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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: Immune checkpoint inhibitors (ICIs) constitute a paradigm shift in cancer therapy, and it has greatly expanded our knowledge of anticancer immunity and has introduced breakthroughs in cancer therapy. However, despite the promising results in the use of immunotherapy in some cancers, numerous patients do not respond to ICIs without the existence of a clear predictive biomarker. This review provides an overview of recent advances in cellular and molecular factors within the tumor microenvironment (TME) to identify possible mechanisms of immunotherapy resistance, as well as to develop novel combination strategies for cancer immunotherapy. The in-depth exploration of complexity within the TME allows for the improvement of therapeutic efficacy and highlights its contribution to cancer immunotherapy. Immune checkpoints play critical roles in the regulation of T-cell effector function, and the effectiveness of their inhibitors in cancer therapy has been established. Immune checkpoint inhibitors (ICIs) constitute a paradigm shift in cancer therapy in general and cancer immunotherapy in particular. Immunotherapy has been indicated to reinvigorate antitumor T-cell activity and dynamically modulate anticancer immune responses. However, despite the promising results in the use of immunotherapy in some cancers, numerous patients do not respond to ICIs without the existence of a clear predictive biomarker. Overall, immunotherapy involves a certain degree of uncertainty and complexity. Research on the exploration of cellular and molecular factors within the tumor microenvironment (TME) aims to identify possible mechanisms of immunotherapy resistance, as well as to develop novel combination strategies involving the specific targeting of the TME for cancer immunotherapy. The combination of this approach with other types of treatment, including immune checkpoint blockade therapy involving multiple agents, most of the responses and effects in cancer therapy could be significantly enhanced, but the appropriate combinations have yet to be established. Moreover, the in-depth exploration of complexity within the TME allows for the exploration of pathways of immune dysfunction. It may also aid in the identification of new therapeutic targets. This paper reviews recent advances in the improvement of therapeutic efficacy on the immune context of the TME and highlights its contribution to cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: This review paper here describes the recent progress that has been made in chimeric antigen receptor (CAR) -based therapies for treatment of tumors and the role of metabolism in the tumor microenvironment in relation to these therapies. Moreover, this manuscript also discusses role of different CAR-based cells for treatment of solid tumors, which is a major challenge in the CAR immunotherapy field. Chimeric antigen receptor (CAR) T cell-based therapies have shown tremendous advancement in clinical and pre-clinical studies for the treatment of hematological malignancies, such as the refractory of pre-B cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL), and large B cell lymphoma (LBCL). However, CAR T cell therapy for solid tumors has not been successful clinically. Although, some research efforts, such as combining CARs with immune checkpoint inhibitor-based therapy, have been used to expand the application of CAR T cells for the treatment of solid tumors. Importantly, further understanding of the coordination of nutrient and energy supplies needed for CAR T cell expansion and function, especially in the tumor microenvironment (TME), is greatly needed. In addition to CAR T cells, there is great interest in utilizing other types of CAR immune cells, such as CAR NK and CAR macrophages that can infiltrate solid tumors. However, the metabolic competition in the TME between cancer cells and immune cells remains a challenge. Bioengineering technologies, such as metabolic engineering, can make a substantial contribution when developing CAR cells to have an ability to overcome nutrient-paucity in the solid TME. This review introduces technologies that have been used to generate metabolically fit CAR-immune cells as a treatment for hematological malignancies and solid tumors, and briefly discusses the challenges to treat solid tumors with CAR-immune cells. [ABSTRACT FROM AUTHOR]

Simple Summary: The introduction of immune checkpoint inhibitors (ICI) in 2011 revolutionized the management of many solid cancers and hematological malignancies. However, there are concerns regarding the use of ICI in the era of COVID-19. We present currently available information on the pros and cons of using ICI in cancer patients with respect to the risk of acquiring an infection by SARS-CoV2 and mortality from COVID-19. By means of the present paper, clinicians and researchers may update their knowledge on a highly topical clinical question—is the use of ICI in cancer patients with SARS-CoV2 infection harmful with respect to COVID-19 outcome? Whether cancer patients receiving immune checkpoint inhibitors (ICI) are at an increased risk of severe infection and mortality during the corona pandemic is a hotly debated topic that will continue to evolve. Here, we summarize and discuss current studies regarding COVID-19 and anti-cancer treatment with an emphasis on ICI. Importantly, several lines of evidence suggest that patients currently treated with ICI do not display an increased vulnerability to infection with SARS-CoV-2. Data regarding morbidity and mortality associated with COVID-19 in cancer patients receiving ICI are less clear and often conflicting. Although mostly based on experimental data, it is possible that ICI can promote the exacerbated immune response associated with adverse outcome in COVID-19 patients. On the other hand, mounting evidence suggests that ICI might even be useful in the treatment of viral infections by preventing or ameliorating T cell exhaustion. In this context, the right timing of treatment might be essential. Nevertheless, some cancer patients treated with ICI experience autoimmune-related side effects that require the use of immunosuppressive therapies, which in turn may promote a severe course of infection with SARS-CoV-2. Although there is clear evidence that withholding ICI will have more serious consequences, further studies are urgently needed in to better evaluate the effects of ICI in patients with COVID-19 and the use of ICI during the corona pandemic in general. [ABSTRACT FROM AUTHOR]

Simple Summary: Combination of radiotherapy and immunotherapy to antagonize tumors is one of hotspot issues currently. Immunotherapy can effectively alleviate the non-lasting effect of radiotherapy and tumor recurrence. Local radiotherapy can mobilize immune cells into tumor microenvironment and make tumors unable to escape from immune supervision. Therefore, the radio-immunotherapy achieves better curative effects on cancer patients. We have reviewed the regulation of multiple immune cells with different functions by radiotherapy, as well as the mechanism research and clinical outcomes combined with immune checkpoint inhibitors for cancer treatment, which provides new insights in the treatment strategies for certain types of cancer patients in clinic. Radiotherapy (RT) is a conventional method for clinical treatment of local tumors, which can induce tumor-specific immune response and cause the shrinkage of primary tumor and distal metastases via mediating tumor infiltration of CD8+ T cells. Ionizing radiation (IR) induced tumor regression outside the radiation field is termed as abscopal effect. However, due to the mobilization of immunosuppressive signals by IR, the activated CD8+T cells are not sufficient to maintain a long-term positive feedback to make the tumors regress completely. Eventually, the "hot" tumors gradually turn to "cold". With the advent of emerging immunotherapy, the combination of immune checkpoint blockade (ICB) and local RT has produced welcome changes in stubborn metastases, especially anti-PD-1/PD-L1 and anti-CTLA-4 which have been approved in clinical cancer treatment. However, the detailed mechanism of the abscopal effect induced by combined therapy is still unclear. Therefore, how to formulate a therapeutic schedule to maximize the efficacy should be took into consideration according to specific circumstance. This paper reviewed the recent research progresses in immunomodulatory effects of local radiotherapy on the tumor microenvironment, as well as the unique advantage for abscopal effect when combined with ICB, with a view to exploring the potential application value of radioimmunotherapy in clinic. [ABSTRACT FROM AUTHOR]