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Background: Neoantigen vaccines can induce or enhance highly specific antitumor immune responses with minimal risk of autoimmunity. We have developed a neoantigen DNA vaccine platform capable of efficiently presenting both HLA class I and II epitopes and performed a phase 1 clinical trial in triple-negative breast cancer patients with persistent disease on surgical pathology following neoadjuvant chemotherapy, a patient population at high risk of disease recurrence. Methods: Expressed somatic mutations were identified by tumor/normal exome sequencing and tumor RNA sequencing. The pVACtools software suite of neoantigen prediction algorithms was used to identify and prioritize cancer neoantigens and facilitate vaccine design for manufacture in an academic GMP facility. Neoantigen DNA vaccines were administered via electroporation in the adjuvant setting (i.e., following surgical removal of the primary tumor and completion of standard of care therapy). Vaccines were monitored for safety and immune responses via ELISpot, intracellular cytokine production via flow cytometry, and TCR sequencing. Results: Eighteen subjects received three doses of a neoantigen DNA vaccine encoding on average 11 neoantigens per patient (range 4–20). The vaccinations were well tolerated with relatively few adverse events. Neoantigen-specific T cell responses were induced in 14/18 patients as measured by ELISpot and flow cytometry. At a median follow-up of 36 months, recurrence-free survival was 87.5% (95% CI: 72.7–100%) in the cohort of vaccinated patients. Conclusion: Our study demonstrates neoantigen DNA vaccines are safe, feasible, and capable of inducing neoantigen-specific immune responses. Clinical trial registration number: NCT02348320. [ABSTRACT FROM AUTHOR]

Simple Summary: Gliomas are diverse types of tumors originating from glial cells. Among these tumors, glioblastoma multiforme (GBM) is the most aggressive form and has a poor prognosis and high mortality rate, with treatment success largely influenced by patient age, tumor location, and genetic mutations. Glioma cells can reprogram their tumor microenvironment (TME) to support tumor proliferation and survival, interacting with other cells through cytokines and growth factors. The TME of gliomas is highly heterogeneous, complex, and often immunosuppressive, interfering with treatment strategies. Current therapeutic strategies focus on modulating immune cell activities and enhancing anti-tumor responses. T-cell-based immunotherapies are being explored to target glioma cells. These include chimeric antigen receptor (CAR) T-cell therapy and T-cell receptor (TCR) therapy, which involve engineering T cells to recognize tumor antigens. However, these therapies face multiple challenges including tumor heterogeneity, immunosuppression by T cell exhaustion, and altered antigen presentation, etc. Future research should focus on boosting T cell functions, targeting immune checkpoints, and developing more effective delivery methods to improve treatment outcomes for glioma patients. Glioma is known for its immunosuppressive microenvironment, which makes it challenging to target through immunotherapies. Immune cells like macrophages, microglia, myeloid-derived suppressor cells, and T lymphocytes are known to infiltrate the glioma tumor microenvironment and regulate immune response distinctively. Among the variety of immune cells, T lymphocytes have highly complex and multifaceted roles in the glioma immune landscape. T lymphocytes, which include CD4+ helper and CD8+ cytotoxic T cells, are known for their pivotal roles in anti-tumor responses. However, these cells may behave differently in the highly dynamic glioma microenvironment, for example, via an immune invasion mechanism enforced by tumor cells. Therefore, T lymphocytes play dual roles in glioma immunity, firstly by their anti-tumor responses, and secondly by exploiting gliomas to promote immune invasion. As an immunosuppression strategy, glioma induces T-cell exhaustion and suppression of effector T cells by regulatory T cells (Tregs) or by altering their signaling pathways. Further, the expression of immune checkpoint inhibitors on the glioma cell surface leads to T cell anergy and dysfunction. Overall, this dynamic interplay between T lymphocytes and glioma is crucial for designing more effective immunotherapies. The current review provides detailed knowledge on the roles of T lymphocytes in the glioma immune microenvironment and helps to explore novel therapeutic approaches to reinvigorate T lymphocytes. [ABSTRACT FROM AUTHOR]

Highlights: We classified the carriers that built cancer nanovaccines, discussed their diversified applications and coincidently compared their advantages and disadvantages. Various cellular targets that guide the design and engineering of cancer nanovaccines are categorized and their characteristics and benefits are highlighted. The clinical cases and encountered challenges in cancer nanovaccines are discussed, during which reasonable solutions and future research direction are provided. Vaccinations are essential for preventing and treating disease, especially cancer nanovaccines, which have gained considerable interest recently for their strong anti-tumor immune capabilities. Vaccines can prompt the immune system to generate antibodies and activate various immune cells, leading to a response against tumor tissues and reducing the negative effects and recurrence risks of traditional chemotherapy and surgery. To enhance the flexibility and targeting of vaccines, nanovaccines utilize nanotechnology to encapsulate or carry antigens at the nanoscale level, enabling more controlled and precise drug delivery to enhance immune responses. Cancer nanovaccines function by encapsulating tumor-specific antigens or tumor-associated antigens within nanomaterials. The small size of these nanomaterials allows for precise targeting of T cells, dendritic cells, or cancer cells, thereby eliciting a more potent anti-tumor response. In this paper, we focus on the classification of carriers for cancer nanovaccines, the roles of different target cells, and clinically tested cancer nanovaccines, discussing strategies for effectively inducing cytotoxic T lymphocytes responses and optimizing antigen presentation, while also looking ahead to the translational challenges of moving from animal experiments to clinical trials. [ABSTRACT FROM AUTHOR]

Stem-like CD8+ T cells (TSL) are a subset of immune cells with superior persistence and antitumor immunity. They are TCF1+ PD-1+ and important for the expansion of tumor specific CD8+ T cells in response to checkpoint blockade immunotherapy. In acute infections, naïve CD8+ T cells differentiate into effector and memory CD8+ T cells; in cancer and chronic infections, persistent antigen stimulation can lead to T cell exhaustion. Recent studies have highlighted the dichotomy between late dysfunctional (or exhausted) T cells (TLD) that are TCF1-- PD-1+ and self-renewing TCF1+ PD-1+ TSL from which they derive. TCF1+ TSL cells are considered to have stem cell-like properties akin to memory T cell populations and can give rise to cytotoxic effector and transitory T cell phenotypes (TTE) which mediate tumor control. In this review, we will discuss recent advances made in research on the formation and expansion of TSL, as well as distinct niches required for their differentiation and maintenance in the setting of cancer. We will also discuss potential strategies to generate these cells, with clinical implications for stemness enhancement in vaccine design, immune checkpoint blockade (ICB), and adoptive T cell therapies. [ABSTRACT FROM AUTHOR]

Slowing and/or reversing brain ageing may alleviate cognitive impairments. Previous studies have found that exercise may mitigate cognitive decline, but the mechanisms underlying this remain largely unclear. Here we provide unbiased analyses of single‐cell RNA sequencing data, showing the impacts of exercise and ageing on specific cell types in the mouse hippocampus. We demonstrate that exercise has a profound and selective effect on aged microglia, reverting their gene expression signature to that of young microglia. Pharmacologic depletion of microglia further demonstrated that these cells are required for the stimulatory effects of exercise on hippocampal neurogenesis but not cognition. Strikingly, allowing 18‐month‐old mice access to a running wheel did by and large also prevent and/or revert T cell presence in the ageing hippocampus. Taken together, our data highlight the profound impact of exercise in rejuvenating aged microglia, associated pro‐neurogenic effects and on peripheral immune cell presence in the ageing female mouse brain. [ABSTRACT FROM AUTHOR]

Antigen presentation is a crucial mechanism that drives the T cell-mediated immune response and the development of Multiple Sclerosis (MS). Genetic alterations within the highly variable Major Histocompatibility Complex Class II (MHC II) have been proven to result in significant changes in the molecular basis of antigen presentation and the clinical course of patients with both Adult-Onset MS (AOMS) and Pediatric-Onset MS (POMS). Among the numerous polymorphisms of the Human Leucocyte Antigens (HLA), within MHC II complex, HLA-DRB1*15:01 has been labeled, in Caucasian ethnic groups, as a high-risk allele for MS due to the ability of its structure to increase affinity to Myelin Basic Protein (MBP) epitopes. This characteristic, among others, in the context of the trimolecular complex or immunological synapsis, provides the foundation for autoimmunity triggered by environmental or endogenous factors. As with all professional antigen presenting cells, macrophages are characterized by the expression of MHC II and are often implicated in the formation of MS lesions. Increased presence of M1 macrophages in MS patients has been associated both with progression and onset of the disease, each involving separate but similar mechanisms. In this critical narrative review, we focus on macrophages, discussing how HLA genetic alterations can promote dysregulation of this population's homeostasis in the periphery and the Central Nervous System (CNS). We also explore the potential interconnection in observed pathological macrophage mechanisms and the function of the diverse structure of HLA alleles in neurodegenerative CNS, seen in MS, by comparing available clinical with molecular data through the prism of HLA-immunogenetics. Finally, we discuss available and experimental pharmacological approaches for MS targeting the trimolecular complex that are based on cell phenotype modulation and HLA genotype involvement and try to reveal fertile ground for the potential development of novel drugs. [ABSTRACT FROM AUTHOR]

Vascular co-option is a consequence of the direct interaction between perivascular cells, known as pericytes (PCs), and glioblastoma multiforme (GBM) cells (GBMcs). This process is essential for inducing changes in the pericytes' anti-tumoral and immunoreactive phenotypes. Starting from the initial stages of carcinogenesis in GBM, PCs conditioned by GBMcs undergo proliferation, acquire a pro-tumoral and immunosuppressive phenotype by expressing and secreting immunosuppressive molecules, and significantly hinder the activation of T cells, thereby facilitating tumor growth. Inhibiting the pericyte (PC) conditioning mechanisms in the GBM tumor microenvironment (TME) results in immunological activation and tumor disappearance. This underscores the pivotal role of PCs as a key cell in the TME, responsible for tumor-induced immunosuppression and enabling GBM cells to evade the immune system. Other cells within the TME, such as tumor-associated macrophages (TAMs) and microglia, have also been identified as contributors to this immunomodulation. In this paper, we will review the role of these three cell types in the immunosuppressive properties of the TME. Our conclusion is that the cellular heterogeneity of immunocompetent cells within the TME may lead to the misinterpretation of cellular lineage identification due to different reactive stages and the identification of PCs as TAMs. Consequently, novel therapies could be developed to disrupt GBM-PC interactions and/or PC conditioning through vascular co-option, thereby exposing GBMcs to the immune system. [ABSTRACT FROM AUTHOR]

Pharmacodynamic assessment of T-cell-based cancer immunotherapies often focus on detecting rare circulating T-cell populations. The therapy-induced immune cells in blood-derived clinical samples are often present in very low frequencies and with the currently available T-cell analytical assays, amplification of the cells of interest prior to analysis is often required. Current approaches aiming to enrich antigen-specific T cells from human Peripheral Blood Mononuclear Cells (PBMCs) depend on in vitro culturing in presence of their cognate peptides and cytokines. In the present work, we improved a standard, publicly available protocol for T-cell immune analyses based on the in vitro expansion of T cells. We used PBMCs from healthy subjects and well-described viral antigens as a model system for optimizing the experimental procedures and conditions. Using the standard protocol, we first demonstrated significant enrichment of antigen-specific T cells, even when their starting frequency ex vivo was low. Importantly, this amplification occurred with high specificity, with no or neglectable enrichment of irrelevant T-cell clones being observed in the cultures. Testing of modified culturing timelines suggested that the protocol can be adjusted accordingly to allow for greater cell yield with strong preservation of the functionality of antigen-specific T cells. Overall, our work has led to the refinement of a standard protocol for in vitro stimulation of antigen-specific T cells and highlighted its reliability and reproducibility. We envision that the optimized protocol could be applied for longitudinal monitoring of rare bloodcirculating T cells in scenarios with limited sample material. [ABSTRACT FROM AUTHOR]

Background: Glioma is a highly heterogeneous brain tumor categorized into World Health Organization (WHO) grades 1–4 based on its malignancy. The suppressive immune microenvironment of glioma contributes significantly to unfavourable patient outcomes. However, the cellular composition and their complex interplays within the glioma environment remain poorly understood, and reliable prognostic markers remain elusive. Therefore, in-depth exploration of the tumor microenvironment (TME) and identification of predictive markers are crucial for improving the clinical management of glioma patients. Results: Our analysis of single-cell RNA-sequencing data from glioma samples unveiled the immunosuppressive role of tumor-associated macrophages (TAMs), mediated through intricate interactions with tumor cells and lymphocytes. We also discovered the heterogeneity within TAMs, among which a group of suppressive TAMs named TAM-SPP1 demonstrated a significant association with Epidermal Growth Factor Receptor (EGFR) amplification, impaired T cell response and unfavourable patient survival outcomes. Furthermore, by leveraging genomic and transcriptomic data from The Cancer Genome Atlas (TCGA) dataset, two distinct molecular subtypes with a different constitution of TAMs, EGFR status and clinical outcomes were identified. Exploiting the molecular differences between these two subtypes, we developed a four-gene-based prognostic model. This model displayed strong associations with an elevated level of suppressive TAMs and could be used to predict anti-tumor immune response and prognosis in glioma patients. Conclusion: Our findings illuminated the molecular and cellular mechanisms that shape the immunosuppressive microenvironment in gliomas, providing novel insights into potential therapeutic targets. Furthermore, the developed prognostic model holds promise for predicting immunotherapy response and assisting in more precise risk stratification for glioma patients. [ABSTRACT FROM AUTHOR]

Glioblastoma (GB) stands out as the most prevalent and lethal form of brain cancer. Although great efforts have been made by clinicians and researchers, no significant improvement in survival has been achieved since the Stupp protocol became the standard of care (SOC) in 2005. Despite multimodality treatments, recurrence is almost universal with survival rates under 2 years after diagnosis. Here, we discuss the recent progress in our understanding of GB pathophysiology, in particular, the importance of glioma stem cells (GSCs), the tumor microenvironment conditions, and epigenetic mechanisms involved in GB growth, aggressiveness and recurrence. The discussion on therapeutic strategies first covers the SOC treatment and targeted therapies that have been shown to interfere with different signaling pathways (pRB/CDK4/RB1/P16ink4, TP53/MDM2/P14arf, PI3k/Akt-PTEN, RAS/RAF/MEK, PARP) involved in GB tumorigenesis, pathophysiology, and treatment resistance acquisition. Below, we analyze several immunotherapeutic approaches (i.e., checkpoint inhibitors, vaccines, CAR-modified NK or T cells, oncolytic virotherapy) that have been used in an attempt to enhance the immune response against GB, and thereby avoid recidivism or increase survival of GB patients. Finally, we present treatment attempts made using nanotherapies (nanometric structures having active anti-GB agents such as antibodies, chemotherapeutic/anti-angiogenic drugs or sensitizers, radionuclides, and molecules that target GB cellular receptors or open the blood–brain barrier) and non-ionizing energies (laser interstitial thermal therapy, high/low intensity focused ultrasounds, photodynamic/sonodynamic therapies and electroporation). The aim of this review is to discuss the advances and limitations of the current therapies and to present novel approaches that are under development or following clinical trials. [ABSTRACT FROM AUTHOR]

Immunotherapies are mainly aimed to promote a CD8+ T cell response rather than a CD4+ T cell response as cytotoxic T lymphocytes (CTLs) can directly kill target cells. Recently, CD4+ T cells have received more attention due to their diverse roles in tumors and chronic viral infections. In antitumor and antichronic viral responses, CD4+ T cells relay help signals through dendritic cells to indirectly regulate CD8+ T cell response, interact with B cells or macrophages to indirectly modulate humoral immunity or macrophage polarization, and inhibit tumor blood vessel formation. Additionally, CD4+ T cells can also exhibit direct cytotoxicity toward target cells. However, regulatory T cells exhibit immunosuppression and CD4+ T cells become exhausted, which promote tumor progression and chronic viral persistence. Finally, we also outline immunotherapies based on CD4+ T cells, including adoptive cell transfer, vaccines, and immune checkpoint blockade. Overall, this review summarizes diverse roles of CD4+ T cells in the antitumor or protumor and chronic viral responses, and also highlights the immunotherapies based on CD4+ T cells, giving a better understanding of their roles in tumors and chronic viral infections. [ABSTRACT FROM AUTHOR]

Glioma is one of the most aggressive types of primary brain tumor with a high-grade glioma known as glioblastoma multiforme (GBM). Patients diagnosed with GBM usually have an overall survival rate of less than 18 months after conventional therapy. This bleak prognosis underlines the need to consider new therapeutic interventions for GBM treatment to overcome current treatment limitations. By highlighting different immunotherapeutic approaches currently in preclinical and clinical trials, including immune checkpoint inhibitors, chimeric antigen receptors T cells, natural killer cells, vaccines, and combination therapy, this review aims to discuss the mechanisms, benefits, and limitations of immunotherapy in treating GBM patients. [ABSTRACT FROM AUTHOR]

Oesophageal adenocarcinoma (OAC) has a relatively poor long‐term survival and limited treatment options. Promising targets for immunotherapy are short peptide neoantigens containing tumour mutations, presented to cytotoxic T‐cells by human leucocyte antigen (HLA) molecules. Despite an association between putative neoantigen abundance and therapeutic response across cancers, immunogenic neoantigens are challenging to identify. Here we characterized the mutational and immunopeptidomic landscapes of tumours from a cohort of seven patients with OAC. We directly identified one HLA‐I presented neoantigen from one patient, and report functional T‐cell responses from a predicted HLA‐II neoantigen in a second patient. The predicted class II neoantigen contains both HLA I and II binding motifs. Our exploratory observations are consistent with previous neoantigen studies in finding that neoantigens are rarely directly observed, and an identification success rate following prediction in the order of 10%. However, our identified putative neoantigen is capable of eliciting strong T‐cell responses, emphasizing the need for improved strategies for neoantigen identification. [ABSTRACT FROM AUTHOR]

Simple Summary: Neoantigens are considered good targets for immunotherapy due to their tumor specificity. However, because neoantigens are unique in individual cancers, it is challenging to select personalized target neoantigens. In this study, we focused on "shared neoantigens", which are neoantigens derived from mutations observed commonly in a subset of cancer patients. We identified a shared neoantigen derived from FGFR3Y373C through bioinformatics and in vitro screening. We identified that TCR-engineered T cells expressing TCRs for FGFR3Y373C showed specific reactivity and cytotoxic activity against mutated FGFR3Y373C. We believe that immunotherapies targeting shared neoantigens would be a good approach for cancer treatment. Immunotherapies, including immune checkpoint blockades, play a critically important role in cancer treatments. For immunotherapies, neoantigens, which are generated by somatic mutations in cancer cells, are thought to be good targets due to their tumor specificity. Because neoantigens are unique in individual cancers, it is challenging to develop personalized immunotherapy targeting neoantigens. In this study, we screened "shared neoantigens", which are specific types of neoantigens derived from mutations observed commonly in a subset of cancer patients. Using exome sequencing data in the Cancer Genome Atlas (TCGA), we predicted shared neoantigen peptides and performed in vitro screening of shared neoantigen-reactive CD8+ T cells using peripheral blood from healthy donors. We examined the functional activity of neoantigen-specific T cell receptors (TCRs) by generating TCR-engineered T cells. Among the predicted shared neoantigens from TCGA data, we found that the mutated FGFR3Y373C peptide induced antigen-specific CD8+ T cells from the donor with HLA-A*02:06 via an ELISPOT assay. Subsequently, we obtained FGFR3Y373C-specific CD8+ T cell clones and identified two different sets of TCRs specifically reactive to FGFR3Y373C. We found that the TCR-engineered T cells expressing FGFR3Y373C-specific TCRs recognized the mutated FGFR3Y373C peptide but not the corresponding wild-type peptide. These two FGFR3Y373C-specific TCR-engineered T cells showed cytotoxic activity against mutated FGFR3Y373C-loaded cells. These results imply the possibility of strategies of immunotherapies targeting shared neoantigens, including cancer vaccines and TCR-engineered T cell therapies. [ABSTRACT FROM AUTHOR]

Diffusely infiltrating gliomas – including glioblastoma (GBM), isocitrate dehydrogenase (IDH) mutant gliomas, and histone 3 (H3) altered gliomas – are primary brain tumors with an invariably fatal outcome. Despite advances in the understanding of their biology, standard, targeted and immune checkpoint inhibitor immunotherapies have proven ineffective in arresting their inexorable progression and associated morbidity and mortality. Recognizing the unique aspects of the immunogenicity of cancer cells, the last decade has seen the development and evaluation of vaccine-based therapies for the treatment of solid tumors, including gliomas. Here we review the current vaccine strategies for the treatment of GBM, IDH-mutant gliomas and diffuse midline glioma H3 K27M-altered. We discuss potential benefits and challenges of vaccine therapies in these specific patient populations. [ABSTRACT FROM AUTHOR]

Elongated peptides (EPs), containing possibly one or multiple epitope/s, are increasingly used for the screening of antigen-specific CD8+ and CD4+ cell responses. Here, we present an in vitro protocol that allows the amplification of antigen-specific cells and the subsequent functional analysis of both T cell types using EPs. Known viral-derived epitopes were elongated to 20 mer EPs on the N-, C-, and both termini for HLA class I binders, or on the N- and C- termini for HLA class II binders. With EP stimulation only, the percentage of responding CD8+ T cells was dependent on the elongation site of the EP, whereas CD4+ T cell responses were completely lost in 22% of the tests performed ex vivo. A short-term amplification step plus the addition of a TLR3 agonist (Poly-ICLC) together with an increased EP concentration improved markedly the detection of CD8+ and CD4+ T cell reactivities. [ABSTRACT FROM AUTHOR]

Pericytes at the blood–brain barrier (BBB) are located between the tight endothelial cell layer of the blood vessels and astrocytic endfeet. They contribute to central nervous system (CNS) homeostasis by regulating BBB development and maintenance. Loss of pericytes results in increased numbers of infiltrating immune cells in the CNS in experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis (MS). However, little is known about their competence to modulate immune cell activation or function in CNS autoimmunity. To evaluate the capacity of pericytes to directly interact with T cells in an antigen-specific fashion and potentially (re)shape their function, we depleted major histocompatibility complex (MHC) class II from pericytes in a cell type-specific fashion and performed T cell-pericyte cocultures and EAE experiments. We found that pericytes present antigen in vitro to induce T cell activation and proliferation. In an adoptive transfer EAE experiment, pericyte-specific MHC II KO resulted in locally enhanced T cell infiltration in the CNS; even though, overall disease course of mice was not affected. Thus, pericytes may serve as non-professional antigen-presenting cells affecting states of T cell activation, thereby locally shaping lesion formation in CNS inflammation but without modulating disease severity. [ABSTRACT FROM AUTHOR]

Immunotherapy has revolutionized cancer treatment. Despite the recent advances in immunotherapeutic approaches for several tumor entities, limited response has been observed in malignant gliomas, including glioblastoma (GBM). Conversely, one of the emerging immunotherapeutic modalities is chimeric antigen receptors (CAR) T cell therapy, which demonstrated promising clinical responses in other solid tumors. Current pre-clinical and interventional clinical studies suggest improved efficacy when CAR-T cells are delivered locoregionally, rather than intravenously. In this review, we summarize possible CAR-T cell administration routes including locoregional therapy, systemic administration with and without focused ultrasound, direct intra-arterial drug delivery and nanoparticle-enhanced delivery in glioma. Moreover, we discuss published as well as ongoing and planned clinical trials involving CAR-T cell therapy in malignant glioma. With increasing neoadjuvant and/or adjuvant combinatorial immunotherapeutic concepts and modalities with specific modes of action for malignant glioma, selection of administration routes becomes increasingly important. [ABSTRACT FROM AUTHOR]

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In contrast to conventional anti-tumor agents, nano-carriers allow co-delivery of distinct drugs in a cell type-specific manner. So far, many nanodrug-based immunotherapeutic approaches aim to target and kill tumor cells directly or to address antigen presenting cells (APC) like dendritic cells (DC) in order to elicit tumor antigen-specific T cell responses. Regulatory T cells (Treg) constitute a major obstacle in tumor therapy by inducing a pro-tolerogenic state in APC and inhibiting T cell activation and T effector cell activity. This review aims to summarize nanodrug-based strategies that aim to address and reprogram Treg to overcome their immunomodulatory activity and to revert the exhaustive state of T effector cells. Further, we will also discuss nano-carrier-based approaches to introduce tumor antigen-specific chimeric antigen receptors (CAR) into T cells for CAR-T cell therapy which constitutes a complementary approach to DC-focused vaccination. [ABSTRACT FROM AUTHOR]

Cancer vaccines offer the potential to enhance T cell-mediated antitumor immunity by expanding and increasing the function of tumor-specific T cells and shaping the recall response against recurring tumors. While the use of cancer vaccines is not a new immunotherapeutic approach, the cancer vaccine field continues to evolve as new antigen types emerge and vaccine formulations and delivery strategies are developed. As monotherapies, cancer vaccines have not been very efficacious in part due to pre-existing peripheral- and tumor-mediated tolerance mechanisms that limit T cell function. Over the years, various agents including Toll-like receptor agonists, cytokines, and checkpoint inhibitors have been employed as vaccine adjuvants and immune modulators to increase antigen-mediated activation, expansion, memory formation, and T effector cell function. A renewed interest in this approach has emerged as better neoepitope discovery tools are being developed and our understanding of what constitutes an effective cancer vaccine is improved. In the coming years, cancer vaccines will likely be vital to enhance the response to current immunotherapies. In this review, we discuss the various types of therapeutic cancer vaccines, including types of antigens and approaches used to enhance cancer vaccine responses such as TLR agonists, recombinant interleukin-2 and interleukin-2 derivatives, and checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Simple Summary: The immunopeptidome represents the entirety of peptides that are presented on the surface of cells on human leukocyte antigen (HLA) molecules and are recognized by the T-cell receptors of CD4+ and CD8+ T-cells. Malignant cells present tumor-associated antigens essential for tumor immune surveillance, which can be targeted by T-cell-based immunotherapy approaches. For ovarian carcinomas, various tumor-associated antigens, such as Mucin-16 and Mesothelin, have been described. The aim of our study is to analyze immunopeptidome-defined tumor antigen presentation in ovarian carcinoma patients in relation to clinical characteristics and disease outcomes to define potential biomarkers. Our work demonstrates the central role of HLA-DR-restricted peptide presentation of the tumor antigen Mesothelin and of CD4+ T-cell responses for tumor immune surveillance, and underlines Mesothelin as a prime target antigen for novel immunotherapeutic approaches for ovarian carcinoma patients. T-cell recognition of HLA-presented antigens is central for the immunological surveillance of malignant disease and key for the development of novel T-cell-based immunotherapy approaches. In recent years, large-scale immunopeptidome studies identified naturally presented tumor-associated antigens for several malignancies. Regarding ovarian carcinoma (OvCa), Mucin-16 (MUC16) and Mesothelin (MSLN) were recently described as the top HLA class I- and HLA class II-presented tumor antigens, respectively. Here, we investigate the role and impact of immunopeptidome-presented tumor antigens on the clinical outcomes of 39 OvCa patients with a follow-up time of up to 50 months after surgery. Patients with a HLA-restricted presentation of high numbers of different MSLN-derived peptides on their tumors exhibited significantly prolonged progression-free (PFS) and overall survival (OS), whereas the presentation of MUC16-derived HLA class I-restricted peptides had no impact. Furthermore, a high HLA-DRB gene expression was associated with increased PFS and OS. In line, in silico prediction revealed that MSLN-derived HLA class II-presented peptides are predominantly presented on HLA-DR allotypes. In conclusion, the correlation of MSLN tumor antigen presentation and HLA-DRB gene expression with prolonged survival indicates a central role of CD4+ T-cell responses for tumor immune surveillance in OvCa, and highlights the importance of immunopeptidome-guided tumor antigen discovery. [ABSTRACT FROM AUTHOR]

The main breakthrough in tumor immunotherapy was the discovery of immune checkpoint (IC) proteins, which act as a potent suppressor of the immune system by a myriad of mechanisms. After that, scientists focused on the immune checkpoint molecules mainly. Thereby, much effort was spent to progress novel strategies for suppressing these inhibitory axes, resulting in the evolution of immune checkpoint inhibitors (ICIs). Then, ICIs have become a promising approach and shaped a paradigm shift in tumor immunotherapies. CTLA-4 plays an influential role in attenuation of the induction of naïve and memory T cells by engagement with its responding ligands like B7-1 (CD80) and B7-2 (CD86). Besides, PD-1 is predominantly implicated in adjusting T cell function in peripheral tissues through its interaction with programmed death-ligand 1 (PD-L1) and PD-L2. Given their suppressive effects on anti-tumor immunity, it has firmly been documented that ICIs based therapies can be practical and rational therapeutic approaches to treat cancer patients. Nonetheless, tumor inherent or acquired resistance to ICI and some treatment-related toxicities restrict their application in the clinic. The current review will deliver a comprehensive overview of the ICI application to treat human tumors alone or in combination with other modalities to support more desired outcomes and lower toxicities in cancer patients. 887-BaRBQ_8_2WbWUGqkG6 Video Abstract [ABSTRACT FROM AUTHOR]

Presentation of tumor-specific or tumor-associated peptides by HLA class I molecules to CD8+ T cells is the foundation of epitope-centric cancer immunotherapies. While often in silico HLA binding predictions or in vitro immunogenicity assays are utilized to select candidates, mass spectrometry-based immunopeptidomics is currently the only method providing a direct proof of actual cell surface presentation. Despite much progress in the last decade, identification of such HLA-presented peptides remains challenging. Here we review typical workflows and current developments in the field of immunopeptidomics, highlight the challenges which remain to be solved and emphasize the importance of direct target validation for clinical immunotherapy development. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy has achieved multiple clinical benefits and has become an indispensable component of cancer treatment. Targeting tumor-specific antigens, also known as neoantigens, plays a crucial role in cancer immunotherapy. T cells of adaptive immunity that recognize neoantigens, but do not induce unwanted off-target effects, have demonstrated high efficacy and low side effects in cancer immunotherapy. Tumor neoantigens derived from accumulated genetic instability can be characterized using emerging technologies, such as high-throughput sequencing, bioinformatics, predictive algorithms, mass-spectrometry analyses, and immunogenicity validation. Neoepitopes with a higher affinity for major histocompatibility complexes can be identified and further applied to the field of cancer vaccines. Therapeutic vaccines composed of tumor lysates or cells and DNA, mRNA, or peptides of neoantigens have revoked adaptive immunity to kill cancer cells in clinical trials. Broad clinical applicability of these therapeutic cancer vaccines has emerged. In this review, we discuss recent progress in neoantigen identification and applications for cancer vaccines and the results of ongoing trials. [ABSTRACT FROM AUTHOR]

Prioritization of immunogenic neoantigens is key to enhancing cancer immunotherapy through the development of personalized vaccines, adoptive T cell therapy, and the prediction of response to immune checkpoint inhibition. Neoantigens are tumor-specific proteins that allow the immune system to recognize and destroy a tumor. Cancer immunotherapies, such as personalized cancer vaccines, adoptive T cell therapy, and immune checkpoint inhibition, rely on an understanding of the patient-specific neoantigen profile in order to guide personalized therapeutic strategies. Genomic approaches to predicting and prioritizing immunogenic neoantigens are rapidly expanding, raising new opportunities to advance these tools and enhance their clinical relevance. Predicting neoantigens requires acquisition of high-quality samples and sequencing data, followed by variant calling and variant annotation. Subsequently, prioritizing which of these neoantigens may elicit a tumor-specific immune response requires application and integration of tools to predict the expression, processing, binding, and recognition potentials of the neoantigen. Finally, improvement of the computational tools is held in constant tension with the availability of datasets with validated immunogenic neoantigens. The goal of this review article is to summarize the current knowledge and limitations in neoantigen prediction, prioritization, and validation and propose future directions that will improve personalized cancer treatment. [ABSTRACT FROM AUTHOR]

Personal neoantigen vaccines are considered to be effective methods for inducing, amplifying and diversifying antitumor T cell responses. We recently conducted a clinical study that combined neoantigen nanovaccine with anti-PD-1 antibody. Here, we reported a case with a clear beneficial outcome from this treatment. We established a process that includes comprehensive identification of individual mutations, computational prediction of new epitopes, and design and manufacture of unique nanovaccines for this patient. Nanovaccine started after a relapse in third-line treatment. We assessed the patient's clinical outcome and circulating immune response. In this advanced pancreatic cancer patient, the OS associated with the vaccine treatment was 10.5 months. A peptide-specific T-cell response against 9 of the 12 vaccine peptides could be detected sequentially. Robust neoantigen-specific T cell responses were also detected by IFN-γ ELISPOT and intracellular cytokine staining. In conclusion, sustained functional neoantigen-specific T cell therapy combined with immune checkpoint targeting may be well suited to help control progressive metastatic pancreatic cancer. [ABSTRACT FROM AUTHOR]

Cancer cells frequently display defects in their antigen-processing pathway and thereby evade CD8 T cell immunity. We described a novel category of cancer antigens, named TEIPP, that emerge on cancers with functional loss of the peptide pump TAP. TEIPPs are non-mutated neoantigens despite their 'self' origin by virtue of their absence on normal tissues. Here, we describe the development of a synthetic long peptide (SLP) vaccine for the most immunogenic TEIPP antigen identified thus far, derived from the TAP-independent LRPAP1 signal sequence. LRPAP121–30-specific CD8 T cells were present in blood of all tested healthy donors as well as patients with non-small cell lung adenocarcinoma. SLPs with natural flanking, however, failed to be cross-presented by monocyte-derived dendritic cells. Since the C-terminus of LRPAP121–30 is an unconventional and weakly binding serine (S), we investigated if replacement of this anchor would result in efficient cross-presentation. Exchange into a valine (V) resulted in higher HLA-A2 binding affinity and enhanced T cell stimulation. Importantly, CD8 T cells isolated using the V-variant were able to bind tetramers with the natural S-variant and respond to TAP-deficient cancer cells. A functional screen with an array of N-terminal and C-terminal extended SLPs pointed at the 24-mer V-SLP, elongated at the N-terminus, as most optimal vaccine candidate. This SLP was efficiently cross-presented and consistently induced a strong polyclonal LRPAP121–30-specific CD8 T cells from the endogenous T cell repertoire. Thus, we designed a TEIPP SLP vaccine from the LRPAP1 signal sequence ready for validation in clinical trials. [ABSTRACT FROM AUTHOR]

The field of neuroimmunology endorses the involvement of the adaptive immune system in central nervous system (CNS) health, disease, and aging. While immune cell trafficking into the CNS is highly regulated, small numbers of antigen-experienced lymphocytes can still enter the cerebrospinal fluid (CSF)-filled compartments for regular immune surveillance under homeostatic conditions. Meningeal lymphatics facilitate drainage of brain-derived antigens from the CSF to deep cervical lymph nodes to prime potential adaptive immune responses. During aging and CNS disorders, brain barriers and meningeal lymphatic functions are impaired, and immune cell trafficking and antigen efflux are altered. In this context, alterations in the immune cell repertoire of blood and CSF and T and B cells primed against CNS-derived autoantigens have been observed in various CNS disorders. However, for many diseases, a causal relationship between observed immune responses and neuropathological findings is lacking. Here, we review recent discoveries about the association between the adaptive immune system and CNS disorders such as autoimmune neuroinflammatory and neurodegenerative diseases. We focus on the current challenges in identifying specific T cell epitopes in CNS diseases and discuss the potential implications for future diagnostic and treatment options. [ABSTRACT FROM AUTHOR]

The use of tumor mutation-derived neoantigen represents a promising approach for cancer vaccines. Preclinical and early phase human clinical studies have shown the successful induction of tumor neoepitope-directed responses; however, overall clinical efficacy of neoantigen vaccines has been limited. One major obstacle of this strategy is the prevailing lack of sufficient understanding of the mechanism underlying the generation of neoantigen-specific CD8+ T cells. Here, we report a correlation between antitumor efficacy of neoantigen/toll-like receptor 3 (TLR3)/CD40 agonists vaccination and an increased frequency of circulating antigen-specific CD8+ T cells expressing CX3C chemokine receptor 1 (CX3CR1) in a preclinical model. Mechanistic studies using mixed bone marrow chimeras identified that CD40 and CD80/86, but not CD70 signaling in Batf3-dependent conventional type 1 dendritic cells (cDC1s) is required for the antitumor efficacy of neoantigen vaccine and generation of neoantigen-specific CX3CR1+ CD8+ T cells. Although CX3CR1+ CD8+ T cells exhibited robust in vitro effector function, in vivo depletion of this subset did not alter the antitumor efficacy of neoantigen/TLR3/CD40 agonists vaccination. These findings indicate that the vaccine-primed CX3CR1+ subset is dispensable for antitumor CD8+ T cell responses, but can be used as a blood-based T-cell biomarker for effective priming of CD8+ T cells as post-differentiated T cells. Taken together, our results reveal a critical role of CD40 and CD80/86 signaling in cDC1s in antitumor efficacy of neoantigen-based therapeutic vaccines, and implicate the potential utility of CX3CR1 as a circulating predictive T-cell biomarker in vaccine therapy. [ABSTRACT FROM AUTHOR]

Objective: Neoantigens arising from gene mutations in tumors can induce specific immune responses, and neoantigen-based immunotherapies have been tested in clinical trials. Here, we characterized the efficacy of altered neoepitopes in improving immunogenicity against gastric cancer. Methods: Raw data of whole-exome sequencing derived from a patient with gastric cancer were analyzed using bioinformatics methods to identify neoepitopes. Neoepitopes were modified by P1Y (the first amino acid was replaced by tyrosine) and P2L (the second amino acid was replaced by leucine). T2 binding and stability assays were used to detect the affinities between the neoepitopes and the HLA molecules, as well as the stabilities of complexes. Dendritic cells (DCs) presented with neoepitopes stimulated naïve CD8+ T cells to induce specific cytotoxic T lymphocytes. ELISA and carboxyfluorescein succinimidyl ester were used to detect IFN-α and TNF-a levels, and T cell proliferation. Perforin was detected by flow cytometry. The cytotoxicity of T cells was determined using the lactate dehydrogenase assay. Results: Bioinformatics analysis, T2 binding, and stability assays indicated that residue substitution increased the affinity between neoepitopes and HLA molecules, as well as the stabilities of complexes. DCs presented with altered neoepitopes stimulated CD8+T cells to release more IFN-γ and had a greater effect on promoting proliferation than wild-type neoepitopes. CD8+T cells stimulated with altered neoepitopes killed more wild-type neoepitope-pulsed T2 cells than those stimulated with wild-type neoepitopes, by secreting more IFN-γ, TNF-a, and perforin. Conclusions: Altered neoepitopes exhibited greater immunogenicity than wild-type neoepitopes. Residue substitution could be used as a new strategy for immunotherapy to target neoantigens. [ABSTRACT FROM AUTHOR]

With the significant advances in cancer genomics using next-generation sequencing technologies, genomic and molecular profiling-based precision medicine is used as a part of routine clinical test for guiding and selecting the most appropriate treatments for individual cancer patients. Although many molecular-targeted therapies for a number of actionable genomic alterations have been developed, the clinical application of such information is still limited to a small proportion of cancer patients. In this review, we summarize the current status of personalized drug selection based on genomic and molecular profiling and highlight the challenges how we can further utilize the individual genomic information. Cancer immunotherapies, including immune checkpoint inhibitors, would be one of the potential approaches to apply the results of genomic sequencing most effectively. Highly cancer-specific antigens derived from somatic mutations, the so-called neoantigens, occurring in individual cancers have been in focus recently. Cancer immunotherapies, which target neoantigens, could lead to a precise treatment for cancer patients, despite the challenge in accurately predicting neoantigens that can induce cytotoxic T cells in individual patients. Precise prediction of neoantigens should accelerate the development of personalized immunotherapy including cancer vaccines and T-cell receptor-engineered T-cell therapy for a broader range of cancer patients. [ABSTRACT FROM AUTHOR]

HPV-independent head and neck squamous cell carcinoma (HNSCC) is a common cancer globally. The overall response rate to anti-PD1 checkpoint inhibitors (CPIs) in HNSCC is ~16%. One major factor influencing the effectiveness of CPI is the level of tumor infiltrating T cells (TILs). Converting TILlow tumors to TILhigh tumors is thus critical to improve clinical outcome. Here we describe a novel DNA vaccines to facilitate the T-cell infiltration and control tumor growth. We evaluated the expression of target antigens and their respective immunogenicity in HNSCC patients. The efficacy of DNA vaccines targeting two novel antigens were evaluated with or without CPI using a syngeneic model. Most HNSCC patients (43/44) co-expressed MAGED4B and FJX1 and their respective tetramer-specific T cells were in the range of 0.06-0.12%. In a preclinical model, antigen-specific T cells were induced by DNA vaccines and increased T cell infiltration into the tumor, but not MDSC or regulatory T cells. The vaccines inhibited tumor growth and improved the outcome alone and upon combination with anti-PD1 and resulted in tumor clearance in approximately 75% of mice. Pre-existence of MAGED4B and FJX1-reactive T cells in HNSCC patients suggests that these widely expressed antigens are highly immunogenic and could be further expanded by vaccination. The DNA vaccines targeting these antigens induced robust T cell responses and with the anti-PD1 antibody conferring excellent tumor control. This opens up an opportunity for combination immunotherapy that might benefit a wider population of HNSCC patients in an antigen-specific manner. [ABSTRACT FROM AUTHOR]

Glioblastoma is considered to be the most malignant disease of the central nervous system, and it is often associated with poor survival. The immune microenvironment plays a key role in the development and treatment of glioblastoma. Among the different types of immune cells, tumor-associated microglia/macrophages (TAM/Ms) and CD8-positive (CD8+) T cells are the predominant immune cells, as well as the most active ones. Current studies have suggested that interaction between TAM/Ms and CD8+ T cells have numerous potential targets that will allow them to overcome malignancy in glioblastoma. In this review, we summarize the mechanism and function of TAM/Ms and CD8+ T cells involved in glioblastoma, as well as update on the relationship and crosstalk between these two cell types, to determine whether this association alters the immune status during glioblastoma development and affects optimal treatment. We focus on the molecular factors that are crucial to this interaction, and the role that this crosstalk plays in the biological processes underlying glioblastoma treatment, particularly with regard to immune therapy. We also discuss novel therapeutic targets that can aid in resolving reticular connections between TAM/Ms and CD8+ T cells, including depletion and reprogramming TAM/Ms and novel TAM/Ms-CD8+ T cell cofactors with potential translational usage. In addition, we highlight the challenges and discuss future perspectives of this crosstalk between TAM/Ms and CD8+ T cells. [ABSTRACT FROM AUTHOR]

Summary: Dysfunction of the immune system underlies a plethora of human diseases, requiring the development of immunomodulatory therapeutic intervention. To date, most strategies employed have been focusing on the modification of T lymphocytes, and although remarkable improvement has been obtained, results often fall short of the intended outcome. Recent cutting‐edge technologies have highlighted macrophages as potential targets for disease control. Macrophages play central roles in development, homeostasis and host defence, and their dysfunction and dysregulation have been implicated in the onset and pathogenesis of multiple disorders including cancer, neurodegeneration, autoimmunity and metabolic diseases. Recent advancements have led to a greater understanding of macrophage origin, diversity and function, in both health and disease. Over the last few years, a variety of strategies targeting macrophages have been developed and these open new therapeutic opportunities. Here, we review the progress in macrophage reprogramming in various disorders and discuss the potential implications and challenges for macrophage‐targeted approaches in human disease. [ABSTRACT FROM AUTHOR]

P2X7 receptors are ion-gated channels activated by ATP. Under pathological conditions, the extensive release of ATP induces sustained P2X7 receptor activation, culminating in induction of proinflammatory pathways with inflammasome assembly and cytokine release. These inflammatory conditions, whether occurring peripherally or in the central nervous system (CNS), increase blood-brain-barrier (BBB) permeability. Besides its well-known involvement in neurodegeneration and neuroinflammation, the P2X7 receptor may induce BBB disruption and chemotaxis of peripheral immune cells to the CNS, resulting in brain parenchyma infiltration. For instance, despite common effects on cytokine release, P2X7 receptor signaling is also associated with metalloproteinase secretion and activation, as well as migration and differentiation of T lymphocytes, monocytes and dendritic cells. Here we highlight that peripheral immune cells mediate the pathogenesis of Multiple Sclerosis and Parkinson's and Alzheimer's disease, mainly through T lymphocyte, neutrophil and monocyte infiltration. We propose that P2X7 receptor activation contributes to neurodegenerative disease progression beyond its known effects on the CNS. This review discusses how P2X7 receptor activation mediates responses of peripheral immune cells within the inflamed CNS, as occurring in the aforementioned diseases. [ABSTRACT FROM AUTHOR]

The use of immunotherapies for the treatment of brain tumors is a topic that has garnered considerable excitement in recent years. Discoveries such as the presence of a glymphatic system and immune surveillance in the central nervous system (CNS) have shattered the theory of immune privilege and opened up the possibility of treating CNS malignancies with immunotherapies. However, despite many immunotherapy clinical trials aimed at treating glioblastoma (GBM), very few have demonstrated a significant survival benefit. Several factors for this have been identified, one of which is that GBMs are immunologically "cold," implying that the cancer does not induce a strong T cell response. It is postulated that this is why clinical trials using an immune checkpoint inhibitor alone have not demonstrated efficacy. While it is well established that anti-cancer T cell responses can be facilitated by the presentation of tumor-specific antigens to the immune system, treatment-related death of GBM cells and subsequent release of molecules have not been shown to be sufficient to evoke an anti-tumor immune response effective enough to have a significant impact. To overcome this limitation, vaccines can be used to introduce exogenous antigens at higher concentrations to the immune system to induce strong tumor antigen-specific T cell responses. In this review, we will describe vaccination strategies that are under investigation to treat GBM; categorizing them based on their target antigens, form of antigens, vehicles used, and pairing with specific adjuvants. We will review the concept of vaccine therapy in combination with immune checkpoint inhibitors, as it is hypothesized that this approach may be more effective in overcoming the immunosuppressive milieu of GBM. Clinical trial design and the need for incorporating robust immune monitoring into future studies will also be discussed here. We believe that the integration of evolving technologies of vaccine development, delivery, and immune monitoring will further enhance the role of these therapies and will likely remain an important area of investigation for future treatment strategies for GBM patients. [ABSTRACT FROM AUTHOR]

Background: World Health Organization (WHO) grade IV glioma remains one of the most lethal tumors with a dismal prognosis and inevitable recurrence. We evaluated the safety and efficacy of immunotherapy with radiotherapy in this population of patients. Methods: This study was a single-arm, open-label, phase I trial based on patients with recurrent WHO grade IV glioma. Patients were treated with intracranial and systemic immunoadjuvants in combination with low-dose reirradiation. The primary endpoint of the present trial was safety. Secondary endpoints were overall survival (OS) and progression-free survival (PFS). This trial is registered at ClinicalTrials.gov, NCT03392545. Results: Thirty patients were enrolled. The most common adverse events (AEs) were fever (66.7%), vomiting (33.3%), headache (30.0%), and fatigue (23.3%). Only a single patient experienced grade 3 fever, and no grade 4 AEs or deaths related to treatment were observed. Of the 30 patients, 1 (3.3%) had a complete response, 5 (16.7%) had a partial response, 9 (30.0%) had stable disease, and 15 (50.0%) had progressive disease, resulting in an objective response rate of 20.0%. The median PFS of the entire cohort was 88.0 (61.0-254.0) days, and the median OS was 362.0 (197.0-601.0) days. Patients could be divided into responders and non-responders, and these groups exhibited a significant difference in terms of survival time, T lymphocyte subsets, frequency of cell division cycle 27 (CDC27) mutation status, and CD15 and CD68 expression (P <0.05). Conclusion: The combination of immunotherapy and radiotherapy is well tolerated and may provide clinical benefit for patients with recurrent WHO grade IV glioma. A prospective phase II study is needed to further validate the efficacy of our therapeutic regimen. [ABSTRACT FROM AUTHOR]

Nanomaterial-based delivery vehicles such as lipid-based, polymer-based, inorganics-based, and bio-inspired vehicles often carry distinct and attractive advantages in the development of therapeutic cancer vaccines. Based on various delivery vehicles, specifically designed nanomaterials-based vaccines are highly advantageous in boosting therapeutic and prophylactic antitumor immunities. Specifically, therapeutic vaccines featuring unique properties have made major contributions to the enhancement of antigen immunogenicity, encapsulation efficiency, biocompatibility, and stability, as well as promoting antigen cross-presentation and specific CD8+ T cell responses. However, for clinical applications, tumor-associated antigen-derived vaccines could be an obstacle, involving immune tolerance and deficiency of tumor specificities, in achieving maximum therapeutic indices. However, when using bioinformatics predictions with emerging innovations of in silico tools, neoantigen-based therapeutic vaccines might become potent personalized vaccines for tumor treatments. In this review, we summarize the development of preclinical therapeutic cancer vaccines and the advancements of nanomaterial-based delivery vehicles for cancer immunotherapies, which provide the basis for a personalized vaccine delivery platform. Moreover, we review the existing challenges and future perspectives of nanomaterial-based personalized vaccines for novel tumor immunotherapies. [ABSTRACT FROM AUTHOR]

The peptide‐based therapeutic cancer vaccines have attracted enormous attention in recent years as one of the effective treatments of tumour immunotherapy. Most of peptide‐based vaccines are based on epitope peptides stimulating CD8+ T cells or CD4+ T helper cells to target tumour‐associated antigens (TAAs) or tumour‐specific antigens (TSAs). Some adjuvants and nanomaterials have been exploited to optimize the efficiency of immune response of the epitope peptide to improve its clinical application. At present, numerous peptide‐based therapeutic cancer vaccines have been developed and achieved significant clinical benefits. Similarly, the combination of peptide‐based vaccines and other therapies has demonstrated a superior efficacy in improving anti‐cancer activity. We delve deeper into the choices of targets, design and screening of epitope peptides, clinical efficacy and adverse events of peptide‐based vaccines, and strategies combination of peptide‐based therapeutic cancer vaccines and other therapies. The review will provide a detailed overview and basis for future clinical application of peptide‐based therapeutic cancer vaccines. [ABSTRACT FROM AUTHOR]

We previously developed TANTIGEN, a comprehensive online database cataloging more than 1000 T cell epitopes and HLA ligands from 292 tumor antigens. In TANTIGEN 2.0, we significantly expanded coverage in both immune response targets (T cell epitopes and HLA ligands) and tumor antigens. It catalogs 4,296 antigen variants from 403 unique tumor antigens and more than 1500 T cell epitopes and HLA ligands. We also included neoantigens, a class of tumor antigens generated through mutations resulting in new amino acid sequences in tumor antigens. TANTIGEN 2.0 contains validated TCR sequences specific for cognate T cell epitopes and tumor antigen gene/mRNA/protein expression information in major human cancers extracted by Human Pathology Atlas. TANTIGEN 2.0 is a rich data resource for tumor antigens and their associated epitopes and neoepitopes. It hosts a set of tailored data analytics tools tightly integrated with the data to form meaningful analysis workflows. It is freely available at http://projects.met-hilab.org/tadb. [ABSTRACT FROM AUTHOR]

Objective: To develop a neoantigen-targeted personalized cancer treatment for non-small cell lung cancer (NSCLC), neoantigens were obtained from collected human lung cancer samples, and the utility of neoantigen and neoantigen-reactive T cells (NRTs) was assessed. Methods: Tumor specimens from three patients with NSCLC were obtained and analyzed by whole-exome sequencing, and neoantigens were predicted accordingly. Dendritic cells and T lymphocytes were isolated, NRTs were elicited and IFN-γ ELISPOT tests were conducted. HLA-A2.1/Kb transgenic mice were immunized with peptides from HLA-A*02:01+patient with high immunogenicity, and NRTs were subjected to IFN-γ, IL-2 and TNF-α ELISPOT as well as time-resolved fluorescence assay for cytotoxicity assays to verify the immunogenicity in vitro. The HLA-A*02:01+lung cancer cell line was transfected with minigene and inoculated into the flanks of C57BL/6nu/nu mice and the NRTs induced by the immunogenic polypeptides from autologous HLA-A2.1/Kb transgenic mice were adoptively transfused to verify their immunogenicity in vivo. Results: Multiple putative mutation-associated neoantigens with strong affinity for HLA were selected from each patient. Immunogenic neoantigen were identified in all three NSCLC patients, the potency of ACAD8-T105I, BCAR1-G23V and PLCG1-M425L as effective neoantigen to active T cells in suppressing tumor growth was further proven both in vitro and in vivo using HLA-A2.1/Kb transgenic mice and tumor-bearing mouse models. Conclusion: Neoantigens with strong immunogenicity can be screened from NSCLC patients through the whole-exome sequencing of patient specimens and machine-learning-based neoantigen predictions. NRTs shown efficient antitumor responses in transgenic mice and tumor-bearing mouse models. Our results indicate that the development of neoantigen-based personalized immunotherapies in NSCLC is possible. Precis: Neoantigens with strong immunogenicity were screened from NSCLC patients. This research provides evidence suggesting that neoantigen-based therapy might serve as feasible treatment for NSCLC. [ABSTRACT FROM AUTHOR]

Adoptive T cell therapy has emerged as a revolutionary immunotherapy for treating cancer. Despite immense promise and clinical success in some hematologic malignancies, limitations remain that thwart its efficacy in solid tumors. Particularly in tumors of the central nervous system (CNS), T cell therapy is often restricted by the difficulty in intratumoral delivery across anatomical niches, suboptimal T cell specificity or activation, and intratumoral T cell dysfunction due to immunosuppressive tumor microenvironments (TMEs). Nanoparticles may offer several advantages to overcome these limitations of T cell therapy, as they can be designed to robustly and specifically activate T cells ex vivo prior to adoptive transfer, to encapsulate T cell stimulating agents for co-localized stimulation, and to be conjugated onto T cells for added functionality. This perspective highlights recent preclinical advances in using nanoparticles to enhance T cell therapy, and discusses the potential applicability and constraints of nanoparticle-enhanced T cells as a new platform for treating CNS tumors. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell therapy has emerged as one of the major breakthroughs in cancer immunotherapy in the last decade. Outstanding results in hematological malignancies and encouraging pre-clinical anti-tumor activity against a wide range of solid tumors have made CAR T cells one of the most promising fields for cancer therapies. CAR T cell therapy is currently being investigated in solid tumors including glioblastoma (GBM), a tumor for which survival has only modestly improved over the past decades. CAR T cells targeting EGFRvIII, Her2, or IL-13Rα2 have been tested in GBM, but the first clinical trials have shown modest results, potentially due to GBM heterogeneity and to the presence of an immunosuppressive microenvironment. Until now, the use of autologous T cells to manufacture CAR products has been the norm, but this approach has several disadvantages regarding production time, cost, manufacturing delay and dependence on functional fitness of patient T cells, often reduced by the disease or previous therapies. Universal "off-the-shelf," or allogeneic, CAR T cells is an alternative that can potentially overcome these issues, and allow for multiple modifications and CAR combinations to target multiple tumor antigens and avoid tumor escape. Advances in genome editing tools, especially via CRISPR/Cas9, might allow overcoming the two main limitations of allogeneic CAR T cells product, i.e., graft-vs.-host disease and host allorejection. Here, we will discuss how allogeneic CAR T cells could allow for multivalent approaches and alteration of the tumor microenvironment, potentially allowing the development of next generation therapies for the treatment of patients with GBM. [ABSTRACT FROM AUTHOR]

Oropharyngeal squamous cell carcinoma (OPSCC) develops as a consequence of several mutations in the tumor suppressor pathways or after a progressive infection with high risk human papillomavirus (HPV). The dismal side effects of the current standard of care and the clear involvement of the immune system has led to a surge in clinical trials that aim to reinforce the tumor-specific immune response as a new treatment option. In this review, we have focused on the most recent literature to discuss the new findings and insights on the role of different immune cells in the context of OPSCC and its etiology. We then applied this knowledge to describe potential biomarkers and analyzed the rationale and outcomes of earlier and ongoing immunotherapy trials. Finally, we describe new developments that are still at the preclinical phase and provide an outlook on what the near future may bring, now that several new and exciting techniques to study the immune system at the single cell level are being exploited. [ABSTRACT FROM AUTHOR]

Summary: Immune tolerance is the main challenge in the field of cancer vaccines, so modified peptide sequences or naturally occurring mutated versions of cancer‐related wild‐type (WT) antigens represent a promising pathway. However, the low immunogenicity of mutation‐induced neoantigens and, particularly, their incapacity to activate CD8+ T cells are generating doubts on the success of neoantigen‐based cancer vaccines in clinical trials. We developed a novel vaccine approach based on a new class of vaccine immunogens, called variable epitope libraries (VELs). We used three regions of survivin (SVN), composed of 40, 49 and 51 amino acids, along with the complete SVN protein to generate the VELs as multiepitope vaccines. BALB/c mice, challenged with the aggressive and highly metastatic 4T1 cell line, were vaccinated in a therapeutic setting. We showed significant tumor growth inhibition and, most importantly, strong suppression of lung metastasis after a single immunization using VEL vaccines. We demonstrated vaccine‐induced broad cellular immune responses concomitant with extensive tumor infiltration of T cells, the activation of CD107a+ IFN‐γ+ T cells in the spleen and a significant increase in the number of CD3+ CD8+ Ly6C+ effector T cells. In addition, we observed the presence of interferon‐γ‐, granzyme B‐ and perforin‐producing lymphocytes along with modifications in the amount of CD11b+ Ly6Cint/low Ly6G+ granulocytic myeloid‐derived suppressor cells and CD4+ CD25+ FoxP3+ regulatory T cells in the lungs and tumors of mice. In summary, we showed that the VELs represent a potent new class of cancer immunotherapy and propose the application of the VEL vaccine concept as a true alternative to currently available vaccine platforms. [ABSTRACT FROM AUTHOR]

Tumor-associated microglia (MG) and macrophages (MΦ) are important components of the glioblastoma (GBM) immune tumor microenvironment (iTME). From the recent advances in understanding how MG and GBM cells evolve and interact during tumorigenesis, we emphasize the cooperation of MG with other immune cell types of the GBM-iTME, mainly MΦ and T cells. We provide a comprehensive overview of current immunotherapeutic clinical trials and approaches for the treatment of GBM, which in general, underestimate the counteracting contribution of immunosuppressive MG as a main factor for treatment failure. Furthermore, we summarize new developments and strategies in MG reprogramming/re-education in the GBM context, with a focus on ways to boost MG-mediated tumor cell phagocytosis and associated experimental models and methods. This ultimately converges in our proposal of novel combinatorial regimens that locally modulate MG as a central paradigm, and therefore may lead to additional, long-lasting, and effective tumoricidal responses. [ABSTRACT FROM AUTHOR]

Tumor-associated antigens (TAAs) have been tested in various clinical trials in cancer treatment but the patterns of specific T cell response to personalized TAA immunization remains to be fully understood. We report antigen-specific T cell responses in patients immunized with dendritic cell vaccines pulsed with personalized TAA panels. Tumor samples from patients were first analyzed to identify overexpressed TAAs. Autologous DCs were then transfected with pre-manufactured mRNAs encoding the full-length TAAs, overexpressed in the patients' tumors. Patients with glioblastoma multiforme (GBM) or advanced lung cancer received DC vaccines transfected with personalized TAA panels, in combination with low-dose cyclophosphamide, poly I:C, imiquimod and anti-PD-1 antibody. Antigen-specific T cell responses were measured. Safety and efficacy were evaluated. A total of ten patients were treated with DC vaccines transfected with personalized TAA panels containing 3–13 different TAAs. Among the seven patients tested for anti-TAA T cell responses, most of the TAAs induced antigen-specific CD4+ and/or CD8+ T cell responses, regardless of their expression levels in the tumor tissues. No Grade III/IV adverse events were observed among these patients. Furthermore, the treated patients were associated with favorable overall survival when compared to patients who received standard treatment in the same institution. Personalized TAA immunization-induced-specific CD4+ and CD8+ T cell responses without obvious autoimmune adverse events and was associated with favorable overall survival. These results support further studies on DC immunization with personalized TAA panels for combined immunotherapeutic regimens in solid tumor patients. Trial registration ClinicalTrials.gov, NCT02709616 (March, 2016), NCT02808364 (June 2016), NCT02808416 (June, 2016). [ABSTRACT FROM AUTHOR]

Over the last decades, T-cell immunotherapy has revealed itself as a powerful, and often curative, strategy to treat blood cancers. In hematopoietic cell transplantation, most of the so-called graft-vs.-leukemia (GVL) effect hinges on the recognition of histocompatibility antigens that reflect immunologically relevant genetic variants between donors and recipients. Whether other variants acquired during the neoplastic transformation, or the aberrant expression of gene products can yield antigenic targets of similar relevance as the minor histocompatibility antigens is actively being pursued. Modern genomics and proteomics have enabled the high throughput identification of candidate antigens for immunotherapy in both autologous and allogeneic settings. As such, these major histocompatibility complex-associated tumor-specific (TSA) and tumor-associated antigens (TAA) can allow for the targeting of multiple blood neoplasms, which is a limitation for other immunotherapeutic approaches, such as chimeric antigen receptor (CAR)-modified T cells. We review the current strategies taken to translate these discoveries into T-cell therapies and propose how these could be introduced in clinical practice. Specifically, we discuss the criteria that are used to select the antigens with the greatest therapeutic value and we review the various T-cell manufacturing approaches in place to either expand antigen-specific T cells from the native repertoire or genetically engineer T cells with minor histocompatibility antigen or TSA/TAA-specific recombinant T-cell receptors. Finally, we elaborate on the current and future incorporation of these therapeutic T-cell products into the treatment of hematological malignancies. [ABSTRACT FROM AUTHOR]

Background: Myeloid derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are two of the major players involved in the inhibition of anti-tumor immune response in cancer patients, leading to poor prognosis. Selective targeting of myeloid cells has therefore become an attractive therapeutic strategy to relieve immunosuppression and, in this frame, we previously demonstrated that lipid nanocapsules (LNCs) loaded with lauroyl-modified gemcitabine efficiently target monocytic MDSCs in melanoma patients. In this study, we investigated the impact of the physico-chemical characteristics of LNCs, namely size and surface potential, towards immunosuppressive cell targeting. We exploited myeloid cells isolated from glioblastoma patients, which play a relevant role in the immunosuppression, to demonstrate that tailored nanosystems can target not only tumor cells but also tumor-promoting cells, thus constituting an efficient system that could be used to inhibit their function. Results: The incorporation of different LNC formulations with a size of 100 nm, carrying overall positive, neutral or negative charge, was evaluated on leukocytes and tumor-infiltrating cells freshly isolated from glioblastoma patients. We observed that the maximum LNC uptake was obtained in monocytes with neutral 100 nm LNCs, while positively charged 100 nm LNCs were more effective on macrophages and tumor cells, maintaining at low level the incorporation by T cells. The mechanism of uptake was elucidated, demonstrating that LNCs are incorporated mainly by caveolae-mediated endocytosis. Conclusions: We demonstrated that LNCs can be directed towards immunosuppressive cells by simply modulating their size and charge thus providing a novel approach to exploit nanosystems for anticancer treatment in the frame of immunotherapy. [ABSTRACT FROM AUTHOR]