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Simple Summary: Recent advancements in cancer research have proven immunotherapies to be a promising strategy for the treatment of hematological malignancies. The bispecific antibody (BsAb) format was developed to overcome the issues of monoclonal antibody-based therapies. T-cell engagers (TCEs) are BsAbs, which directly activate T-cells and their anti-tumor features, ultimately resulting in the lysis of the targeted tumor cells. In 2014, the FDA approved blinatumomab for treatment of acute lymphoblastic leukemia. As of November 2023, seven clinically approved TCE therapies are on the market. In this paper, we summarized the technical basis of the TCE technology, its application in hematology, and its current issues and prospects. Recent advancements in cancer immunotherapy have made directing the cellular immune response onto cancer cells a promising strategy for the treatment of hematological malignancies. The introduction of monoclonal antibody-based (mAbs) targeted therapy has significantly improved the prognosis for hematological patients. Facing the issues of mAb-based therapies, a novel bispecific antibody (BsAb) format was developed. T-cell engagers (TCEs) are BsAbs, which simultaneously target tumor-associated antigens on tumor cells and CD3 molecules present on T-cells. This mechanism allows for the direct activation of T-cells and their anti-tumor features, ultimately resulting in the lysis of tumor cells. In 2014, the FDA approved blinatumomab, a TCE directed to CD3 and CD19 for treatment of acute lymphoblastic leukemia. Since then, numerous TCEs have been developed, allowing for treating different hematological malignancies such as acute myeloid leukemia, multiple myeloma, and non-Hodgkin lymphoma and Hodgkin lymphoma. As of November 2023, seven clinically approved TCE therapies are on the market. TCE-based therapies still have their limitations; however, improving the properties of TCEs, as well as combining TCE-based therapies with other forms of treatment, give hope to find the cures for currently terminal diseases. In this paper, we summarized the technical basis of the TCE technology, its application in hematology, and its current issues and prospects. [ABSTRACT FROM AUTHOR]

Simple Summary: This article addresses the topic of primary immunodeficiencies, with particular emphasis on antibody deficiencies with near-normal immunoglobulin levels or hyperimmunoglobulinemia. This paper goes beyond genetics and emphasizes the importance of the immune system and particularly immune checkpoints and Epstein–Barr virus (EBV) reactivation in the context of these disorders. The article delves into the immune dysregulations occurring in the course of this type of disease and the potential role of EBV reactivation, which affects the clinical picture of patients and, in the future, may contribute to the development of cancer, especially those related to hematological malignancies. Disturbances observed in the immunopathogenesis of the presented diseases go beyond the accepted scheme, with the development of PID largely associated only with genetic disorders, and the article emphasizes that the regulation of immunity and virus reactivation also contributes to the progression of PID. This study delves into the intricate landscape of primary immunodeficiencies, with a particular focus on antibody deficiencies characterized by near-normal immunoglobulin levels or hyperimmunoglobulinemia. Contrary to the conventional focus on genetic dysregulation, these studies investigate the key roles of immune checkpoints, such as PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200, on selected subpopulations of T and B lymphocytes and their serum concentrations of soluble forms in patients recruited for the studies in healthy volunteers. In addition, the studies also show the role of Epstein–Barr virus (EBV) reactivation and interactions with tested pathways of immune checkpoints involved in the immunopathogenesis of this disease. By examining the context of antibody deficiencies, this study sheds light on the nuanced interplay of factors beyond genetics, particularly the immune dysregulations that occur in the course of this type of disease and the potential role of EBV reactivation, which affects the clinical presentation of patients and may contribute to the development of cancer in the future, especially related to hematological malignancies. [ABSTRACT FROM AUTHOR]

Simple Summary: The following paper was developed as a reference for healthcare workers who are looking for information on advanced non-small cell lung cancers that lack driver mutations and their treatment with immunotherapy. The aim of the present study is to provide a reliable data source based on a review of the most current papers on the PD-1/PD-L1 and CTLA-4 inhibitors, as well as their use in medical practice. From a complete literature review, we were able to present in this paper what is most current in the treatment with immunotherapy for advanced non-small cell lung cancer (NSCLC). Especially the use of immunotherapy, particularly inhibitors of PD-1 (programmed cell death protein 1), PDL-1 (programmed cell death protein ligand 1), and CTLA-4 (cytotoxic T-lymphocyte antigen 4). Since 2015, these drugs have transformed the treatment of advanced NSCLC lacking driver mutations, evolving from second-line therapy to first-line, with excellent results. The arrival of new checkpoint inhibitors such as cemiplimab and the use of checkpoint inhibitors earlier in the therapy of advanced and metastatic cancers has been making the future prospects for treating NSCLC lacking driver mutations more favorable and optimistic. In addition, for those patients who have low PDL-1 positivity tumors, the combination of cytotoxic chemotherapy, VEGF inhibitor, and immunotherapy have shown an important improvement in global survival and progression free survival regardless the PDL-1 status. We also explored the effectiveness of adding radiotherapy to immunotherapy and the most current results about this combination. One concern that cannot be overlooked is the safety profile of immune checkpoint inhibitors (ICI) and the most common toxicities are described throughout this paper as well as tumor resistance to ICI. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian cancer has remained the leading cause of death among gynecologic malignancies. The current standard of treatment, in most cases, is a combination of surgery and chemotherapy, based on platinum agents and taxanes. Despite the increasing usage of newer drug groups, such as bevacizumab and PARP inhibitors, and the expansion of patient groups for these drugs, ovarian cancer is characterized by recurrences, particularly in the form of peritoneal implants. This review focuses on immunotherapy for ovarian cancer. It considers the current state of knowledge in areas such as cancer vaccines, adoptive cell therapy, CAR-T therapy, and anti-CTLA-4 monotherapy. The paper specifically considers PD-1/PDL-1 as drug targets. Anti-PD-1/PD-L1 monotherapy, and anti-PD-1/PD-L1 immunotherapy in combination with other agents, are analyzed. Ovarian cancer is one of the most fatal cancers in women worldwide. Cytoreductive surgery combined with platinum-based chemotherapy has been the current first-line treatment standard. Nevertheless, ovarian cancer appears to have a high recurrence rate and mortality. Immunological processes play a significant role in tumorigenesis. The production of ligands for checkpoint receptors can be a very effective, and undesirable, immunosuppressive mechanism for cancers. The CTLA-4 protein, as well as the PD-1 receptor and its PD-L1 ligand, are among the better-known components of the control points. The aim of this paper was to review current research on immunotherapy in the treatment of ovarian cancer. The authors specifically considered immune checkpoints molecules such as PD-1/PDL-1 as targets for immunotherapy. We found that immune checkpoint-inhibitor therapy does not have an improved prognosis in ovarian cancer; although early trials showed that a combination of anti-PD-1/PD-L1 therapy with targeted therapy might have the potential to improve responses and outcomes in selected patients. However, we must wait for the final results of the trials. It seems important to identify a group of patients who could benefit significantly from treatment with immune checkpoints inhibitors. However, despite numerous trials, ICIs have not become part of routine clinical practice for the treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we evaluated the status and dynamics of peripheral T cell subpopulations in hepatocellular carcinoma (HCC) patients receiving immune checkpoint blockade with atezolizumab plus bevacizumab (Atez/Bev) treatment and explored biomarkers that are predictive of therapeutic response. The results showed that a higher proportion of CD8+ central memory T cells at baseline is associated with tumor inflammation in HCC, as well as with longer progression-free survival in response to Atez/Bev treatment, especially in cases with an increased proportion of CD8+ effector memory T cells after 3 weeks. Our findings suggest that the peripheral T cell subpopulation can serve as a potential noninvasive biomarker predicting benefits from Atez/Bev treatment. The therapeutic benefits of the immunotherapeutic combination of atezolizumab and bevacizumab (Atez/Bev) in hepatocellular carcinoma (HCC) vary. Therapeutic biomarkers might help improve outcomes for HCC patients receiving Atez/Bev therapy. The role of systemic immune profiles in HCC progression also remains unclear. This study aimed to evaluate the status and dynamics of peripheral T cell subpopulations in HCC patients receiving Atez/Bev treatment and to explore biomarkers predictive of a therapeutic response. We enrolled 83 unresectable advanced HCC patients who commenced Atez/Bev treatment at our hospital between October 2020 and June 2022. Peripheral T cell subpopulations in peripheral blood mononuclear cells at baseline and 3 weeks post-treatment were investigated using flow cytometry and compared with those in control samples from 18 healthy individuals. We retrospectively analyzed the association between peripheral T cell subpopulation profiles and clinical outcomes. Baseline peripheral T cell subpopulations could be profiled in 70 patients with sufficient cell counts, among whom 3-week subpopulations could be evaluated in 51 patients. Multivariate analysis showed that a high baseline proportion of CD8+ central memory T (TCM) cells was independently associated with longer progression-free survival (PFS). Further, overall survival (OS) was significantly prolonged in patients with increased CD8+ effector memory T (TEM) cell proportions. In conclusion, TCM proportion at baseline might be a good indicator of the efficacy of Atez/Bev therapy. Furthermore, observation of increasing TEM proportions might be an early predictor of the potential clinical benefits of treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Renal cell carcinoma (RCC) is common, affecting over 400,000 patients globally each year. In limited stage disease and where surgery is a feasible therapeutic option, event free survival rates are high. In contrast, locally advanced disease is associated with frequent relapse, and up to 30% of patients present with metastatic disease. Standard of care treatments for metastatic disease include tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI), but clinical responses are variable and generally not durable. Novel cell-based immunotherapy approaches such as Chimeric Antigen Receptor T-cells (CAR-T) and T-cell receptor engineered T-cells (TCR-T) have shown efficacy in some blood cancers and are currently under evaluation in solid tumours including RCC. Here, we review the landscape of cellular immunotherapy for RCC in the context of currently available therapies and outline how advanced engineering solutions may further enhance this therapeutic approach. Renal cell carcinoma (RCC) affects over 400,000 patients globally each year, and 30% of patients present with metastatic disease. Current standard of care therapy for metastatic RCC involve TKIs and ICIs, including combinatorial strategies, but this offers only modest clinical benefit. Novel treatment approaches are warranted, and cell-based immunotherapies for RCC hold significant promise. These are currently being tested in the pre-clinical setting and in early phase clinical trials. Here, we review the landscape of cellular immunotherapy for RCC in the context of currently available therapies, with a particular focus on defining the current best antigenic targets, the range of cell therapy products being explored in RCC, and how advanced engineering solutions may further enhance these therapies in the RCC space. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite that a paradoxical response of immune checkpoint inhibition (ICI) is tuberculosis (TB) reactivation, our knowledge of cross-compartmental immune cellularity in human tissues remains limited. Existing studies mainly focused on treatment-associated malignant transformation or TB persistence. Unifying cellular heterogeneity across healthy and pathological tissues is crucial for developing treatments that overcome ICIs-related adverse events. In this study, we highlight the complexity of anti-PD1 functions, which go beyond enhancing immunity solely within the tumor microenvironment (TME) and can be influenced by shifts in CD137-rich immune niches. Each pathological lesion exhibited a unique tissue-specific immune microenvironment (TSIME) associated with ICI, emphasizing the need to tailor cancer therapy considering the characteristics of each TSIME for effective treatment. We also provide evidence of a niche-shift in the CD137-rich hostile TSIME, which may contribute to the reactivation of TB associated with ICI treatment. These findings serve as proof-of-concept for the potential clinical development of selectively activating anti-CD137 signaling within the TME, in combination with checkpoint blockade. The use of immune checkpoint inhibitors (ICIs) in cancer treatment has shown promise but can also have unintended consequences, such as reactivating latent tuberculosis (TB). To develop treatments that address ICIs-related adverse events, it is essential to understand cellular heterogeneity across healthy and pathological tissues. We performed cross-tissue multiplexed staining analysis on samples from two patients with TB reactivation during pembrolizumab treatment for metastatic nasopharyngeal carcinoma. CD8+ T cells, rather than CD4+ T cells, accumulated preferentially in the tuberculoma and were associated with increased production of IFNγ and expression of CD137. Additionally, CD137 enrichment played a role in the spatial organization of the tuberculoma, with specific interaction limited to spatial proximal cells between IFNγ+ CD137+ CD8+ T cells and IL12+ CD137+ type-1 macrophages. This unique feature was not observed in non-tumoral or tumoral tissues. Our analysis of public transcriptomic datasets supported the notion that this cellular interaction was more prominent in patients with durable ICI responses compared to those with non-ICI-related TB. We suggest that shifts towards CD137-rich immune niches are correlated with both off-target immune-related adverse events and anti-tumor efficacy. Targeting the tumor microenvironment through conditional activation of anti-CD137 signaling in combination with ICIs can modulate the reactivity of T cells and macrophages for localized tumor killing without the potential off-target immune-related risks associated with ICIs alone. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioma is the most common and aggressive brain tumor worldwide, and most patients suffer from a recurrence. Additionally, recurrent glioma is often resistant to chemotherapies and radiotherapy. Hence, immunotherapy has come into people's sights. The most-used immunotherapy is immune checkpoint blockade (ICB), which has shown encouraging efficacy when combined with other immune strategies, especially with antiangiogenetic antibodies. Other promising immune regimes include multiple immunotherapies which function through different mechanisms, such as oncolytic viruses, chimeric antigen receptor T cell therapies and vaccination strategies. In this review, we discuss current immune therapies applied to recurrent glioma, based on the literature of preclinical animal models, and current ongoing clinical trials published in the last 5 years. These immunotherapies have been proved to be safe and tolerant, while some combinational regimes have provided satisfying efficacy on a subgroup of patients with specific gene mutation backgrounds. Though great progress has been made, further exploration of different combination strategies is needed. Glioma is the most aggressive malignant tumor of the central nervous system, and most patients suffer from a recurrence. Unfortunately, recurrent glioma often becomes resistant to established chemotherapy and radiotherapy treatments. Immunotherapy, a rapidly developing anti-tumor therapy, has shown a potential value in treating recurrent glioma. Multiple immune strategies have been explored. The most-used ones are immune checkpoint blockade (ICB) antibodies, which are barely effective in monotherapy. However, when combined with other immunotherapy, especially with anti-angiogenesis antibodies, ICB has shown encouraging efficacy and enhanced anti-tumor immune response. Oncolytic viruses and CAR-T therapies have shown promising results in recurrent glioma through multiple mechanisms. Vaccination strategies and immune-cell-based immunotherapies are promising in some subgroups of patients, and multiple new tumor antigenic targets have been discovered. In this review, we discuss current applicable immunotherapies and related mechanisms for recurrent glioma, focusing on multiple preclinical models and clinical trials in the last 5 years. Through reviewing the current combination of immune strategies, we would like to provide substantive thoughts for further novel therapeutic regimes treating recurrent glioma. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy has become the standard frontline treatment for patients with advanced hepatocellular carcinoma (HCC). However, drug resistance is a major limitation and novel strategies are needed for better clinical outcomes. In this review, we discuss adoptive cell therapy (ACT) as an emerging cancer therapy in the treatment of HCC and provide a summary of ongoing clinical trials. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Immune checkpoint inhibitors (ICIs) have become the new reference standard in first-line HCC treatment, replacing tyrosine kinase inhibitors (TKIs) such as sorafenib. Many clinical trials with different combinations are already in development to validate novel immunotherapies for the treatment of patients with HCC. Adoptive cell therapy (ACT), also known as cellular immunotherapy, with chimeric antigen receptors (CAR) or gene-modified T cells expressing novel T cell receptors (TCR) may represent a promising alternative approach to modify the immune system to recognize tumor cells with better clinical outcomes. In this review, we briefly discuss the overview of ACT as a promising treatment modality in HCC, along with recent updates of ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy has made tremendous clinical progress in breast cancer. However, in some patients, the response rate to immunotherapy is low because the tumor microenvironment (TME) is highly immunosuppressive and the tumors are not sufficiently immunogenic. Photodynamic therapy (PDT) can not only kill tumor cells directly but also induce immunogenic cell death (ICD), which provides antitumor immunity. This review discusses the recent advances in crosstalk between photodynamic therapy and immunotherapy in breast cancer, aiming to provide new perspectives on the treatment of breast cancer. Breast cancer (BC) is the world's second most frequent malignancy and the leading cause of mortality among women. All in situ or invasive breast cancer derives from terminal tubulobular units; when the tumor is present only in the ducts or lobules in situ, it is called ductal carcinoma in situ (DCIS)/lobular carcinoma in situ (LCIS). The biggest risk factors are age, mutations in breast cancer genes 1 or 2 (BRCA1 or BRCA2), and dense breast tissue. Current treatments are associated with various side effects, recurrence, and poor quality of life. The critical role of the immune system in breast cancer progression/regression should always be considered. Several immunotherapy techniques for BC have been studied, including tumor-targeted antibodies (bispecific antibodies), adoptive T cell therapy, vaccinations, and immune checkpoint inhibition with anti-PD-1 antibodies. In the last decade, significant breakthroughs have been made in breast cancer immunotherapy. This advancement was principally prompted by cancer cells' escape of immune regulation and the tumor's subsequent resistance to traditional therapy. Photodynamic therapy (PDT) has shown potential as a cancer treatment. It is less intrusive, more focused, and less damaging to normal cells and tissues. It entails the employment of a photosensitizer (PS) and a specific wavelength of light to create reactive oxygen species. Recently, an increasing number of studies have shown that PDT combined with immunotherapy improves the effect of tumor drugs and reduces tumor immune escape, improving the prognosis of breast cancer patients. Therefore, we objectively evaluate strategies for their limitations and benefits, which are critical to improving outcomes for breast cancer patients. In conclusion, we offer many avenues for further study on tailored immunotherapy, such as oxygen-enhanced PDT and nanoparticles. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer survivors can experience neurological complications after exposure to anticancer therapy. Chemotherapy-induced peripheral neurotoxicity (CIPN), mainly consisting of sensory loss and neuropathic pain in hands and feet, is most commonly encountered. Cognitive impairment, although less frequent, is also a severe adverse event, significantly diminishing patients' quality of life. The introduction of immunotherapy has resulted in durable remissions in several types of solid tumor malignancies, although severe neurological immune-related adverse events involving both the central and peripheral nervous system can occur in up to 10% of patients. We herein describe what it is currently known on the topic, and provide directions for future neuroprotection and symptomatic treatment studies. Various neurological complications, affecting both the central and peripheral nervous system, can frequently be experienced by cancer survivors after exposure to conventional chemotherapy, but also to modern immunotherapy. In this review, we provide an overview of the most well-known adverse events related to chemotherapy, with a focus on chemotherapy induced peripheral neurotoxicity, but we also address some emerging novel clinical entities related to cancer treatment, including chemotherapy-related cognitive impairment and immune-mediated adverse events. Unfortunately, efficacious curative or preventive treatment for all these neurological complications is still lacking. We provide a description of the possible mechanisms involved to drive future drug discovery in this field, both for symptomatic treatment and neuroprotection. [ABSTRACT FROM AUTHOR]

Simple Summary: Natural killer (NK) cells are immune cells with potent anti-tumor and anti-infection activity. The potential benefit of NK cell therapy against chronic lymphocytic leukemia (CLL) has long been recognized, but efforts to develop effective NK cell therapies have been hampered by multiple factors including the immunosuppressive effects of CLL against NK cells. In this review, we first outline the specific NK cell impairment seen in CLL and the known mechanisms causing these defects. We then discuss the NK-altering effects of current CLL therapeutics as well as the past and present progress towards developing NK cell therapy for CLL. Immunotherapy approaches have advanced rapidly in recent years. While the greatest therapeutic advances so far have been achieved with T cell therapies such as immune checkpoint blockade and CAR-T, recent advances in NK cell therapy have highlighted the therapeutic potential of these cells. Chronic lymphocytic leukemia (CLL), the most prevalent form of leukemia in Western countries, is a very immunosuppressive disease but still shows significant potential as a target of immunotherapy, including NK-based therapies. In addition to their antileukemia potential, NK cells are important immune effectors in the response to infections, which represent a major clinical concern for CLL patients. Here, we review the interactions between NK cells and CLL, describing functional changes and mechanisms of CLL-induced NK suppression, interactions with current therapeutic options, and the potential for therapeutic benefit using NK cell therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: The association between papillary thyroid cancer and Hashimoto's thyroiditis went through a long-standing human debate recently elucidated by the establishment of a novel mouse model. Papillary thyroid carcinoma is an excellent model for studying the tumor immune microenvironment because it is naturally accompanied by immune cells, making it a good candidate for the treatment with immune checkpoint inhibitors. Papillary thyroid cancer (PTC) often co-occurs with Hashimoto's thyroiditis, an association that has long been reported in clinical studies, remaining controversial. Experimental evidence has recently shown that pre-existing thyroiditis has a beneficial effect on PTC growth and progression by a distinctive expansion of effector memory CD8 T cells. Although the link between inflammation and PTC might involve different components of the immune system, a deep characterization of them which includes T cells, B cells and tertiary lymphoid structures, Mye-loid cells, Neutrophils, NK cells and dendritic cells will be desirable. The present review article considers the role of the adaptive and innate immune response surrounding PTC in the context of Hashimoto's thyroiditis. This review will focus on the current knowledge by in vivo and in vitro studies specifically performed on animals' models; thyroid cancer cells and human samples including (i) the dual role of tumor-infiltrating lymphocytes; (ii) the emerging role of B cells and tertiary lymphoid structures; (iii) the role of myeloid cells, dendritic cells, and natural killer cells; (iv) the current knowledge of the molecular biomarkers implicated in the complex link between thyroiditis and PTC and the potential implication of cancer immunotherapy in PTC patients in the context of thyroiditis. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer immunotherapy, also known as immuno-oncology (IO), has made impressive progress in recent decades and is becoming an essential approach for cancer treatments. For IO drug development, a pertinent preclinical model is indispensable for the rapid and efficient transition from preclinical evaluation through to clinical progress. To date, rodents represent the most-often used models for preclinical evaluation. However, their use presents several drawbacks, including ethical constraints, and time-consuming and costly experiments, which could slow down IO drug development. The aim of our study was to assess the use of the chicken embryo (in ovo) model as an alternative in vivo model for evaluating IO drugs. We confirmed in ovo the anti-tumor efficacy of programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors based on the Chicken Chorioallantoic Membrane (CAM) assay, revealing the pertinence of the chicken embryo model in its use for IO research. (1) Purpose: To assess the use of the chicken embryo (in ovo) model as an alternative in vivo model for immuno-oncology (IO) drug development, focusing on programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors. (2) Methods: First, the presence of immune cells in the model was detected through the immunophenotyping of chicken peripheral blood mononuclear cells (PBMCs) based on fluorescence activated cell sorting (FACS) analysis and the immunohistochemistry (IHC) analysis of in ovo tumor-infiltrating lymphocytes. Second, the cross-reactivity between one anti-human PD-1 Ab, pembrolizumab (KEYTRUDA®), and chicken PD-1 was verified through the labelling of chicken splenocytes with pembrolizumab by FACS analysis. Third, the blockade effect of pembrolizumab on chicken PBMCs was assessed in vitro through cytotoxicity assay based on MTT. Fourth, the CAM assay was used to estimate the anti-tumor performance of pembrolizumab through the analyses of tumor growth and chicken immune cell infiltration in tumors. Finally, the efficacy of several PD-1 or PD-L1 inhibitors (nivolumab, atezolizumab and avelumab) on tumor growth was further assessed using the CAM assay. (3) Results: The presence of CD3+, CD4+, CD8+ T lymphocytes and monocytes was confirmed by FACS and IHC analyses. During in vitro assays, pembrolizumab cross-reacted with chicken lymphocytes and induced PD-1/PD-L1 blockade, which permitted the restoration of chicken T-cell's cytotoxicity against human lung cancer H460 tumor cells. All these in vitro results were correlated with in ovo findings based on the CAM assay: pembrolizumab inhibited H460 tumor growth and induced evident chicken immune cell infiltration (with significant chicken CD45, CD3, CD4, CD8 and CD56 markers) in tumors. Furthermore, the potency of the CAM assay was not limited to the application of pembrolizumab. Nivolumab, atezolizumab and avelumab also led to tumor growth inhibition in ovo, on different tumor models. (4) Conclusions: The chicken embryo affords a physiological, immune reactive, in vivo environment for IO research, which allows observation of how the immune system defense against tumor cells, as well as the different immune tolerance mechanisms leading to tumor immune escape. The encouraging results obtained with PD-1/PD-L1 inhibitors in this study reveal the potential use of the chicken embryo model as an alternative, fast, and reliable in vivo model in the different fields of IO drug discovery. [ABSTRACT FROM AUTHOR]

Simple Summary: Clear cell renal cell carcinoma (ccRCC) is a highly immunogenic tumor, with highly heterogeneous responses to immune checkpoint inhibition therapy. The role of immune cells infiltrating distant metastases and their impact on prognosis and response to immunotherapy are still unclear. To elucidate the prognostic value of immune cell subtypes, we analyzed the immune cell infiltrate in ccRCC primary tumors and paired distant metastases. We hypothesized that specific subtypes of immune cells may be involved in the control of metastases and may have an impact on the prognosis of ccRCC. Clear cell renal cell carcinoma (ccRCC) is a highly immunogenic tumor with variable responses to immune checkpoint therapy. The significance of the immune cell infiltrate in distant metastases, their association with the immune infiltrate in the primary tumors and their impact on prognosis are poorly described. We hypothesized that specific subtypes of immune cells may be involved in the control of metastases and may have an impact on the prognosis of ccRCC. We analyzed the immune microenvironment in ccRCC primary tumors with distant metastases, paired distant metastases and non-metastasized ccRCC (n = 25 each group) by immunohistochemistry. Confirmatory analyses for CD8+ and CD103+ cells were performed in a large ccRCC cohort (n = 241) using a TCGA-KIRC data set (ITGAE/CD103). High immune cell infiltration in primary ccRCC tumors was significantly correlated with the development of distant tumor metastasis (p < 0.05). A high density of CD103+ cells in ccRCC was more frequent in poorly differentiated tumors (p < 0.001). ccRCCs showed high levels of ITGAE/CD103 compared with adjacent non-neoplastic tissue. A higher density of CD103+ cells and a higher ITGAE/CD103 expression were significantly correlated with poor overall survival in ccRCC (log rank p < 0.05). Our results show a major prognostic value of the immune pattern, in particular CD103+ cell infiltration in ccRCC, and highlight the importance of the tumor immune microenvironment. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite recent progress achieved in the management of acute myeloid leukemia (AML), it remains a life-threatening disease with a poor prognosis, particularly in the elderly, having an average 5-year survival of approximately 28%. However, recent evidence suggests that immunotherapy can provide the background for developing personalized targeted therapy to improve the clinical course of AML patients. Our review aimed to assess the immunotherapy effectiveness in AML by discussing the impact of monoclonal antibodies, immune checkpoint inhibitors, chimeric antigen receptor T cells, and vaccines in AML preclinical and clinical studies. Acute myeloid leukemia (AML) is a malignant disease of hematopoietic precursors at the earliest stage of maturation, resulting in a clonalproliferation of myoblasts replacing normal hematopoiesis. AML represents one of the most common types of leukemia, mostly affecting elderly patients. To date, standard chemotherapy protocols are only effective in patients at low risk of relapse and therapy-related mortality. The average 5-year overall survival (OS) is approximately 28%. Allogeneic hematopoietic stem cell transplantation (HSCT) improves prognosis but is limited by donor availability, a relatively young age of patients, and absence of significant comorbidities. Moreover, it is associated with significant morbidity and mortality. However, increasing understanding of AML immunobiology is leading to the development of innovative therapeutic strategies. Immunotherapy is considered an attractive strategy for controlling and eliminating the disease. It can be a real breakthrough in the treatment of leukemia, especially in patients who are not eligible forintensive chemotherapy. In this review, we focused on the progress of immunotherapy in the field of AML by discussing monoclonal antibodies (mAbs), immune checkpoint inhibitors, chimeric antigen receptor T cells (CAR-T cells), and vaccine therapeutic choices. [ABSTRACT FROM AUTHOR]

Simple Summary: This review focuses on the effects that a class of drugs, PI3Kδ inhibitors, used for the treatment of patients with lymphoma can have not on the neoplastic cells but on the normal cells and how this effect can modulate the immune response and potentially contribute to the anti-tumor response. The development of small molecules able to block specific or multiple isoforms of phosphoinositide 3-kinases (PI3K) has already been an active field of research for many years in the cancer field. PI3Kδ inhibitors are among the targeted agents most extensively studied for the treatment of lymphoma patients and PI3Kδ inhibitors are already approved by regulatory agencies. More recently, it became clear that the anti-tumor activity of PI3K inhibitors might not be due only to a direct effect on the cancer cells but it can also be mediated via inhibition of the kinases in non-neoplastic cells present in the tumor microenvironment. T-cells represent an important component of the tumor microenvironment and they comprise different subpopulations that can have both anti- and pro-tumor effects. In this review article, we discuss the effects that PI3Kδ inhibitors exert on the immune system with a particular focus on the T-cell compartment. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancer (TNBC) is the most refractory subtype of breast cancer. Immune checkpoint inhibitor (ICI) therapy has made progress in TNBC treatment. PD-L1 expression is a useful biomarker of ICI therapy efficacy. However, tumor-immune microenvironment (TIME) factors, such as immune cell compositions and tumor-infiltrating lymphocyte (TIL) status, also influence tumor immunity. Therefore, it is necessary to seek biomarkers that are associated with multiple aspects of TIME in TNBC. In this study, we developed an immune-related gene prognostic index (IRGPI) with a substantial prognostic value for TNBC. Moreover, the results from multiple cohorts reproducibly demonstrate that IRGPI is significantly associated with immune cell compositions, the exclusion and dysfunction of TILs, as well as PD-1 and PD-L1 expression in TIME. Therefore, IRGPI is a promising biomarker closely related to patient survival and TIME of TNBC and may have a potential effect on the immunotherapy strategy of TNBC. Tumor-immune cell compositions and immune checkpoints comprehensively affect TNBC outcomes. With the significantly improved survival rate of TNBC patients treated with ICI therapies, a biomarker integrating multiple aspects of TIME may have prognostic value for improving the efficacy of ICI therapy. Immune-related hub genes were identified with weighted gene co-expression network analysis and differential gene expression assay using The Cancer Genome Atlas TNBC data set (n = 115). IRGPI was constructed with Cox regression analysis. Immune cell compositions and TIL status were analyzed with CIBERSORT and TIDE. The discovery was validated with the Molecular Taxonomy of Breast Cancer International Consortium data set (n = 196) and a patient cohort from our hospital. Tumor expression or serum concentrations of CCL5, CCL25, or PD-L1 were determined with immunohistochemistry or ELISA. The constructed IRGPI was composed of CCL5 and CCL25 genes and was negatively associated with the patient's survival. IRGPI also predicts the compositions of M0 and M2 macrophages, memory B cells, CD8+ T cells, activated memory CD4 T cells, and the exclusion and dysfunction of TILs, as well as PD-1 and PD-L1 expression of TNBC. IRGPI is a promising biomarker for predicting the prognosis and multiple immune characteristics of TNBC. [ABSTRACT FROM AUTHOR]

Simple Summary: Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are bone marrow cancers that have a poor prognosis. They have traditionally been treated with chemotherapy with limited success, and stem cell transplant, which many patients are too frail to receive. Perturbations in the immune system play a role in the development of MDS and AML. Recently, there has been progress in understanding how the immune system can be harnessed to treat these cancers. Effective immune therapies for MDS and AML have been developed at a rapid pace, including novel immune checkpoint inhibitor antibodies, bispecific T-cell-engaging antibodies, antibody drug conjugates, vaccine therapies, and cellular therapeutics including chimeric antigen receptor T-cells and natural killer cells. This review article highlights advances in this field for the practicing clinician to aid in understanding new developments for treating patients with MDS and AML. Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic malignancies arising from the bone marrow. Despite recent advances in treating these diseases, patients with higher-risk MDS and AML continue to have a poor prognosis with limited survival. It has long been recognized that there is an immune component to the pathogenesis of MDS and AML, but until recently, immune therapies have played a limited role in treating these diseases. Immune suppressive therapy exhibits durable clinical responses in selected patients with MDS, but the question of which patients are most suitable for this treatment remains unclear. Over the past decade, there has been remarkable progress in identifying genomic features of MDS and AML, which has led to an improved discernment of the molecular pathogenesis of these diseases. An improved understanding of immune and inflammatory molecular mechanisms of MDS and AML have also recently revealed novel therapeutic targets. Emerging treatments for MDS and AML include monoclonal antibodies such as immune checkpoint inhibitors, bispecific T-cell-engaging antibodies, antibody drug conjugates, vaccine therapies, and cellular therapeutics including chimeric antigen receptor T-cells and NK cells. In this review, we provide an overview of the current understanding of immune dysregulation in MDS and AML and an update on novel immune therapies for these bone marrow malignancies. [ABSTRACT FROM AUTHOR]