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CAR-T cell therapy offers a promising way for prolonged cancer remission, specifically in the case of blood cancers. However, its application in the treatment of solid tumors still faces many limitations. This review paper provides a comprehensive overview of the challenges and strategies associated with CAR-T cell therapy for solid tumors, with a focus on gynecological cancer. This study discusses the limitations of CAR-T therapy for solid tumor treatment, such as T cell exhaustion, stromal barrier, and antigen shedding. Additionally, it addresses possible approaches to increase CAR-T efficacy in solid tumors, including combination therapies with checkpoint inhibitors and chemotherapy, as well as the novel approach of combining CAR-T with oncolytic virotherapy. Given the lack of comprehensive research on CAR-T combination therapies for treating gynecological cancers, this review aims to provide insights into the current landscape of combination therapies for solid tumors and highlight the potential of such an approach in gynecology. [ABSTRACT FROM AUTHOR]

With the deepening of people's understanding of lung cancer, the research of lung cancer immunotherapy has gradually become the focus of attention. As we all know, the treatment of many diseases relies on the rich sources, complex and varied compositions and wide range of unique biological properties of natural products. Studies have shown that natural products can exert anticancer effects by inducing tumor cell death, inhibiting tumor cell proliferation, and enhancing tumor cell autophagy. More notably, natural products can adjust and strengthen the body's immune response, which includes enhancing the function of NK cells and promoting the differentiation and proliferation of T lymphocytes. In addition, these natural products may enhance their anticancer effects by affecting inhibitory factors in the immune system, hormone levels, enzymes involved in biotransformation, and modulating other factors in the tumor microenvironment. The importance of natural products in lung cancer immunotherapy should not be underestimated. However, the specific links and correlations between natural products and lung cancer immunity are not clear enough, and further studies are urgently needed to clarify the relationship between the two. In this paper, we will focus on the correlation between natural products and lung cancer immune responses, with a view to providing new research perspectives for immunotherapy of lung cancer. [ABSTRACT FROM AUTHOR]

Efforts to treat cancer using chimeric antigen receptor (CAR)-T therapy have made astonishing progress and clinical trials against hematopoietic malignancies have demonstrated their use. However, there are still disadvantages which need to be addressed: high costs, and side effects such as Graft-versus-Host Disease (GvHD) and Cytokine Release Syndrome (CRS). Therefore, recent efforts have been made to harness the properties of certain immune cells to treat cancer—not just T cells, but also natural killer (NK) cells, macrophages (Mφ), dendritic cells (DC), etc. In this paper, we will introduce immune cell-based cellular therapies that use various immune cells and describe their characteristics and their clinical situation. The development of immune cell-based cancer therapy fully utilizing the unique advantages of each and every immune cell is expected to enhance the survival of tumor patients owing to their high efficiency and fewer side effects. [ABSTRACT FROM AUTHOR]

Cancer is a worldwide health problem. Nevertheless, new technologies in the immunotherapy field have emerged. Chimeric antigen receptor (CAR) technology is a novel biological form to treat cancer; CAR-T cell genetic engineering has positively revolutionized cancer immunotherapy. In this paper, we review the latest developments in CAR-T in cancer treatment. We present the structure of the different generations and variants of CAR-T cells including TRUCK (T cells redirected for universal cytokine killing. We explain the approaches of the CAR-T cells manufactured ex vivo and in vivo. Moreover, we describe the limitations and areas of opportunity for this immunotherapy and the current challenges of treating hematological and solid cancer using CAR-T technology as well as its constraints and engineering approaches. We summarize other immune cells that have been using CAR technology, such as natural killer (NK), macrophages (M), and dendritic cells (DC). We conclude that CAR-T cells have the potential to treat not only cancer but other chronic diseases. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockade (ICB) therapies are revolutionary cancer treatments; however, they only benefit about a third of patients. Therefore, extensive research is underway to find methods to improve their therapeutic efficacy. One avenue of study that has recently emerged is to consider the role the gut microbiome plays in therapeutic success. Several high‐impact studies have repeatedly shown that the presence, composition and level of diversity of the gut flora directly impact cancer treatment outcome in both mice and patients. These studies have also highlighted the danger of using antibiotics shortly before or during cancer treatments. However, there are still several questions that need to be answered, including which bacteria promote the greatest benefit, the mechanisms by which they act and how we can use this information to influence treatment outcome. In this review, we explain how the gut microbiome was realized to be of such importance and propose hypotheses for why gut flora have such a critical impact on ICB therapeutic success. We also describe a hypothetical mechanism involving bacterial translocation out of the gut and into the tumor, whereby the bacteria act in an adjuvant capacity to facilitate an antitumor response. By highlighting key papers in the field, we hope to hasten research on the subject so as to find a means to improve the therapeutic efficacy of these ground‐breaking cancer treatments. [ABSTRACT FROM AUTHOR]

Background: Metabolic reprogramming occurs in the tumor microenvironment and influences the survival and function of tumor and immune cells. Interferon-γ (IFN-γ) produced by T cells up-regulates PD-L1 expression in tumors. However, reports regarding the relationship between nutrient metabolism and the up-regulation of PD-L1 expression are lacking.Materials and methods: In this paper, we analyzed the metabolic changes in T cells and bladder cancer cells in a simulated tumor microenvironment to provide evidence regarding their relevance to PD-L1 up-regulation.Results: The glutaminolysis was increased in both activated T cells and glucose-deprived T cells. IFN-γ production by T cells was decreased in a glucose-free medium and severely decreased when cells were simultaneously deprived of glutamine. Furthermore, the glutaminolysis of the bladder cancer cells under glucose deprivation exhibited a compensatory elevation. The glucose concentration of T cells co-cultured with bladder cancer cells was decreased and T cell proliferation was reduced, but IFN-γ production and glutaminolysis were increased. However, in bladder cancer cells, the elevation in glutaminolysis under co-culture conditions did not compensate for glucose deprivation because the glucose concentration in the culture medium did not significantly differ between the cultures with and without T cells. Our data also show that inhibiting glutamine metabolism in bladder cancer cells could reduce the elevation in PD-L1 expression induced by IFN-γ.Conclusion: In a simulated tumor microenvironment, elevated glutaminolysis may play an essential role in IFN-γ production by T cells, ultimately improving the high PD-L1 expression, and also directly contributing to producing more PD-L1 in bladder cancer cells. [ABSTRACT FROM AUTHOR]

Oncolytic virus (OV) is a replication competent virus that selectively invades cancer cells; as these cells die under the viral burden, the released virus particles proceed to infect other cancer cells. Oncolytic viruses are designed to also be able to stimulate the anticancer immune response. Thus, one may represent an OV by two parameters: its replication potential and its immunogenicity. In this paper we consider a combination therapy with OV and a checkpoint inhibitor, anti-PD-1. We evaluate the efficacy of the combination therapy in terms of the tumor volume at some later time, for example, 6 months from initial treatment. Since T cells kill not only virus-free cancer cells but also virus-infected cancer cells, the following question arises: Does increasing the amount of the checkpoint inhibitor always improve the efficacy? We address this question, by a mathematical model consisting of a system of partial differential equations. We use the model to construct, by simulations, an efficacy map in terms of the doses of the checkpoint inhibitor and the OV injection. We show that there are regions in the map where an increase in the checkpoint inhibitor actually decreases the efficacy of the treatment. We also construct efficacy maps with checkpoint inhibitor vs. the replication potential of the virus that show the same antagonism, namely, an increase in the checkpoint inhibitor may actually decrease the efficacy. These results have implications for clinical trials. [ABSTRACT FROM AUTHOR]

Abstract: Soft tissue and bone sarcomas are a rare and heterogeneous form of cancer. With standard of care treatment options including surgery, radiation, and chemotherapy, the long‐term survival is still low for high‐risk soft tissue sarcoma patients. New treatment strategies are needed. Immunotherapy offers a new potential treatment paradigm with great promise. Immunotherapy of soft tissue sarcomas dates back to Dr. Coley's first use of toxins in the late 1800s. A variety of strategies of immunotherapy have been tried in soft tissue and bone sarcomas, including various vaccines and cytokines, with limited success. Results of these early clinical trials with vaccines and cytokines were disappointing, but there are reasons to be optimistic. Recent advances, particularly with the use of adoptive T‐cell therapy and immune checkpoint inhibitors, have led to a resurgence of this field for all cancer patients. Clinical trials utilizing adoptive T‐cell therapy and immune checkpoint inhibitors in soft tissue and bone sarcomas are under way. This paper reviews the current state of evidence for the use of immunotherapy, as well as current immunotherapy strategies (vaccines, adopative T‐cell therapy, and immune checkpoint blockade), in soft tissue and bone sarcomas. By understanding the tumor microenviroment of sarcomas and how it relates to their immunoresponsiveness, better immunotherapy clinical trials can be designed, hopefully with improved outcomes for soft tissue and bone sarcoma patients. Implications for Practice: Immunotherapy is a promising treatment paradigm that is gaining acceptance for the management of several cancers, including melanoma, renal cell carcinoma, prostate cancer, and lung cancer. There is a long history of immunotherapy in the treatment of soft tissue and bone sarcomas, although with little success. It is important to understand past failures to develop future immunotherapy treatment strategies with an improved possibility of success. This article reviews the history of and current state of immunotherapy research in the treatment of soft tissue and bone sarcomas, with particular regard to vaccine trials, adoptive T‐cell therapy, and immune checkpoint blockade. [ABSTRACT FROM AUTHOR]

T cell receptor (TCR)-engineered T cell therapy is a promising potential treatment for solid tumors, with preliminary efficacy demonstrated in clinical trials. However, obtaining clinically effective TCR molecules remains a major challenge. We have developed a strategy for cloning tumor-specific TCRs from long-term surviving patients who have responded to immunotherapy. Here, we report the identification of a TCR (10F04), which is human leukocyte antigen (HLA)-DRA/DRB1*09:01 restricted and human papillomavirus type 18 (HPV18) E784-98 specific, from a multiple antigens stimulating cellular therapy (MASCT) benefited metastatic cervical cancer patient. Upon transduction into human T cells, the 10F04 TCR demonstrated robust antitumor activity in both in vitro and in vivo models. Notably, the TCR effectively redirected both CD4+ and CD8+ T cells to specifically recognize tumor cells and induced multiple cytokine secretion along with durable antitumor activity and outstanding safety profiles. As a result, this TCR is currently being investigated in a phase I clinical trial for treating HPV18-positive cancers. This study provides an approach for developing safe and effective TCR-T therapies, while underscoring the potential of HLA class II-restricted TCR-T therapy as a cancer treatment. The use of TCR engineered T cells holds promise for treatment of tumours, but is limited by awareness of clinically effective TCR molecules. Here the authors identify an MHC II restricted TCR that targets viral E7 of human papillomavirus type 18 and show effectivity in a murine model of solid tumour. [ABSTRACT FROM AUTHOR]

PD1 blockade therapy, harnessing the cytotoxic potential of CD8+ T cells, has yielded clinical success in treating malignancies. However, its efficacy is often limited due to the progressive differentiation of intratumoral CD8+ T cells into a hypofunctional state known as terminal exhaustion. Despite identifying CD8+ T cell subsets associated with immunotherapy resistance, the molecular pathway triggering the resistance remains elusive. Given the clear association of CD38 with CD8+ T cell subsets resistant to anti-PD1 therapy, we investigated its role in inducing resistance. Phenotypic and functional characterization, along with single-cell RNA sequencing analysis of both in vitro chronically stimulated and intratumoral CD8+ T cells, revealed that CD38-expressing CD8+ T cells are terminally exhausted. Exploring the molecular mechanism, we found that CD38 expression was crucial in promoting terminal differentiation of CD8+ T cells by suppressing TCF1 expression, thereby rendering them unresponsive to anti-PD1 therapy. Genetic ablation of CD38 in tumor-reactive CD8+ T cells restored TCF1 levels and improved the responsiveness to anti-PD1 therapy in mice. Mechanistically, CD38 expression on exhausted CD8+ T cells elevated intracellular Ca2+ levels through RyR2 calcium channel activation. This, in turn, promoted chronic AKT activation, leading to TCF1 loss. Knockdown of RyR2 or inhibition of AKT in CD8+ T cells maintained TCF1 levels, induced a sustained anti-tumor response, and enhanced responsiveness to anti-PD1 therapy. Thus, targeting CD38 represents a potential strategy to improve the efficacy of anti-PD1 treatment in cancer. [ABSTRACT FROM AUTHOR]

In this paper we consider a combination therapy of cancer. One drug is a vaccine which activates dendritic cells so that they induce more T cells to infiltrate the tumor. The other drug is a checkpoint inhibitor, which enables the T cells to remain active against the cancer cells. The two drugs are positively correlated in the sense that an increase in the amount of each drug results in a reduction in the tumor volume. We consider the question whether a treatment with combination of the two drugs at certain levels is preferable to a treatment by one of the drugs alone at ‘roughly’ twice the dosage level; if that is the case, then we say that there is a positive ‘synergy’ for this combination of dosages. To address this question, we develop a mathematical model using a system of partial differential equations. The variables include dendritic and cancer cells, CD4+ and CD8+ T cells, IL-12 and IL-2, GM-CSF produced by the vaccine, and a T cell checkpoint inhibitor associated with PD-1. We use the model to explore the efficacy of the two drugs, separately and in combination, and compare the simulations with data from mouse experiments. We next introduce the concept of synergy between the drugs and develop a synergy map which suggests in what proportion to administer the drugs in order to achieve the maximum reduction of tumor volume under the constraint of maximum tolerated dose. [ABSTRACT FROM AUTHOR]

This article explores the relationship between certain cancer therapies and the risk of fungal infections. It focuses on three types of therapies: BTK inhibitors, PI3K inhibitors, and CD-52 monoclonal antibodies. These therapies have been found to increase susceptibility to invasive fungal infections (IFIs) by impairing the immune response or depleting T cells. The article suggests that repurposing existing cancer therapeutics could be a strategy to address the limited options for antifungal treatments. It also discusses the potential of using targeted therapies, immunotherapy, and interferon-gamma in combination with antifungals to improve outcomes. Further research is needed to evaluate the effectiveness of these approaches. [Extracted from the article]

Simple Summary: Despite the advances in the treatment of pre-B-ALL leukemia in children, adult pre-B-ALL continues to represent a major challenge. This work focuses on the use of differential responses to fasting conditions between normal and cancer cells to achieve cancer-free survival. We show that a fasting-mimicking diet in combination with vincristine causes a synergistic increase in the toxicity to pre-B-ALL cells resulting in high cancer cell death. While fasting is not sufficient to promote cancer-free survival, the combination of fasting/FMD and vincristine promotes autophagy inhibition, which is at the center of the high toxicity phenotype specific to leukemia cells, possibly through a mechanism involving immune cells. Fasting mimicking diets (FMDs) are effective in the treatment of many solid tumors in mouse models, but their effect on hematologic malignancies is poorly understood, particularly in combination with standard therapies. Here we show that cycles of a 3-day FMD given to high-fat-diet-fed mice once a week increased the efficacy of vincristine to improve survival from BCR-ABL B acute lymphoblastic leukemia (ALL). In mice fed a standard diet, FMD cycles in combination with vincristine promoted cancer-free survival. RNA seq and protein assays revealed a vincristine-dependent decrease in the expression of multiple autophagy markers, which was exacerbated by the fasting/FMD conditions. The autophagy inhibitor chloroquine could substitute for fasting/FMD to promote cancer-free survival in combination with vincristine. In vitro, targeted inhibition of autophagy genes ULK1 and ATG9a strongly potentiated vincristine's toxicity. Moreover, anti-CD8 antibodies reversed the effects of vincristine plus fasting/FMD in promoting leukemia-free survival in mice, indicating a central role of the immune system in this response. Thus, the inhibition of autophagy and enhancement of immune responses appear to be mediators of the fasting/FMD-dependent cancer-free survival in ALL mice. [ABSTRACT FROM AUTHOR]

CD73 plays a critical role in the pathogenesis and immune escape in pancreatic ductal adenocarcinoma (PDAC). AB680, an exceptionally potent and selective inhibitor of CD73, is administered in an early clinical trial, in conjunction with gemcitabine and anti‐PD‐1 therapy, for the treatment of PDAC. Nevertheless, the specific therapeutic efficacy and immunoregulation within the microenvironment of AB680 monotherapy in PDAC have yet to be fully elucidated. In this study, AB680 exhibits a significant effect in augmenting the infiltration of responsive CD8+ T cells and prolongs the survival in both subcutaneous and orthotopic murine PDAC models. In parallel, it also facilitates chemotaxis of myeloid‐derived suppressor cells (MDSCs) by tumor‐derived CXCL5 in an AMP‐dependent manner, which may potentially contribute to enhanced immunosuppression. The concurrent administration of AB680 and PD‐1 blockade, rather than gemcitabine, synergistically restrain tumor growth. Notably, gemcitabine weakened the efficacy of AB680, which is dependent on CD8+ T cells. Finally, the supplementation of a CXCR2 inhibitor is validated to further enhance the therapeutic efficacy when combined with AB680 plus PD‐1 inhibitor. These findings systematically demonstrate the efficacy and immunoregulatory mechanism of AB680, providing a novel, efficient, and promising immunotherapeutic combination strategy for PDAC. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. This is due to its aggressive course, late diagnosis and its intrinsic drugs resistance. The complexity of the tumor, in terms of cell components and heterogeneity, has led to the approval of few therapies with limited efficacy. The study of the early stages of carcinogenesis provides the opportunity for the identification of actionable pathways that underpin therapeutic resistance. Methods: We analyzed 43 Intraductal papillary mucinous neoplasms (IPMN) (12 Low-grade and 31 High-grade) by Spatial Transcriptomics. Mouse and human pancreatic cancer organoids and T cells interaction platforms were established to test the role of mucins expression on T cells activity. Syngeneic mouse model of PDAC was used to explore the impact of mucins downregulation on standard therapy efficacy. Results: Spatial transcriptomics showed that mucin O-glycosylation pathway is increased in the progression from low-grade to high-grade IPMN. We identified GCNT3, a master regulator of mucins expression, as an actionable target of this pathway by talniflumate. We showed that talniflumate impaired mucins expression increasing T cell activation and recognition using both mouse and human organoid interaction platforms. In vivo experiments showed that talniflumate was able to increase the efficacy of the chemotherapy by boosting immune infiltration. Conclusions: Finally, we demonstrated that combination of talniflumate, an anti-inflammatory drug, with chemotherapy effectively improves anti-tumor effect in PDAC. [ABSTRACT FROM AUTHOR]

Tertiary lymphoid structures (TLS) are lymph node-like aggregates that can form in association with chronic inflammation or cancer. Mature TLS are organized into B and T cell zones, and are not encapsulated but include all cell types necessary for eliciting an adaptive immune response. TLS have been observed in various cancer types and are generally associated with a positive prognosis as well as increased sensitivity to cancer immunotherapy. However, a comprehensive understanding of the roles of TLS in eliciting anti-tumor immunity as well as the mechanisms involved in their formation and function is still lacking. Further studies in orthotopic, immunocompetent cancer models are necessary to evaluate the influence of TLS on cancer therapies, and to develop new treatments that promote their formation in cancer. Here, we review key insights obtained from functional murine studies, discuss appropriate models that can be used to study cancer-associated TLS, and suggest guidelines on how to identify TLS and distinguish them from other antigen-presenting niches. [ABSTRACT FROM AUTHOR]

Allogeneic Vγ9Vδ2 (Vδ2) T cells have emerged as attractive candidates for developing cancer therapy due to their established safety in allogeneic contexts and inherent tumor-fighting capabilities. Nonetheless, the limited clinical success of Vδ2 T cell-based treatments may be attributed to donor variability, short-lived persistence, and tumor immune evasion. To address these constraints, we engineer Vδ2 T cells with enhanced attributes. By employing CD16 as a donor selection biomarker, we harness Vδ2 T cells characterized by heightened cytotoxicity and potent antibody-dependent cell-mediated cytotoxicity (ADCC) functionality. RNA sequencing analysis supports the augmented effector potential of Vδ2 T cells derived from CD16 high (CD16Hi) donors. Substantial enhancements are further achieved through CAR and IL-15 engineering methodologies. Preclinical investigations in two ovarian cancer models substantiate the effectiveness and safety of engineered CD16Hi Vδ2 T cells. These cells target tumors through multiple mechanisms, exhibit sustained in vivo persistence, and do not elicit graft-versus-host disease. These findings underscore the promise of engineered CD16Hi Vδ2 T cells as a viable therapeutic option for cancer treatment. Vγ9Vδ2 (Vδ2) T cells have been proposed as cell carriers for off-the-shelf CAR therapies. Here the authors describe CD16 as a biomarker for the selection of Vδ2 T cells with high levels of cytotoxicity and report the anti-tumor activity of engineered CD16high Vδ2 T cells in ovarian cancer preclinical models. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the second most common malignancy in women and the third most frequent cancer in men. Evidence has revealed that the survival of patients with metastatic CRC is very low, between one and three years. Neoantigens are known proteins encoded by mutations in tumor cells. It is theorized that recognizing neoantigens by T cells leads to T cell activation and further antitumor responses. Neoantigen‐reactive T cells (NRTs) are designed against the mentioned neoantigens expressed by tumor cells. NRTs selectively kill tumor cells without damage to non‐cancerous cells. Identifying patient‐specific and high immunogen neoantigens is important in NRT immunotherapy of patients with CRC. However, the main challenges are the side effects and preparation of NRTs, as well as the effectiveness of these cells in vivo. This review summarized the properties of neoantigens as well as the preparation and therapeutic outcomes of NRTs for the treatment of CRC. [ABSTRACT FROM AUTHOR]

Introduction: Intestinal non-Hodgkin's lymphoma (NHL) is uncommon but not rare. This paper aims to review the recent evidence for the management of perforated NHL of the intestine, consider when chemotherapy should be commenced and examine the likely outcomes and prognosis for patients presenting as surgical emergencies with this condition. Methods: MEDLINE and Cochrane databases were searched using intestinal lymphoma, clinical presentation, perforation, management and prognosis. The full text of relevant articles was retrieved and reference lists checked for additional articles. Findings: Emergency surgery was required at disease presentation for between 11 and 64 % of intestinal NHL cases. Perforation occurs in 1-25 % of cases, and also occurs whilst on chemotherapy for NHL. Intestinal bleeding occurs in 2-22 % of cases. Obstruction occurs more commonly in small bowel (5-39 %) than large bowel NHL and intussusceptions occur in up to 46 %. Prognosis is generally poor, especially for T cell lymphomas. Conclusions: There is a lack of quality evidence for the elective and emergency treatment of NHL involving the small and large intestine. There is a lack of information regarding the impact an emergency presentation has on the timing of postoperative chemotherapy and overall prognosis. It is proposed that in order to develop evidence-based treatment protocols, there should be an intestinal NHL registry. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR)-T cell therapy is rapidly advancing as cancer treatment, however, designing an optimal CAR remains challenging. A single-chain variable fragment (scFv) is generally used as CAR targeting moiety, wherein the complementarity-determining regions (CDRs) define its specificity. We report here that the CDR loops can cause CAR clustering, leading to antigen-independent tonic signalling and subsequent CAR-T cell dysfunction. We show via CARs incorporating scFvs with identical framework and varying CDR sequences that CARs may cluster on the T cell surface, which leads to antigen-independent CAR-T cell activation, characterized by increased cell size and interferon (IFN)-γ secretion. This results in CAR-T cell exhaustion, activation-induced cell death and reduced responsiveness to target-antigen-expressing tumour cells. CDR mutagenesis confirms that the CAR-clustering is mediated by CDR-loops. In summary, antigen-independent tonic signalling can be induced by CDR-mediated CAR clustering, which could not be predicted from the scFv sequences, but could be tested for by evaluating the activity of unstimulated CAR-T cells. The challenge of designing chimeric antigen receptor (CAR)-T cells for cancer therapy is not limited to finding targetable cellular proteins, but also in optimising the effector properties. Here authors show that single-chain variable fragment targeting moieties could unpredictably prompt spontaneous CAR-T cell activation via CAR clustering, which argues for empirical screening for tonic signalling. [ABSTRACT FROM AUTHOR]

Interleukin-12 is a pro-inflammatory cytokine which promotes Th1 and cytotoxic T lymphocyte activities, such as Interferon- secretion. For this reason Interleukin-12 could be a powerful therapeutic agent for cancer treatment. However, Interleukin-12 is also excessively toxic. Interleukin-27 is an immunoregulatory cytokine from the Interleukin-12 family, but it is not as toxic as Interleukin-12. In recent years, Interleukin-27 has been considered as a potential anti-tumor agent. Recent experiments in vitro and in vivo have shown that cancer cells transfected with IL-27 activate CD8+ T cells to promote the secretion of anti-tumor cytokines Interleukin-10, although, at the same time, IL-27 inhibits the secretion of Interferon- by CD8+ T cells. In the present paper we develop a mathematical model based on these experimental results. The model involves a dynamic network which includes tumor cells, CD8+ T cells and cytokines Interleukin-27, Interleukin-10 and Interferon-. Simulations of the model show how Interleukin-27 promotes CD8+ T cells to secrete Interleukin-10 to inhibit tumor growth. On the other hand Interleukin-27 inhibits the secretion of Interferon- by CD8+ T cells which somewhat diminishes the inhibition of tumor growth. Our numerical results are in qualitative agreement with experimental data. We use the model to design protocols of IL-27 injections for the treatment of cancer and find that, for some special types of cancer, with a fixed total amount of drug, within a certain range, continuous injection has better efficacy than intermittent injections in reducing the tumor load while the treatment is ongoing, although the decrease in tumor load is only temporary. [ABSTRACT FROM AUTHOR]

Lack of immunogenicity of cancer cells has been considered a major reason for their failure in induction of a tumor specific T cell response. In this paper, we present evidence that decitabine (DAC), a DNA methylation inhibitor that is currently used for the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and other malignant neoplasms, is capable of eliciting an anti-tumor cytotoxic T lymphocyte (CTL) response in mouse EL4 tumor model. C57BL/6 mice with established EL4 tumors were treated with DAC (1.0 mg/kg body weight) once daily for 5 days. We found that DAC treatment resulted in infiltration of IFN-γ producing T lymphocytes into tumors and caused tumor rejection. Depletion of CD8+, but not CD4+ T cells resumed tumor growth. DAC-induced CTL response appeared to be elicited by the induction of CD80 expression on tumor cells. Epigenetic evidence suggests that DAC induces CD80 expression in EL4 cells via demethylation of CpG dinucleotide sites in the promoter of CD80 gene. In addition, we also showed that a transient, low-dose DAC treatment can induce CD80 gene expression in a variety of human cancer cells. This study provides the first evidence that epigenetic modulation can induce the expression of a major T cell co-stimulatory molecule on cancer cells, which can overcome immune tolerance, and induce an efficient anti-tumor CTL response. The results have important implications in designing DAC-based cancer immunotherapy. [ABSTRACT FROM AUTHOR]

In the last decades a new class of therapeutic drugs have been developed that block tumor angiogenesis. These antiangiogenic molecules, which target VEGF or VEGFR, PDGFR, and c-kit, can act not only on endothelial cells but also on immune cells. Some antiangiogenic molecules inhibit the development of immunosuppressive mechanisms developed by the tumors to escape the immune system (such as regulatory T cells, myeloid-derived suppressor cells, and immunosuppressive cytokines). These immunomodulatory effects must be characterized in detail to enable a better prescription of these treatments. In this paper we will focus on the impact of anti-angiogenic drugs on immunosuppression and their potential combination with immunotherapeutic strategies. Interestingly, immune parameters or their modulation during treatment could serve as potential biomarkers of response or resistance to anti-angiogenic therapies. [ABSTRACT FROM AUTHOR]

Advances in cancer therapy have been substantial in terms of molecular understanding of disease mechanisms, however these advances have not translated into increased survival in the majority of cancer types. One unsolved problem in current cancer therapeutics is the substantial immune suppression seen in patients. Conventionally, investigations in this area have focused on antigennonspecific immune suppressive molecules such as cytokines and T cell apoptosis inducing molecules such as Fas ligand. More recently, studies have demonstrated nanovesicle particles termed exosomes are involved not only in stimulation but also inhibition of immunity in physiological conditions. Interestingly, exosomes secreted by cancer cells have been demonstrated to express tumor antigens, as well as immune suppressive molecules such as PD-1L and FasL. Concentrations of exosomes from plasma of cancer patients have been associated with spontaneous T cell apoptosis, which is associated in some situations with shortened survival. In this paper we place the "exosome-immune suppression" concept in perspective of other tumor immune evasion mechanisms. We conclude by discussing a novel therapeutic approach to cancer immune suppression by extracorporeal removal of exosomes using hollow fiber filtration technology. [ABSTRACT FROM AUTHOR]

The activation of T cells plays a central role in antitumor immunity. In order to activate naïve T cells, two key signals are required. Signal one is provided through the T-cell receptor (TCR) while signal two is that of costimulation. The CD28:B7 molecules are one of the best-studied costimulatory pathways, thought to be the main mechanism through which primary T-cell stimulation occurs. However, a number of molecules have been identified which serve to amplify and diversify the T-cell response, following initial T-cell activation. These include the more recently described 4-1BB:4-1BB ligand (4-1BBL) molecules. 4-1BB:4-1BBL are a member of the TNFR:TNF ligand family, which are expressed on T cells and antigen-presenting cells (APCs), respectively. Therapies utilizing the 4-1BB:4-1BBL signaling pathway have been shown to have antitumor effects in a number of model systems. In this paper, we focus on the 4-1BB:4-1BBL costimulatory molecules. In particular, we will describe the structure and function of the 4-1BB molecule, its receptor and how 4-1BB:4-1BBL costimulation has and may be used for the immunotherapy of cancer.Cancer Gene Therapy (2004) 11, 215-226. doi:10.1038/sj.cgt.7700670 Published online 12 December 2003 [ABSTRACT FROM AUTHOR]

During the last decade use of dendritic cells (DC) has moved from murine and in vitro studies to clinical trials as adjuvant in cancer immunotherapy. Here they function as delivery vehicles for exogenous tumor antigens, promoting an efficient antigen presentation. The development of protocols for large-scale generation of dendritic cells for clinical applications has made possible phase I/II studies designed to analyze the toxicity, feasibility and efficacy of this approach. In clinical trials, DC-based vaccination of patients with advanced cancer has in many cases led to immunity and in selected patients to tumor regression. However, the majority of clinical trials are still in phase I, and interpretations are hampered by pronounced variation in study design related to technical aspects of DC preparation, treatment and schedule, monitoring of immune response, and clinically relevant endpoints, including toxicity and response evaluation. This paper aims to review the technical aspects and clinical impact of vaccination trials, focusing on the generation of DC-based vaccines, evaluation of immunologic parameters and design of clinical trials necessary to meet the need for good laboratory and clinical practice. [ABSTRACT FROM AUTHOR]

Immunotherapies including adaptive immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T cells, have developed the treatment of cancer in clinic, and most of them focus on activating T cell immunity. Although these strategies have obtained unprecedented clinical responses, only limited subsets of cancer patients could receive long-term benefits, highlighting the demand for identifying novel targets for the new era of tumor immunotherapy. Innate immunity has been demonstrated to play a determinative role in the tumor microenvironment (TME) and influence the clinical outcomes of tumor patients. A thorough comprehension of the innate immune cells that infiltrate tumors would allow for the development of new therapeutics. In this review, we outline the role and mechanism of innate immunity in TME. Moreover, we discuss innate immunity-based cancer immunotherapy in basic and clinical studies. Finally, we summarize the challenges in sufficiently motivating innate immune responses and the corresponding strategies and measures to improve anti-tumor efficacy. This review could aid the comprehension of innate immunity and inspire the creation of brand-new immunotherapies for the treatment of cancer. [ABSTRACT FROM AUTHOR]

Immunotherapy has revolutionized cancer treatment over the past decade. As it is increasingly introduced into routine clinical practice, immune-related complications have become more frequent. Accurate diagnosis and treatment are essential, with the goal of reduced patient morbidity. This review aims to discuss the various clinical manifestations, diagnosis, treatments, and prognosis of neurologic complications associated with the use of immune checkpoint inhibitors, adoptive T-cell therapies, and T-cell redirecting therapies. We also outline a suggested clinical approach related to the clinical use of these agents. [ABSTRACT FROM AUTHOR]

Primary liver cancer (PLC) that originates in the liver is a malignant tumor with the worst prognosis. Hepatocellular carcinoma (HCC) is the most common type of PLC. Most PLC cases are diagnosed at advanced stages mainly due to their insidious onset and rapid progression. Patients with PLC undergo surgical intervention or localized treatment, but their survival is often affected by its high relapse rate. Medical treatment is the primary option for patients with liver cancer, especially with advanced extrahepatic metastases. Molecular targeted therapy exerts an anti-tumor effect by acting on various signaling pathways involved in molecular pathogenesis; however, high drug resistance and low therapeutic responsiveness of PLC to molecular targets challenge the treatment option. In recent years, after surgical intervention, radiotherapy, chemotherapy, and/or molecular targeted therapy, autologous cell immunotherapy has been adopted for PLC. As a typical autologous cell immunotherapy, CAR T-cell therapy uses genetically modified T cells to express tumor-specific chimeric antigen receptors (CARs). Its targeting ability, persistent nature, and tumor-killing function result in a significant impact on the treatment of hematological tumors. However, no breakthrough has happened in the research specific to the curation of lung cancer, liver cancer, breast cancer, and other common solid tumors. In this context, a combination of molecular targeted therapy and CAR T-cell therapy was used to treat a patient with advanced HCC to achieve a partial remission(PR) and facilitate further liver transplantation. [ABSTRACT FROM AUTHOR]

This paper addresses the need for receptors involved in recirculation of T lymphocytes both during development and during an immune response or inflammation. Some known receptors present on T lymphocytes which are important in maintaining normal T-cell localization and function, i.e. the integrins, LECAMs, LPAM-1 and H-CAM (CD44) are considered in terms of the specificity which they confer on lymphocyte recirculation. A clear understanding of lymphocyte trafficking patterns and of the receptors involved may provide, for example, novel therapies for treatment of malignant cancer, alleviation of damage caused by lymphocytes during inflammatory responses, and targeting of cells to sites of infection. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor (CAR)-T cell therapies for the treatment of hematological malignancies experienced tremendous progress in the last decade. However, essential limitations need to be addressed to further improve efficacy and reduce toxicity to assure CAR-T cell persistence, trafficking to the tumor site, resistance to an hostile tumor microenvironment (TME), and containment of toxicity restricting production of powerful but potentially toxic bioproducts to the TME; the last could be achieved through contextual release upon tumor antigen encounter of factors capable of converting an immune suppressive TME into one conducive to immune rejection. Methods: We created an HER2-targeting CAR-T (RB-312) using a clustered regularly interspaced short palindromic repeats (CRISPR) activation (CRISPRa) system, which induces the expression of the IL-12 heterodimer via conditional transcription of its two endogenous subunits p35 and p40. This circuit includes two lentiviral constructs. The first one (HER2-TEV) expresses an anti-human epidermal growth factor receptor 2 (HER2) CAR single chain variable fragment (scFv), with CD28 and CD3z co-stimulatory domains linked to the tobacco etch virus (TEV) protease and two single guide RNAs (sgRNA) targeting the interleukin (IL)-12A and IL12B transcription start site (TSS), respectively. The second construct (LdCV) encodes linker for activation of T cells (LAT) fused to nuclease-deactivated Streptococcus Pyogenes Cas9 (dCas9)-VP64-p65-Rta (VPR) via a TEV-cleavable sequence (TCS). Activation of the CAR brings HER2-TEV in close proximity to LdCV releasing dCas9 for nuclear localization. This conditional circuit leads to conditional and reversible induction of the IL-12/p70 heterodimer. RB-312 was compared in vitro to controls (cRB-312), lacking the IL-12 sgRNAs and conventional HER2 CAR (convCAR). Results: The inducible CRISPRa system activated endogenous IL-12 expression resulting in enhanced secondary interferon (FN)-γ production, cytotoxicity, and CAR-T proliferation in vitro, prolonged in vivo persistence and greater suppression of HER2+ FaDu oropharyngeal cancer cell growth compared to the conventional CAR-T cell product. No systemic IL-12 was detected in the peripheral circulation. Moreover, the combination with programmed death ligand (PD-L1) blockade demonstrated robust synergistic effects. Conclusions: RB-312, the first clinically relevant product incorporating a CRISPRa system with non-gene editing and reversible upregulation of endogenous gene expression that promotes CAR-T cells persistence and effectiveness against HER2-expressing tumors. The autocrine effects of reversible, nanoscale IL-12 production limits the risk of off-tumor leakage and systemic toxicity. [ABSTRACT FROM AUTHOR]

Low response rate and treatment resistance are frequent problems in the immunotherapy of tumors, resulting in the unsatisfactory therapeutic effects. Ferroptosis is a form of cell death characterized by the accumulation of lipid peroxides. In recent years, it has been found that ferroptosis may be related to the treatment of cancer. Various immune cells (including macrophages and CD8+ T cells) can induce ferroptosis of tumor cells, and synergistically enhance the anti-tumor immune effects. However, the mechanisms are different for each cell types. DAMP released in vitro by cancer cells undergoing ferroptosis lead to the maturation of dendritic cells, cross-induction of CD8+ T cells, IFN-g production andM1macrophage production. Thus, it activates the adaptability of the tumor microenvironment and forms positive feedback of the immune response. It suggests that induction of ferroptosis may contribute to reducing resistance of cancer immunotherapy and has great potential in cancer therapy. Further research into the link between ferroptosis and tumor immunotherapy may offer hope for those cancers that are difficult to treat. In this review, we focus on the role of ferroptosis in tumor immunotherapy, explore the role of ferroptosis in various immune cells, and discuss potential applications of ferroptosis in tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Non‐small cell lung cancer is the most prevalent lung cancer, and almost three‐fourths of patients are diagnosed in the advanced stage directly. In this stage, chemotherapy gives only a 15% 5‐year survival rate. As people have varied symptoms and reactions to a specific cancer type, treatment for the tumor is likely to fall short, complicating cancer therapy. Immunotherapy is a breakthrough treatment involving drugs targeting novel immune checkpoint inhibitors like CTLA‐4 and PD‐1/PD‐L1, along with combination therapies. In addition, the utility of engineered CAR‐T and CAR‐NK cells can be an effective strategy to promote the immune response against tumors. The concept of personalized cancer vaccines with the discovery of neoantigens loaded on dendritic cell vectors can also be an effective approach to cure cancer. Advances in genetic engineering tools like CRISPR/Cas9‐mediated gene editing of T cells to enhance their effector function is another ray of hope. This review aims to provide an overview of recent developments in cancer immunotherapy, which can be used in first‐ and second‐line treatments in the clinical space. Further, the intervention of artificial intelligence to detect cancer tumors at an initial stage with the help of machine learning techniques is also explored. [ABSTRACT FROM AUTHOR]

Background: Preclinical in vivo studies using small animals are considered crucial in translational cancer research and clinical implementation of novel treatments. This is of paramount relevance in radiobiology, especially for any technological developments permitted to deliver high doses in single or oligo-fractionated regimens, such as stereotactic ablative radiotherapy (SABR). In this context, clinical success in cancer treatment needs to be guaranteed, sparing normal tissue and preventing the potential spread of disease or local recurrence. In this work we introduce a new dose-response relationship based on relevant publications concerning preclinical models with regard to delivered dose, fractionation schedule and occurrence of biological effects on non-irradiated tissue, abscopal effects. Methods: We reviewed relevant publications on murine models and the abscopal effect in radiation cancer research following PRISMA methodology. In particular, through a log-likelihood method, we evaluated whether the occurrence of abscopal effects may be related to the biologically effective dose (BED). To this aim, studies accomplished with different tumor histotypes were considered in our analysis including breast, colon, lung, fibrosarcoma, pancreas, melanoma and head and neck cancer. For all the tumors, the α / β ratio was assumed to be 10 Gy, as generally adopted for neoplastic cells. Results: Our results support the hypothesis that the occurrence rate of abscopal effects in preclinical models increases with BED. In particular, the probability of revealing abscopal effects is 50% when a BED of 60 Gy is generated. Conclusion: Our study provides evidence that SABR treatments associated with high BEDs could be considered an effective strategy in triggering the abscopal effect, thus shedding light on the promising outcomes revealed in clinical practice. [ABSTRACT FROM AUTHOR]

With the rapid growth of advanced nanoengineering strategies, there are great implications for therapeutic immunostimulators formulated in nanomaterials to combat cancer. It is crucial to direct immunostimulators to the right tissue and specific immune cells at the right time, thereby orchestrating the desired, potent, and durable immune response against cancer. The flexibility of nanoformulations in size, topology, softness, and multifunctionality allows precise regulation of nano‐immunological activities for enhanced therapeutic effect. To grasp the modulation of immune response, research efforts are needed to understand the interactions of immune cells at lymph organs and tumor tissues, where the nanoformulations guide the immunostimulators to function on tissue specific subsets of immune cells. In this review, recent advanced nanoformulations targeting specific subset of immune cells, such as dendritic cells (DCs), T cells, monocytes, macrophages, and natural killer (NK) cells are summarized and discussed, and clinical development of nano‐paradigms for targeted cancer immunotherapy is highlighted. Here the focus is on the targeting nanoformulations that can passively or actively target certain immune cells by overcoming the physiobiological barriers, instead of directly injecting into tissues. The opportunities and remaining obstacles for the clinical translation of immune cell targeting nanoformulations in cancer therapy are also discussed. [ABSTRACT FROM AUTHOR]

Distinct thermal therapies have been used for cancer therapy. For hyperthermia (HT) treatment the tumour tissue is heated to temperatures between 39 and 45°C, while during ablation (AB) temperatures above 50°C are achieved. HT is commonly used in combination with different treatment modalities, such as radiotherapy and chemotherapy, for better clinical outcomes. In contrast, AB is usually used as a single modality for direct tumour cell killing. Both thermal therapies have been shown to result in cytotoxicity as well as immune response stimulation. Immunogenic responses encompass the innate and adaptive immune systems and involve the activation of macrophages, dendritic cells, natural killer cells and T cells. Several heat technologies are used, but great interest arises from nanotechnology‐based thermal therapies. Spontaneous tumours in dogs can be a model for cancer immunotherapies with several advantages. In addition, veterinary oncology represents a growing market with an important demand for new therapies. In this review, we will focus on nanoparticle‐mediated thermal‐induced immunogenic effects, the beneficial potential of integrating thermal nanomedicine with immunotherapies and the results of published works with thermotherapies for cancer using dogs with spontaneous tumours, highlighting the works that evaluated the effect on the immune system in order to show dogs with spontaneous cancer as a good model for evaluated the immunomodulatory effect of nanoparticle‐mediated thermal therapies. [ABSTRACT FROM AUTHOR]

Adoptive cellular therapy with chimeric antigen receptor (CAR) T cells has emerged as a potential novel treatment for various cancers. In this study, we have generated CAR T cells targeting mucin-1 (MUC1), which is an aberrantly glycosylated antigen overexpressed on breast cancer cells. Two different signaling domains, including CD28 and 41BB, were incorporated and directly compared the superiority of different costimulatory signals. Two different CAR MUC1 constructs were transduced into primary T cells and evaluated their characteristics and antitumor activities against MUC1+ cancer cells. CAR MUC1 T cells showed high transduction efficiency and antigen specificity toward MUC1+ cancer cell lines and primary breast cancer cells. When coculturing with target cells, the transduced cells exhibited potent antitumor activity in vitro and secrete proinflammatory cytokines. Upon antigen stimulation, incorporation of the 41BB signaling domain was able to improve T cell proliferation and reduce surface PD1 expression and the upregulation of suppressive cytokines, when compared with CAR MUC1 containing the CD28 domain. Our findings show that CAR T cell targeting MUC1 can be effective against MUC1+ breast cancer cell and support the further development of CAR MUC1 T cells containing 41BB signaling in preclinical and clinical studies of breast cancer treatment. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR)-engineered T (CAR-T) cells have obtained prominent achievement in the clinical immunotherapy of hematological malignant tumors, leading to a rapid development of cellular immunotherapy in cancer treatment. Scientists are also aware of the prospective advantages of CAR engineering in cellular immunotherapy. Due to various limitations such as the serious side effects of CAR-T therapy, researchers began to investigate other immune cells for CAR modification. Natural killer (NK) cells are critical innate immune cells with the characteristic of non-specifically recognizing target cells and with the potential to become "off-the-shelf" products. In recent years, many preclinical studies on CAR-engineered NK (CAR-NK) cells have shown their remarkable efficacy in cancer therapy and their superiority over autologous CAR-T cells. In this review, we summarize the generation, mechanisms of anti-tumor activity and unique advantages of CAR-NK cells, and then analyze some challenges and recent clinical trials about CAR-NK cells therapy. We believe that CAR-NK therapy is a promising prospect for cancer immunotherapy in the future. [ABSTRACT FROM AUTHOR]

Graph: Graphical Abstract The registry data presented by Mahmood et al.9 demonstrate that CAR T-cell recipients experience severe cardiac events (SCEs) at significant rates. Adoptive T-cell transfer therapies represent a therapeutic option with high initial response rates for an increasing spectrum of patients. [Extracted from the article]

Identifying a strategy with strong efficacy against non-inflamed tumours is vital in cancer immune therapy. ERY974 is a humanized IgG4 bispecific T cell-redirecting antibody that recognizes glypican-3 and CD3. Here we examine the combination effect of ERY974 and chemotherapy (paclitaxel, cisplatin, and capecitabine) in the treatment of non-inflamed tumours in a xenograft model. ERY974 monotherapy shows a minor antitumour effect on non-inflamed NCI-H446 xenografted tumours, as infiltration of ERY974-redirected T cells is limited to the tumour-stromal boundary. However, combination therapy improves efficacy by promoting T cell infiltration into the tumour centre, and increasing ERY974 distribution in the tumour. ERY974 increases capecitabine-induced cytotoxicity by promoting capecitabine conversion to its active form by inducing thymidine phosphorylase expression in non-inflamed MKN45 tumour through ERY974-induced IFNγ and TNFα in T cells. We show that ERY974 with chemotherapy synergistically and reciprocally increases antitumour efficacy, eradicating non-inflamed tumours. T-cell redirecting bispecific antibodies have emerged as therapeutic agents to promote T-cell mediated killing of tumor cells. Here the authors show that a combination of chemotherapy and ERY974, a bispecific antibody that targets glypican-3 and CD3, facilitates T cell infiltration and promotes anti-tumor responses also in non-inflamed tumors. [ABSTRACT FROM AUTHOR]

Advances in immuno‐oncology have provided a variety of novel therapeutics that harness the innate immune system to identify and destroy neoplastic cells. It is noteworthy that acceptable safety profiles accompany the development of these targeted therapies, which result in efficacious cancer treatment with higher survival rates and lower toxicities. Adoptive cellular therapy (ACT) has shown promising results in inducing sustainable remissions in patients suffering from refractory diseases. Two main types of ACT include engineered Chimeric Antigen Receptor (CAR) T cells and T cell receptor (TCR) T cells. The application of these immuno‐therapies in the last few years has been successful and has demonstrated a safe and rapid treatment regimen for solid and non‐solid tumors. The current review presents an insight into the clinical pharmacology aspects of immuno‐therapies, especially CAR‐T cells. Here, we summarize the current knowledge of TCR and CAR‐T cell immunotherapy with particular focus on the structure of CAR‐T cells, the effects and toxicities associated with these therapies in clinical trials, risk mitigation strategies, dose selection approaches, and cellular kinetics. Finally, the quantitative approaches and modeling techniques used in the development of CAR‐T cell therapies are described. [ABSTRACT FROM AUTHOR]

Nonreplicating type I uracil auxotrophic mutants of Toxoplasma gondii possess a potent ability to activate therapeutic immunity to established solid tumors by reversing immune suppression in the tumor microenvironment. Here we engineered targeted deletions of parasite secreted effector proteins using a genetically tractable Δku80 vaccine strain to show that the secretion of specific rhoptry (ROP) and dense granule (GRA) proteins by uracil auxotrophic mutants of T. gondii in conjunction with host cell invasion activates antitumor immunity through host responses involving CD8α+ dendritic cells, the IL-12/interferon-gamma (IFN-γ) TH1 axis, as well as CD4+ and CD8+ T cells. Deletion of parasitophorous vacuole membrane (PVM) associated proteins ROP5, ROP17, ROP18, ROP35 or ROP38, intravacuolar network associated dense granule proteins GRA2 or GRA12, and GRA24 which traffics past the PVM to the host cell nucleus severely abrogated the antitumor response. In contrast, deletion of other secreted effector molecules such as GRA15, GRA16, or ROP16 that manipulate host cell signaling and transcriptional pathways, or deletion of PVM associated ROP21 or GRA3 molecules did not affect the antitumor activity. Association of ROP18 with the PVM was found to be essential for the development of the antitumor responses. Surprisingly, the ROP18 kinase activity required for resistance to IFN-γ activated host innate immunity related GTPases and virulence was not essential for the antitumor response. These data show that PVM functions of parasite secreted effector molecules, including ROP18, manipulate host cell responses through ROP18 kinase virulence independent mechanisms to activate potent antitumor responses. Our results demonstrate that PVM associated rhoptry effector proteins secreted prior to host cell invasion and dense granule effector proteins localized to the intravacuolar network and host nucleus that are secreted after host cell invasion coordinately control the development of host immune responses that provide effective antitumor immunity against established ovarian cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Photodynamic therapy (PDT) by means of a photosensitizer is a clinically used therapeutic treatment in a variety of cancers. To further improve the anti-cancer efficiency of PDT, combination therapy with immune agents is a promising option. In this study, we used a viral vaccine as the immune therapeutic partner for PDT. We studied the biological properties of single and combined modalities. Our research suggests that combination therapy enhances innate and humoral immunity, improved survival, and generated a long-term memory capacity in the MC-38 murine colorectal tumor model to prevent a recurrence. Photodynamic therapy (PDT), which combines light and oxygen with a photosensitizer to induce reactive oxygen species (ROS)-mediated killing of primary tumor cells, benefits from non-invasive properties and its negligible toxicity to surrounding healthy tissues. In this study, we have shown that the second-generation photosensitizer FOSCAN can be internalized by tumor cells and effectively induce tumor cell death when exposed to laser irradiation in vitro. In addition, these dying tumor cells can be phagocytosed by dendritic cells and lead to their activation and maturation as assessed by in vitro co-culture models. While PDT induces immunogenic tumor cell apoptosis, its application for the treatment of tumors located in deep tissues and advanced malignancies has been limited. In this study, we demonstrate that hepatitis B core virus-like particles (HBc VLPs) can serve as a vaccine to enhance PDT-induced anti-cancer immunity by priming humoral immune responses and inducing CD8+ T cell responses. The combination of PDT and HBc VLPs increased the survival rate of MC-38 tumor-bearing mice to 55%, compared to 33% in PDT alone and no tumor-free mice in vaccine alone. Moreover, the combination effectively prevented tumor recurrence in vivo through enhanced immune memory T cells after therapy. Therefore, as both are clinically approved techniques, this combination provides a promising strategy for cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Previous studies have revealed conflicting findings concerning the efficacy of radiotherapy (RT) and radiochemotherapy (RCT) in IE/IIE extranodal nasal-type natural killer/T cell lymphoma (ENKTL). In this study, we conducted a comprehensive meta-analysis to address this issue. Methods: We systematically searched PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), EmBase, BISOS, Clinical Trials and some Chinese databases for relevant studies, and 2 prospective and 15 retrospective studies involving a total of 1595 patients met our inclusion criteria. Results: The meta-analysis showed no significant differences in complete remission (CR) [odds ratio (OR) 0.85, 95% confidence interval (CI) 0.42–1.72, p = 0.65], 5-year overall survival (OS) [hazard ratio (HR) 1.11, 95% CI 0.85–1.45, p = 0.43] and 5-year progression free survival (PFS) (HR 1.07, 95% CI 0.75–1.53, p = 0.70) in patients who received RT versus RCT. Furthermore, the addition of CT decreased neither systemic failure (SL) (OR 0.75, 95% CI 0.47–1.21, p = 0.24) nor locoregional failure (LF) (OR 1.17, 95% CI 0.68–2.01, p = 0. 57). Conclusions: RCT did not have an obvious advantage over RT for treating IE/IIE ENKTL. [ABSTRACT FROM AUTHOR]

Tumor immune escape has emerged as the most significant barrier to cancer therapy. A thorough understanding of tumor immune escape therapy mechanisms is critical for further improving clinical treatment strategies. Currently, research indicates that combining several immunotherapies can boost antitumor efficacy and encourage T cells to play a more active part in the immune assault. To generate a more substantial therapeutic impact, it can establish an ideal tumor microenvironment (TME), encourage T cells to play a role, prevent T cell immune function reversal, and minimize tumor immune tolerance. In this review, we will examine the mechanisms of tumor immune escape and the limits of tumor immune escape therapy, focusing on the current development of immunotherapy based on tumor immune escape mechanisms. Individualized tumor treatment is becoming increasingly apparent as future treatment strategies. In addition, we forecast the future research direction of cancer and the clinical approach for cancer immunotherapy. It will serve as a better reference for researchers working in cancer therapy research. [ABSTRACT FROM AUTHOR]

As a revolutionary cancer treatment, the chimeric antigen receptor (CAR) T cell therapy suffers from complications such as cytokine release syndromes and T cell exhaustion. Their mitigation desires controllable activation of CAR‐T cells that is achievable through regulatory display of CARs. By embedding the hepatitis C virus NS3 protease (HCV‐NS3) between the single‐chain variable fragment (scFv) and the hinge domain, we showed that the display of anti‐CD19 scFv on CAR‐T cells was positively correlated to the presence of a clinical HCV‐NS3 inhibitor asunaprevir (ASV). This novel CAR design that allows the display of anti‐CD19 scFv in the presence of ASV and its removal in the absence of ASV creates a practically reversible chemical switch. We demonstrated that the intact CAR on T cells can be repeatedly turned on and off by controlling the presence of ASV in a dose dependent manner both in vitro and in vivo, which enables delicate modulation of CAR‐T activation during cancer treatment. [ABSTRACT FROM AUTHOR]

In people living with HIV (PLWH) on antiretroviral therapy (ART), virus persists in a latent form where there is minimal transcription or protein expression. Latently infected cells are a major barrier to curing HIV. Increasing HIV transcription and viral production in latently infected cells could facilitate immune recognition and reduce the pool of infected cells that persist on ART. Given that programmed cell death protein 1 (PD-1) expressing CD4+ T cells are preferentially infected with HIV in PLWH on ART, we aimed to determine whether administration of antibodies targeting PD-1 would reverse HIV latency in vivo. We therefore evaluated the impact of intravenous administration of pembrolizumab every 3 weeks on HIV latency in 32 PLWH and cancer on ART. After the first infusion of anti–PD-1, we observed a median 1.32-fold increase in unspliced HIV RNA and 1.61-fold increase in unspliced RNA:DNA ratio in sorted blood CD4+ T cells compared to baseline. We also observed a 1.65-fold increase in plasma HIV RNA. The frequency of CD4+ T cells with inducible virus evaluated using the tat/rev limiting dilution assay was higher after 6 cycles compared to baseline. Phylogenetic analyses of HIV env sequences in a participant who developed low concentrations of HIV viremia after 6 cycles of pembrolizumab did not demonstrate clonal expansion of HIV-infected cells. These data are consistent with anti–PD-1 being able to reverse HIV latency in vivo and support the rationale for combining anti–PD-1 with other interventions to reduce the HIV reservoir. PD-1 blockade for HIV: Strategies to target and reverse the latent HIV reservoir are required to cure HIV. Because CD4+ T cells expressing programmed cell death protein 1 (PD-1) are preferentially infected with HIV in an individual on antiretroviral therapy, PD-1 is an attractive target to manipulate the latent reservoir. To this end, Uldrick et al. measured the impact of anti–PD-1 treatment with pembrolizumab on the HIV reservoir in 32 individuals living with HIV on suppressive antiretroviral therapy and diagnosed with cancer. They observed evidence of increased unspliced HIV RNA and of the unspliced RNA:DNA ratio, consistent with anti–PD-1 treatment having the potential to reverse HIV latency. Further studies are needed to evaluate the dose and frequency of anti–PD-1 treatment required for latency reversal. [ABSTRACT FROM AUTHOR]

T cell receptor-engineered T cell (TCR-T) therapy is free from the limit of surface antigen expression of the target cells, which is a potential cellular immunotherapy for cancer treatment. Significant advances in the treatment of hematologic malignancies with cellular immunotherapy have aroused the interest of researchers in the treatment of solid tumors. Nevertheless, the overall efficacy of TCR-T cell immunotherapy in solid tumors was not significantly high when compared with hematological malignancies. In this article, we pay attention to the barriers of TCR-T cell immunotherapy for solid tumors, as well as the strategies affecting the efficacy of TCR-T cell immunotherapy. To provide some reference for researchers to better overcome the impact of TCR-T cell efficiency in solid tumors. [ABSTRACT FROM AUTHOR]

Cancer has a major impact on society across the world. There are different strategies such as chemotherapy, radiotherapy, surgical intervention, and immunotherapy for treating carcinoma. Nowadays, phytochemicals are gaining a lot of interest for their chemopreventive action in the treatment of carcinoma. Recent investigations demonstrated that extract/bioactive compounds from Ananas comosus (A. comosus) resulting in the reduction of inflammatory cytokines release and proliferation of T-cell was also inhibited. Therefore, A. comosus nanoemulsion have been proposed in the treatment of cancer. Based on previous literature, we have postulated that nanoemulsion of A. comosus may be beneficial because of its safety and efficacy profile. [ABSTRACT FROM AUTHOR]

Objective: Patients with non-small cell lung cancer (NSCLC) respond differently to cytokine-induced killer cell (CIK) treatment. Therefore, potential prognostic markers to identify patients who would benefit from CIK treatment must be elucidated. The current research aimed at identifying predictive prognostic markers for efficient CIK treatment of patients with NSCLC. Methods: Patients histologically diagnosed with NSCLC were enrolled from the Tianjin Medical University Cancer Institute and Hospital. We performed whole-exome sequencing (WES) on the tumor tissues and paired adjacent benign tissues collected from 50 patients with NSCLC, and RNA-seq on tumor tissues of 17 patients with NSCLC before CIK immunotherapy treatment. Multivariate Cox proportional hazard regression analysis was used to analyze the association between clinical parameters and prognostic relevance. WES and RNA-seq data between lung squamous cell carcinoma (SCC) and adenocarcinoma (Aden) were analyzed and compared. Results: The pathology subtype of lung cancer was the most significantly relevant clinical parameter associated with DFS, as analyzed by multivariate Cox proportional hazard regression (P = 0.031). The patients with lung SCC showed better CIK treatment efficacy and extended DFS after CIK treatment. Relatively low expression of HLA class II genes and checkpoint molecules, and less immunosuppressive immune cell infiltration were identified in the patients with lung SCC. Conclusions: Coordinated suppression of the expression of HLA class II genes and checkpoint molecules, as well as less immune suppressive cell infiltration together contributed to the better CIK treatment efficacy in lung SCC than lung Aden. [ABSTRACT FROM AUTHOR]