. reports Advisory Boards from: Surface Oncology and Tarus Therapeutics. Stocks/Shares, Personal: Surface Oncology. Research Grant, Institutional, Financial interest: Surface Oncology. B.H.K. is co-Founder of the MAQC (Massive Analysis and Quality Control) Society. SAB of: Consortium de recherche biopharmaceutique (CQDM), Quebec; Canada Break Through Cancer; Commonwealth Cancer Consortium, United States; Canadian Institute of Health Research – Institute of Genetics, Canada; IONIQ Sciences, US. Executive Committee of the Terry Fox Digital Health and Discovery Platform, Canada, and Board of Directors of AACR International – Canada, The American Association for Cancer Research, United States. Consultant for Code Ocean Inc, United States. T.J.P. reports Consulting or Advisory Role: Chrysallis Biomedical Advisors, Axiom Healthcare Strategies, and SAGA Diagnostics. Patents, Roaylties, other intellectual property: Hybrid-capture sequencing for determining immune cell clonality. Honoraria: Merck, AstraZeneca, Illumina, and PACT Pharma Research Funding: Roche. O.M. reports honoraria: Roche, Kyowa Kirin, Ferrer. Travel grant: Kyowa Kirin. C.V. reports financial interest as advisory board, personal: Bayer, Boehringer Ingelheim, GSK, Lilly, Mundipharma, PharmaMar. Invited speaker, personal: Roche. Local PI, Institutional, Financial interest, clinical trial: Adaptimmune, Ayala Therapeutics, Bayer (coordinating PI), Foghorn Therapeutics, Inhibrx, Karyopharm, and Lilly. Non-financial interest: GEIS-Spanish Sarcoma Group for Research, Member of Board of Directors. President since 2018. E.M. reports advisory boards from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi. Honoraria: Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche. Clinical trial participation (principal investigator): Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche. C.S reports financial interests as invited speaker from Astellas pharma, Bristol Myers Sqquib (Inst), Hoffmann-La Roche LTD, Ipsen, Pfizer S.L.U. Advisory board, personal: Astellas pharma, Bayer, Bristol Myers Sqquib (Inst), Hoffmann-La Roche LTD, Ipsen, Merck Sharp Dohme, Pfizer S.L.U, Sanofi-Aventis. E.E. reports advisory boards from Amgen, Bayer, Hoffman LA-Roche, Merck Serono, MSD, Pierre Fabre, Sanofi, Servier. Invited Speaker, personal: Novartis, Organon. Funding, Institutional, Financial interest: Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, Genentech Inc, HalioDX SAS, Foffmann-La Roche Ltd, Hutchison MediPharma International, Janssen-Cilag SA, Medimmune, Menarini, Merck Health KGAA, Merck Sharp & Dohme de España SA, Merus NVS, Mirati, Novartis Farmaceútica SA, Pfizer, PharmaMar SA, Sanofi Aventis Recherche & Développement, Servier, and Taiho Pharma USA Inc. Non-Financial Interest: American Society of Clinical Oncology (ASCO), Other, Volunteer member of the ASCO Annual Meeting Scientific Program Committee: Developmental Therapeutics – Immunotherapy; European Society for Medical Oncology (ESMO), Other, Speaker of the ESMO Academy; Sociedad Española de Oncología Médica (SEOM), Other: Coordinator of the SEOM +MIR Section of Residents and Young Assistants. Other (travel accomodations, expenses): Amgen, Array BioPharma, Bristol-Myers Squibb, Merck Serono, Roche, Sanofi and Servier. J.C. reports personal conflicts of interest: Scientific consultancy role (Speaker and advisory roles) from Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Huchinson Pharma, ITM, Advanz, Merck Serono, Esteve, Roche. Research support: research grants from Novartis, Pfizer, Astrazeneca, Advanced Accelerator Applications, Eisai, Amgen, and Bayer. A.O. has served on advisory boards for Agenus, AstraZeceneca. Clovis Oncology, Inc., Corcept Therapeutics, Deciphera Pharmaceutical, Eisai Europe Limited, EMD Serono, Inc., F. Hoffmann-La Roche, GlaxoSmithKline, GOG, Immunogen, Medison Pharma, Merck Sharp & Dohme de España, Mersana Therapeutics, Novocure GmbH, Pharma Mar, prIME Oncology, ROCHE FARMA, Sattucklabs, Sutro Biopharma, Inc, and received support for travel or accommodation from Roche, AstraZeneca, PharmaMar and GSK. Clovis. C.S. has served as consultant, participated in advisory boards or received travel grants from: AstraZeneca, AX'Consulting, Byondis B.V, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F.Hoffmann-La Roche Ltd, ISSECAM, MediTech, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Pierre Fabre, PintPharma, Puma Biotechnology, SeaGen, and Zymeworks. T.M. has received honoraria for consultancy from: Ability Pharmaceuticals, Amgen, AstraZeneca, Basilea Pharma, Baxter, BioLineRX Ltd, Celgene, Eisai, Ellipses, Esteve, Pharmaceuticals, Incyte, Ipsen Bioscience, Inc, Janssen, Lilly, MDS Medscape, Novocure, QED Therapeutics, Roche Farma, Sanofi-Aventis, Servier, and Zymeworks. Travel expenses from Servier, AstraZeneca, Sanofi, and Incyte. J.C. reports advisory boards from Astellas Pharma, AstraZeneca, Bayer, Johnson & Johnson, MSD Oncology, Novartis (AAA), Roche, Sanofi. Local PI, Institutional, No financial interest: Janssen-Cilag International NV. Lilly, S.A, Medimmune, Novartis Farmacéutica S.A, Sanofi-Aventis S.A. E.F. reports advisory boards from Amgen, Astra Zeneca, Bayer, Bristol-Myers Squibb, Daichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, Glaxo Smith Kline, Janssen, Merck Sharp & Dohme, Merck Serono, Novartis, Peptomyc, Pfizer, Sanofi, Takeda. Invited speaker: Amgen, Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Janssen, Medscape, Merck Sharp & Dohme, Peervoice, Pfizer, Medical Trends, Merck Serono, Sanofi, Takeda, TouchOncology. Research funding: Merck Healthcare KGAa, Fundación Merck Salud. Independent member of the Board: Grífols. R.D. declares advisory role for Roche, Boehringer Ingelheim, received a speaker’s fee from Roche, Boehringer Ingelheim, Ipsen, Amgen, Servier, Sanofi, Libbs, Merck Sharp & Dohme, Lilly and AstraZeneca and research grants from Merck and Pierre Fabre. P.B. is a local PI institutional: Amgen, AstraZeneca, Bicara, BMS, Genentech/Roche, Lilly, Merck, Nektar Therapeutics, Novartis, Pfizer, Sanofi, SeaGen, and Zymeworks. Research grant, institutional: Pfizer. Funding, institutional: Servier. P.N. reports advisory board from Bayer, MSD Oncology. Invited speaker, personal: Novartis. Other, personal, consultant: Targos Molecular Pathology GmbH. J.S. reports membership on Board of Directors, personal: Northern Biologics Inc. Ownership interest, Personal, Co-Founder: Mosaic Biomedicals. Research Grant, Institutional, No financial interest: Astra Zeneca, Hoffmann-La Roche LTD, Isarna Therapeutics, Mosaic Biomedicals SL, Northern Biologics INC, Ridgeline Therapeutics and Roche Glycart AG. Non-financial interests: Asociación Española contra el cancer (Member of Board of Directors), European Association for Cancer Research (ECR) (Member of Board of Directors, Secretary General). J.T. reports personal financial interest in form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, and TheraMyc. Stocks: Oniria Therapeutics and also educational collaboration with Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER). E.G. reports consulting or advisory role: Roche, Ellipses pharma, Neomed Therapeutics, Janssen, Boehringer Ingelheim. Seattle Genetics. TFS. Alkermes. Thermo Fisher Scientific. Bristol-Myers Squibb. MabDiscovery. Anaveon. F-Star Therapeutics. Speakers Bureau MSD, Roche, Thermo Fisher Scientific and Lilly. Research funding (recipient institution): Novartis. Roche. Thermo Fisher Scientific, AstraZeneca/MEdImmune, Taiho Oncology, BeiGene. Other relationship (recipient institution): Affimed Gmbh, Amgen SA, Anaveon AG, AstraZeneca AB, Biontech Gmbh, Catalym Gmbh, CytomX Therapeutics. F. Hoffmann La Roche Ltd, F-Satar Beta Limited, Genentech Inc, Genmab B.v, Hutchison MEdipharma Limited, Imcheck Therapeutics, Immunoscore Ltd, Janssen-Cilag SA, Medimmune Llc, Merck kgga, Novartis Farmaceutica, S.a, peptomyc, Ribon Therapeutics, Roche Farma SA, Seattle Genetics Inc, Symphogen A/S, Taiho Pharma Usa Inc. A.V. reports advisory boards from Bayer, Bristol Meyers Squibb, Guardant Health, Incyte, Roche. Stocks or Shares: Reveal Genomics. Research grant, institutional, financial interest, preclinical research grant: Incyte and Roche., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Cervical cancer is the fourth most common cancer among women worldwide, and the prognosis of advanced/recurrent cervical cancer remains poor. Metastasis and invasion of this type of cancer are closely associated with the tumor microenvironment. Studying the complex interactions between tumor progression and immune cells or stromal cells can provide new insights into treatment for patients with aggressive tumor, recurrence and drug resistance. In the present study, a bioinformatics method (Gene Expression Profiling Interactive Analysis, differentially expressed genes, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, protein-protein interactions and survival analysis) was used to explore the mRNA and protein level discrepancy gene signature of ERBB3 via the PI3K/AKT/mTOR pathway from the speculation in immuno-oncology and experimental verification of different cervical cancer cell lines. The high expression of ERBB3 in cervical cancer tissues (especially HPV-positive and adenocarcinoma-related) promoted the activation of the PI3K/AKT/mTOR pathway. The increased expression of MMP9 changed the macrophage infiltration in the tumor microenvironment and affected prognosis of patients with cervical cancer. In conclusion, the present study identified 14 EMT-related genes and 30 genes involved in the PI3K/AKT/mTOR pathway in cervical cancer, and they might provide novel clues for future treatment. The MMP family may be a notable factor associated with tumor cells and immune cells. [ABSTRACT FROM AUTHOR]

The fight against cancer has seen major breakthroughs in recent years. More than a decade ago, tyrosine kinase inhibitors targeting constitutively activated signaling cascades within the tumor inaugurated a new era of oncological therapy. Recently, immunotherapy with immune checkpoint inhibitors has started to revolutionize the treatment of several malignancies, most notably malignant melanoma, leading to the renaissance and the long-awaited breakthrough of immunooncology. This review provides an overview of the basis of immunotherapy from its initial concepts of anti-tumor immunity and cell-based therapy to the development of immune checkpoint inhibitors and discusses published studies and the perspectives of immunooncology for the treatment of endocrine malignancies. [ABSTRACT FROM AUTHOR]

Although immune signaling has emerged as a defining feature of the glioma microenvironment, how the underlying structure of the glioma-infiltrating T-cell population differs from that of the blood from which it originates has been difficult to measure directly in patients. High-throughput sequencing of T-cell receptor (TCR) repertoires (TCRseq) provides a population-wide statistical description of how T cells respond to disease. We have defined immunophenotypes of whole repertoires based on TCRseq of the α- and β-chains from glioma tissue, nonneoplastic brain tissue, and peripheral blood from patients. Using information theory, we partitioned the diversity of these TCR repertoires into that from the distribution of VJ cassette combinations and diversity due to VJ-independent factors, such as selection due to antigen binding. Tumor-infiltrating lymphocytes (TILs) possessed higher VJ-independent diversity than nonneoplastic tissue, stratifying patients according to tumor grade. We found that the VJ-independent components of tumor-associated repertoires diverge more from their corresponding peripheral repertoires than T-cell populations in nonneoplastic brain tissue, particularly for low-grade gliomas. Finally, we identified a "signature" set of TCRs whose use in peripheral blood is associated with patients exhibiting low TIL divergence and is depleted in patients with highly divergent TIL repertoires. This signature is detectable in peripheral blood, and therefore accessible noninvasively. We anticipate that these immunophenotypes will be foundational to monitoring and predicting response to antiglioma vaccines and immunotherapy. [ABSTRACT FROM AUTHOR]

Arising from melanocytes in skin, mucosal membranes, eye, and meninges, melanoma is a tumor that has been associated with poor prognosis in advanced disease stages. Given the poor response to chemotherapy and radiation therapy, new treatment approaches with targeted therapy, immunotherapy, and adoptive T-cell therapy have revolutionized the standard of care for patients with advanced melanoma. This review provides a short overview of past, present, and future immunotherapeutic approaches and their limitations, with a focus on new combination agents in early clinical trials. [ABSTRACT FROM AUTHOR]