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Simple Summary: In recent years, there has been a paradigm shift in first-line treatment for unresectable hepatocellular carcinoma (HCC) from multitargeted tyrosine kinase inhibitors to immune checkpoint inhibitor-based therapies. Despite the unprecedented improvement in clinical outcomes, responses to these therapies are still only observed in a minority of HCC patients. In this review, we discuss the tumor intrinsic and extrinsic mechanisms of resistance to standard immune checkpoint inhibitors, explore novel approaches to optimize immunotherapy-based regimens, and highlight notable clinical trials that have the potential to change future standard care for HCC. Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, and, with only 15–20% of HCC patients being suitable for potentially curative treatments, the vast majority of patients with HCC ultimately require systemic therapy. For decades, the choice of effective systemic therapy for HCC remained sparse. In recent years, after the combination of atezolizumab and bevacizumab demonstrated superior overall survival over the first-line standard, sorafenib, there has been a major therapeutic paradigm shift to immunotherapy-based regimens for HCC. While representing a great leap forward for the treatment of this cancer, the reality is that less than one-third of patients achieve an objective response to immune checkpoint inhibitor-based therapy, so there remains a significant clinical need for further therapeutic optimization. In this review, we provide an overview of the current landscape of immunotherapy for unresectable HCC and delve into the tumor intrinsic and extrinsic mechanisms of resistance to established immunotherapies with a focus on novel therapeutic targets with strong translational potential. Following this, we spotlight emerging immunotherapy approaches and notable clinical trials aiming to optimize immunotherapy efficacy in HCC that include novel immune checkpoint inhibitors, tumor microenvironment modulators, targeted delivery systems, and locoregional interventions. [ABSTRACT FROM AUTHOR]

Simple Summary: The application of electric pulses to promote the delivery of anticancer molecules in in vitro and in vivo models is a widely accepted technique known as electroporation (EP). This technique has been diffusely adopted to increase the effectiveness of different antitumor therapies both in pets and in humans. Moreover, this approach has been instrumental to devise and develop novel charging systems to generate nanovesicles embedded drugs and vaccines. This article summarizes the state of art of different EP applications, such as electrochemotherapy (ECT), irreversible electroporation, and EP-based cancer vaccines, in veterinary and human oncology, describing the most recent progresses and the most striking obtained clinical results. Electroporation (EP) is a broadly accepted procedure that, through the application of electric pulses with appropriate amplitudes and waveforms, promotes the delivery of anticancer molecules in various oncology therapies. EP considerably boosts the absorptivity of targeted cells to anticancer molecules of different natures, thus upgrading their effectiveness. Its use in veterinary oncology has been widely explored, and some applications, such as electrochemotherapy (ECT), are currently approved as first-line treatments for several neoplastic conditions. Other applications include irreversible electroporation and EP-based cancer vaccines. In human oncology, EP is still mostly restricted to therapies for cutaneous tumors and the palliation of cutaneous and visceral metastases of malignant tumors. Fields where veterinary experience could help smooth the clinical transition to humans include intraoperative EP, interventional medicine and cancer vaccines. This article recapitulates the state of the art of EP in veterinary and human oncology, recounting the most relevant results to date. [ABSTRACT FROM AUTHOR]

Simple Summary: Nasopharyngeal carcinoma (NPC) is a malignancy prevalent in Southeast Asia with the highest metastatic rate amongst other head and neck cancers. The absence of symptoms and unique anatomical positioning often result in late diagnosis, with resistance to chemo/radiotherapy further impacting its prognosis. While immunotherapies such as immune-checkpoint inhibitors (ICIs) and cytotoxic-T-lymphocytes (CTLs)-based cellular therapy have been progressively developed and approved, the mechanisms underlying the immunosuppressive tumour microenvironment (TME) in NPC remain poorly understood. Exosomes, small extracellular vesicles ranging in size from 30 to 150 nm, have emerged as important mediators of cell–cell communications within the TME. Accumulating evidence points tumour-derived exosomes (TEX) to NPC immune evasion and progression. Additionally, the detectability of TEX-bound NPC-specific markers in bodily fluids shows promise in enabling early diagnosis and prognostication. In this review, we aim to uncover TEX-mediated cellular–pathogenic pathways to open new avenues for an immunotherapeutic regimen in NPC and highlight the potential of exosome-based biomarkers in bettering NPC outcomes. Nasopharyngeal carcinoma (NPC) is an epithelial malignancy situated in the posterolateral nasopharynx. NPC poses grave concerns in Southeast Asia due to its late diagnosis. Together with resistance to standard treatment combining chemo- and radiotherapy, NPC presents high metastatic rates and common recurrence. Despite advancements in immune-checkpoint inhibitors (ICIs) and cytotoxic-T-lymphocytes (CTLs)-based cellular therapy, the exhaustive T cell profile and other signs of immunosuppression within the NPC tumour microenvironment (TME) remain as concerns to immunotherapy response. Exosomes, extracellular vesicles of 30–150 nm in diameter, are increasingly studied and linked to tumourigenesis in oncology. These bilipid-membrane-bound vesicles are packaged with a variety of signalling molecules, mediating cell–cell communications. Within the TME, exosomes can originate from tumour, immune, or stromal cells. Although there are studies on tumour-derived exosomes (TEX) in NPC and their effects on tumour processes like angiogenesis, metastasis, therapeutic resistance, there is a lack of research on their involvement in immune evasion. In this review, we aim to enhance the comprehension of how NPC TEX contribute to cellular immunosuppression. Furthermore, considering the detectability of TEX in bodily fluids, we will also discuss the potential development of TEX-related biomarkers for liquid biopsy in NPC as this could facilitate early diagnosis and prognostication of the disease. [ABSTRACT FROM AUTHOR]

Simple Summary: According to the stem cell theory of cancer, we should be judicious with immunotherapy in cancer care. When we do not realize that cancer originates from a stem cell and has stem-ness capabilities, immunotherapy could be gratifying for the wrong reasons and challenging with a cautionary tale. A simple way to understand the immune system is to separate the self from non-self. If it is self, the immune system tolerates and spares. If it is non-self, the immune system attacks and destroys. Consequently, if cancer has a stem cell origin and is a stem cell disease, we have a serious problem and a major dilemma with immunotherapy. Because many refractory cancers are more self than non-self, immunotherapy may become an uphill battle and pyrrhic victory in cancer care. In this article, we elucidate cancer immunity. We demonstrate for whom, with what, as well as when and how to apply immunotherapy in cancer care. We illustrate that a stem cell theory of cancer affects our perspectives and narratives of cancer. Without a pertinent theory about cancer's origin and nature, we may unwittingly perform misdirected cancer research and prescribe misguided cancer treatments. In the ongoing saga of immunotherapy, we are at a critical juncture. Because of the allure and promises of immunotherapy, we will be treating more patients not immediately threatened by their cancer. They may have more to lose than to gain, if we have a misconception and if we are on a wrong mission with immunotherapy. According to the stem cell theory of cancer, we should be careful with immunotherapy. When we do not know or realize that cancer originates from a stem cell and has stem-ness capabilities, we may cause more harm than good in some patients and fail to separate the truth from the myth about immunotherapy in cancer care. [ABSTRACT FROM AUTHOR]

Simple Summary: Adoptive cellular therapy (ACT) is a subset of immunotherapy that offers a compelling personalised alternative to immune checkpoint inhibition. However, there are challenges to be overcome in the use of ACT in solid organ malignancies and their investigation is currently in the early stages. In this review, we aim to discuss the benefits and challenges of available modalities of ACT in ovarian cancer, presenting the results of clinical trials and the rationale for upcoming studies. Ovarian cancers are typically poorly immunogenic and have demonstrated disappointing responses to immune checkpoint inhibitor (ICI) therapy. Adoptive cellular therapy (ACT) offers an alternative method of harnessing the immune system that has shown promise, especially with the success of chimeric antigen receptor T-cell (CAR-T) therapy in haematologic malignancies. So far, ACT has led to modest results in the treatment of solid organ malignancies. This review explores the possibility of ACT as an effective alternative or additional treatment to current standards of care in ovarian cancer. We will highlight the potential of ACTs, such as CAR-T, T-cell receptor therapy (TCR-T), tumour-infiltrating lymphocytes (TILs) and cell-based vaccines, whilst also discussing their challenges. We will present clinical studies for these approaches in the treatment of immunologically 'cold' ovarian cancer and consider the rationale for future research. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma (GBM) is the deadliest primary central nervous system (CNS) cancer in adults despite aggressive treatment. Once progressed, the prognosis is very poor and the effective traditional medicine treatment options are limited, so the management of recurrent glioblastoma (rGBM) remains challenging. Immunotherapy has revolutionized the prospects for many cancer types, but the intrinsic complexity of treating intracerebral tumors and the highly immunosuppressive environment have hampered the development of effective immunotherapies. The current focus of research in rGBM is on combination therapy, identifying predictive markers, and establishing synergy between immunotherapy and standard treatment. In this review, we discuss the current state of immunotherapy for rGBM, its future directions, and the challenges associated with each strategy. Recurrent glioblastoma (rGBM) is a highly aggressive form of brain cancer that poses a significant challenge for treatment in neuro-oncology, and the survival status of patients after relapse usually means rapid deterioration, thus becoming the leading cause of death among patients. In recent years, immunotherapy has emerged as a promising strategy for the treatment of recurrent glioblastoma by stimulating the body's immune system to recognize and attack cancer cells, which could be used in combination with other treatments such as surgery, radiation, and chemotherapy to improve outcomes for patients with recurrent glioblastoma. This therapy combines several key methods such as the use of monoclonal antibodies, chimeric antigen receptor T cell (CAR-T) therapy, checkpoint inhibitors, oncolytic viral therapy cancer vaccines, and combination strategies. In this review, we mainly document the latest immunotherapies for the treatment of glioblastoma and especially focus on rGBM. [ABSTRACT FROM AUTHOR]

Simple Summary: Toll-like receptor (TLR) agonists induce strong immune responses, which are used as an effective adjuvant system for vaccine development. L-pampo™ is our innovative adjuvant system containing TLR2 and TLR3 agonists, and it provides robust humoral and cellular immune responses against infectious diseases. Cancer vaccines are a type of cancer immunotherapy that activate the host immune system to recognize and eliminate cancer cells. Here, we investigate the anti-tumor efficacy and the mechanism of action of vaccines formulated with L-pampo™. We demonstrate that L-pampo™ directly stimulates the maturation and function of dendritic cells, which are essential antigen-presenting cells. Additionally, the vaccine formulated with L-pampo™ induces the recruitment of dendritic cells into lymph nodes, where they prime antigen-specific T-cell responses and induce potent anti-tumor effects. Interestingly, combining vaccines formulated with L-pampo™ with immune checkpoint inhibitors induces a synergistic anti-tumor effect, indicating that L-pampo™ can be a powerful cancer vaccine adjuvant and a potent partner for combination immunotherapy. TLR agonists have emerged as an efficient cancer vaccine adjuvant system that induces robust immune responses. L-pampo™, a proprietary vaccine adjuvant of TLR2 and TLR3 agonists, promotes strong humoral and cellular immune responses against infectious diseases. In this study, we demonstrate that vaccines formulated with L-pampo™ affect the recruitment and activation of dendritic cells (DCs) in draining lymph nodes (dLNs) and leading to antigen-specific T-cell responses and anti-tumor efficacy. We analyzed DC maturation and T-cell proliferation using flow cytometry and ELISA. We determined the effect of L-pampo™ on DCs in dLNs and antigen-specific T-cell responses using flow cytometric analysis and the ELISPOT assay. We employed murine tumor models and analyzed the anti-tumor effect of L-pampo™. We found that L-pampo™ directly enhanced the maturation and cytokine production of DCs and, consequently, T-cell proliferation. OVA or OVA peptide formulated with L-pampo™ promoted DC migration into dLNs and increased activation markers and specific DC subsets within dLNs. In addition, vaccines admixed with L-pampo™ promoted antigen-specific T-cell responses and anti-tumor efficacy. Moreover, the combination of L-pampo™ with an immune checkpoint inhibitor synergistically improved the anti-tumor effect. This study suggests that L-pampo™ can be a potent cancer vaccine adjuvant and a suitable candidate for combination immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer is a deadly disease with limited effective treatments. Despite growing interest in immunotherapy for other cancer types, immunotherapy has not shown significant utility in metastatic pancreatic cancer. However, investigators are examining the role of immunotherapy in the preoperative setting in order to prime the immune system to detect and prevent micrometastatic disease and recurrence. This scoping review describes 9 published trials of preoperative immunotherapy and summarizes 27 ongoing trials using preoperative immunotherapy, generally in combination with other standard neoadjuvant therapy. The results of these early trials have been promising but have not conclusively established a role for preoperative immunotherapy in pancreatic cancer. The results of the ongoing trials may be able to demonstrate whether combination immunotherapy prior to surgery can improve long-term outcomes. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease due to its late presentation and tendency to recur early even after optimal surgical resection. Currently, there are limited options for effective systemic therapy. In addition, PDAC typically generates an immune-suppressive tumor microenvironment; trials of immunotherapy in metastatic PDAC have yielded disappointing results. There is considerable interest in using immunotherapy approaches in the neoadjuvant setting in order to prime the immune system to detect and prevent micrometastatic disease and recurrence. A scoping review was conducted to identify published and ongoing trials utilizing preoperative immunotherapy. In total, 9 published trials and 27 ongoing trials were identified. The published trials included neoadjuvant immune checkpoint inhibitors, cancer vaccines, and other immune-modulating agents that target mechanisms distinct from that of immune checkpoint inhibition. Most of these are early phase trials which suggest improvements in disease-free and overall survival when combined with standard neoadjuvant therapy. Ongoing trials are exploring various combinations of these agents with each other and with chemotherapy and/or radiation. Rational combination immunotherapy in addition to standard neoadjuvant therapy has the potential to improve outcomes in PDAC, but further clinical trials are needed, particularly those which utilize an adaptive trial design. [ABSTRACT FROM AUTHOR]

Simple Summary: Given that selecting an appropriate target is the first step in developing effective cancer immunotherapy, we focus on melanoma-associated antigens (MAGEs), which are a subclass of cancer/testis (CT) antigens characterized by restricted expression in immune-privileged tissues and a variety of cancers. For a long time, possessing this combination of characteristics has made MAGEs a remarkable candidate for effective treatment. Based on promising clinical data from combinatorial therapies, ongoing clinical trials targeting MAGE-A antigens, as well as a thorough understanding of the crosstalk between cancer and immune control, a new era in cancer immunotherapy is expected. The goal of this review is to provide an in-depth understanding of the various strategies for targeting the MAGE-A family for cancer treatment, as well as to highlight some of the most exciting recent advances in this area. Early efforts to identify tumor-associated antigens over the last decade have provided unique cancer epitopes for targeted cancer therapy. MAGE-A proteins are a subclass of cancer/testis (CT) antigens that are presented on the cell surface by MHC class I molecules as an immune-privileged site. This is due to their restricted expression to germline cells and a wide range of cancers, where they are associated with resistance to chemotherapy, metastasis, and cancer cells with an increasing potential for survival. This makes them an appealing candidate target for designing an effective and specific immunotherapy, thereby suggesting that targeting oncogenic MAGE-As with cancer vaccination, adoptive T-cell transfer, or a combination of therapies would be promising. In this review, we summarize and discuss previous and ongoing (pre-)clinical studies that target these antigens, while bearing in mind the benefits and drawbacks of various therapeutic strategies, in order to speculate on future directions for MAGE-A-specific immunotherapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Among all intracranial tumors, 31.5% are malignant, and among those, glioblastomas account for 47%. Recently, our group reported the case of a patient with glioblastoma who underwent vaccination based on dendritic cells and experienced near-complete tumor remission. Here we report the results of a phase I/II prospective, non-controlled clinical trial with 37 patients harboring glioblastoma or grade 4 astrocytomas. Patients received monthly intradermal injections of allogenic dendritic cell vaccinations. The survival curves of the vaccinated populations were compared with patients from the GDC (Genomics Data Commons) database, which revealed that overall survival was 75% greater in the vaccinated glioblastoma group (16 to 28 months, hazard ratio 0.53) and 200% greater in the vaccinated astrocytoma grade 4 group (20 to 60 months, hazard ratio 0.18). Furthermore, seven patients remain alive to this day. We believe that the data reported here can foster the continued improvement of treatment protocols based on cellular immunotherapy. Immunotherapy for cancer treatment has gained increased attention in recent years. Recently, our group reported the case of a patient with glioblastoma who underwent vaccination based on dendritic cells and experienced a strong Th1 immune response together with near-complete tumor remission. Here we report the results of a phase I/II prospective, non-controlled clinical trial with 37 patients harboring glioblastoma or grade 4 astrocytomas. At the time of first recurrence after surgery, patients began receiving monthly intradermal injections of allogenic DC-autologous tumor cell hybridomas. Overall survival, quality of life, and immunological profiles were assessed prospectively. Compared with patients in the Genomic Data Commons data bank, overall survival for vaccinated patients with glioblastoma was 27.6 ± 2.4 months (vs. 16.3 ± 0.7, log-rank p < 0.001, hazard ratio 0.53, 95%CI 0.36–0.78, p < 0.01), and it was 59.5 ± 15.9 for vaccinated astrocytoma grade 4 patients (vs. 19.8 ± 2.5, log-rank p < 0.05, hazard ratio 0.18, 95%CI 0.05–0.62, p < 0.01). Furthermore, seven vaccinated patients (two IDH-1-mutated and five wild type) remain alive at the time of this report (overall survival 47.9 months, SD 21.1, range: 25.4–78.6 months since diagnosis; and 34.2 months since recurrence, range: 17.8 to 40.7, SD 21.3). We believe that the data reported here can foster the improvement of treatment protocols for high-grade gliomas based on cellular immunotherapy. [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]

Simple Summary: Therapeutic options for rare cancers are frequently limited and less effective than for common cancers. Therefore, novel therapeutic strategies to treat rare cancers are urgently required. Our clinical study on rare cancers showed that the biweekly WT1 Trio peptide vaccine comprising two WT1-cytotoxic T lymphocyte (CTL)-peptides and one WT1-helper T lymphocyte-peptide induced more robust immune responses targeting WT1 than the weekly WT1-CTL peptide (WT1-235) vaccine. In addition, the safety of WT1 Trio was confirmed without severe treatment-related adverse events, except grade 3 myasthenia gravis-like symptoms observed in a patient with thymic cancer (TC). Fifteen (33.3%) of the 45 patients with recurrent or advanced rare cancers, including malignant glioma, soft-tissue sarcoma, TC, and malignant pleural mesothelioma, achieved stable disease after 3 months of protocol treatment. Therefore, since WT1 is widely overexpressed in rare cancers, WT1-targeted immunotherapy may be a therapeutic strategy for rare cancers. No standard treatment has been established for most rare cancers. Here, we report a clinical trial of a biweekly WT1 tri-peptide-based vaccine for recurrent or advanced rare cancers. Due to the insufficient number of patients available for a traditional clinical trial, the trial was designed for rare cancers expressing shared target molecule WT1. The recruitment criteria included WT1-expressing tumors as well as HLA-A*24:02 or 02:01. The primary endpoints were immunoglobulin G (IgG) antibody (Ab) production against the WT1-235 cytotoxic T lymphocyte (CTL) epitope and delayed-type hypersensitivity (DTH) skin reactions to targeted WT1 CTL epitopes. The secondary endpoints were safety and clinical efficacy. Forty-five patients received WT1 Trio, and 25 (55.6%) completed the 3-month protocol treatment. WT1-235 IgG Ab was positive in 88.0% of patients treated with WT1 Trio at 3 months, significantly higher than 62.5% of the weekly WT1-235 CTL peptide vaccine. The DTH positivity rate in WT1 Trio was 62.9%, which was not significantly different from 60.7% in the WT1-235 CTL peptide vaccine. The WT1 Trio safety was confirmed without severe treatment-related adverse events, except grade 3 myasthenia gravis-like symptoms observed in a patient with thymic cancer. Fifteen (33.3%) patients achieved stable disease after 3 months of treatment. In conclusion, the biweekly WT1 Trio vaccine containing the WT1-332 helper T lymphocyte peptide induced more robust immune responses targeting WT1 than the weekly WT1-235 CTL peptide vaccine. Therefore, WT1-targeted immunotherapy may be a potential therapeutic strategy for rare cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: The Irish Association for Cancer Research (IACR) held its 58th annual conference from the 30th of March to the 1st of April 2022, in Cork, Ireland. The following article is a report of knowledge conveyed at the conference. There was a focus on cancer prevention in both "Early Detection" and "Cancer Vaccines" sessions, and cancer treatment in "Novel Therapeutics" and "Breakthrough Research" sessions. The research presented at this conference highlighted the interplay of both prevention and treatment, as many speakers focused on the same cancer but at different times in the treatment process. There was a push for more non-invasive early detection techniques, the current impact of cancer vaccines and new ways of further stratifying selection criteria for easier identification of high-risk individuals. This was coupled with novel treatment strategies and identification of new therapeutic targets. Innovation in both detection and treatment of cancer is necessary for the constant improvement in therapeutic strategies, especially in patients with novel or resistant variants of cancer. Cancer mortality rates have declined by almost 30% since 1991, however, depending on the cancer type, acquired resistance can occur to varying degrees. To combat this, researchers are looking towards advancing our understanding of cancer biology, in order to inform early detection, and guide novel therapeutic approaches. Through combination of these approaches, it is believed that a more complete and thorough intervention on cancer can be achieved. Here, we will discuss the advances and approaches in both detection and treatment of cancer, presented at the 58th Irish Association for Cancer Research (IACR) annual conference. [ABSTRACT FROM AUTHOR]

Simple Summary: The clinical use of immunoadjuvants is limited by transient responses and various side effects. This study investigated the multi-adjuvant approach of combining a TLR 7/8 agonist (522) and a STING agonist (DMXAA) to generate a robust anticancer immune response. Immunization with ovalbumin+DMXAA+522 resulted in the activation of DCs in lymph nodes, spleen, and tumor. The combination also elicited stronger antigen-specific CD8+ T cell and NK cell responses than the control or individual treatments. Immunization with OVA+DMXAA+522 resulted in significant tumor growth inhibition and improved survival compared to other controls. Immunostimulatory adjuvants that potently activate antigen-presenting cells and (in turn) prime cytotoxic T cells are a key component of anticancer vaccines. In this study, we investigated a multi-adjuvant approach combining a TLR 7/8 agonist (522) and a STING agonist (DMXAA) to promote enhanced antigen cross-presentation, stimulate specific antitumor T-cell responses, and provide improved anticancer efficacy. In vitro experiments using bone marrow-derived dendritic cells (BMDCs) confirmed enhanced activation with the 522-DMXAA combination based on both co-stimulatory molecule expression and pro-inflammatory cytokine secretion. The immunization of mice with vaccines comprising both 522 and DMXAA resulted in greater antitumor efficacy in B16F10 melanoma and MB49 bladder tumor models relative to mono-agonist vaccines. Flow cytometry-based analysis of immune cells from immunized mice revealed the significant activation of antigen-presenting cells, increased numbers of activated and Ag-specific CD8+ T cells in the spleen and lymph nodes, modest NK cell activation, and an overall reduction in CD206+ macrophages. These results were supported by an increase in the levels of IFN-γ and a reduction in IL-10 levels in the sera. Taken together, these findings demonstrate the potential of the TLR7/8 and STING agonist combination as vaccine adjuvants to activate both innate and adaptive immune responses. [ABSTRACT FROM AUTHOR]

Simple Summary: Personalized neoantigen vaccines are a diverse group of personally tailored cancer vaccines that strengthen patients´ own immune reaction against cancer antigens. We analyzed 147 neoantigen vaccine clinical trials from ClinicalTrials.gov database and showed that peptide vaccines were the dominating vaccine type, while there were multiple new neoantigen vaccine types in the field. We also showed that neoantigen vaccines were mostly used in the treatment of small cell lung cancer, non-small cell lung cancer, melanoma, and glioma. According to our results neoantigen vaccines work at their best when combined with other treatments such as immune checkpoint inhibitors, chemotherapy, and radiation therapy. The effect of some neoantigen vaccine types were also often promoted with adjuvant therapy where poly-ICLC were the most recurrent adjuvant choice. Personalized neoantigen vaccines are a highly specific cancer treatment designed to induce a robust cytotoxic T-cell attack against a patient's cancer antigens. In this study, we searched ClinicalTrials.gov for neoantigen vaccine clinical trials and systematically analyzed them, a total of 147 trials. Peptide vaccines are the largest neoantigen vaccine type, comprising up to 41% of the clinical trials. However, mRNA vaccines are a growing neoantigen vaccine group, especially in the most recent clinical trials. The most common cancer types in the clinical trials are glioma, lung cancer, and malignant melanoma, being seen in more than half of the clinical trials. Small-cell lung cancer and non-small-cell lung cancer are the largest individual cancer types. According to the results from the clinical trials, neoantigen vaccines work best when combined with other cancer treatments, and popular combination treatments include immune checkpoint inhibitors, chemotherapy, and radiation therapy. Additionally, half of the clinical trials combined neoantigen vaccines with an adjuvant to boost the immune effects, with poly-ICLC being the most recurrent adjuvant choice. This study clarifies the rapid clinical trial development of personalized neoantigen vaccines as an emerging class of cancer treatment with increasingly diversified opportunities in classes, indications, and combinatorial treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer vaccine therapy is promising, though its efficacy is compromised in an immunosuppressive tumor microenvironment. Tumor-associated macrophages (TAMs) have the potential to be repolarized to an antitumor subtype, and their antigen-presenting ability might enhance the efficacy of cancer vaccination. Here, we aimed to develop a nanoparticle with adjuvant effect that could be a carrier for neoantigen-based vaccine to target and repolarize TAMs in situ. Therefore, we prepared a hyaluronic acid and mannose dual-modified iron oxide nanoparticle, and the enhanced efficiency of nanoparticle intake of macrophages was confirmed. It could repolarize macrophages and outperformed a commercialized iron oxide nanoparticle, ferumoxytol. Combined with peptides, this nanoparticle strongly inhibited TC1 tumor growth, and 40% of mice reached complete regression. This is the first report using mannose, hyaluronic acid, and iron oxide to target TAMs and achieve ideal outcomes in vivo. This study provides a facile nanoplatform for neoantigen-based vaccine therapy and a reference for repolarizing TAMs to promote immunotherapy. Neoantigen-based cancer vaccine therapy is a breakthrough in the field of immunotherapy. However, it is difficult for vaccines against neoantigens to overcome the immunosuppressive microenvironment, where tumor-associated macrophages (TAMs) play a significant role. Herein, we report an iron oxide nanoparticle modified with hyaluronic acid and mannose to reshape the tumor microenvironment by targeting and repolarizing TAMs from protumor M2 to antitumor M1 phenotype. Mannose decoration could confer the nanoparticle-enhanced TAM targeting ability, while hyaluronic acid and iron oxide could repolarize M2-like macrophages both in vitro and in vivo. Combined with antigenic peptides, this nanovaccine could significantly increase the infiltration of CD8+ T cells into tumor tissue and strongly activate dendritic cells in sentinel lymph nodes. Finally, we used the dual-modified nanoparticles to first convert the tumor microenvironment and then the nanovaccine administration in a TC1 tumor model to further enhance efficacy. This strategy inhibited tumor growth and achieved a 40% cure rate in mice (two of five). In summary, this study provides a potent and rationally designed nanoadjuvant to enhance antitumor efficiency and facilitate delivery of neoantigen vaccines by repolarizing TAMs and harmonizing immune cells. [ABSTRACT FROM AUTHOR]

Simple Summary: The immunopeptidome of cancer cells is a treasure trove of neoantigens bound to MHC molecules, thus a great source for mining immunopeptides for immunotherapy applications, including cancer vaccines. Immunopeptides may encompass post-translational modifications that are overlooked by genomic and transcriptomic tools. We review post-translational modifications that have been uncovered, and how this information could be harnessed for cancer vaccines. Although harnessing the immune system for cancer therapy has shown success, response to immunotherapy has been limited. The immunopeptidome of cancer cells presents an opportunity to discover novel antigens for immunotherapy applications. These neoantigens bind to MHC class I and class II molecules. Remarkably, the immunopeptidome encompasses protein post-translation modifications (PTMs) that may not be evident from genome or transcriptome profiling. A case in point is citrullination, which has been demonstrated to induce a strong immune response. In this review, we cover how the immunopeptidome, with a special focus on PTMs, can be utilized to identify cancer-specific antigens for immunotherapeutic applications. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite recent therapeutic advances in the treatment of prostate cancer, metastatic castration-resistant prostate cancer continues to cause significant morbidity and mortality. New research into highly expressed proteins in metastatic castration-resistant prostate cancer shows that Six-Transmembrane Epithelial Antigen of the Prostate 1–4 (STEAP1–4) are significant drivers of prostate cancer aggressiveness and metastasis. STEAP1, in particular, is highly expressed on the plasma membrane of prostate cancer cells and has received significant attention as a potential therapeutic target. This review highlights what is known about STEAP1–4 and identifies knowledge gaps that require further research. Six-Transmembrane Epithelial Antigen of the Prostate 1–4 (STEAP1–4) compose a family of metalloproteinases involved in iron and copper homeostasis and other cellular processes. Thus far, five homologs are known: STEAP1, STEAP1B, STEAP2, STEAP3, and STEAP4. In prostate cancer, STEAP1, STEAP2, and STEAP4 are overexpressed, while STEAP3 expression is downregulated. Although the metalloreductase activities of STEAP1–4 are well documented, their other biological functions are not. Furthermore, the properties and expression levels of STEAP heterotrimers, homotrimers, heterodimers, and homodimers are not well understood. Nevertheless, studies over the last few decades have provided sufficient impetus to investigate STEAP1–4 as potential biomarkers and therapeutic targets for prostate cancer. In particular, STEAP1 is the target of many emerging immunotherapies. Herein, we give an overview of the structure, physiology, and pathophysiology of STEAP1–4 to provide context for past and current efforts to translate STEAP1–4 into the clinic. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy helps a person's immune system to target tumor cells. Recent advances in cancer immunotherapy, including immune checkpoint inhibition, chimeric antigen receptor T-cell therapy and cancer vaccination, have changed the landscape of cancer treatment. These approaches have had profound success in certain cancer types but still fail in the majority of cases. This review will cover both successes and current challenges in cancer immunotherapy, as well as recent advances in the field of basic tumor immunology that will allow us to overcome resistance to existing treatments. Cancer immunotherapy has revolutionized the field of oncology in recent years. Harnessing the immune system to treat cancer has led to a large growth in the number of novel immunotherapeutic strategies, including immune checkpoint inhibition, chimeric antigen receptor T-cell therapy and cancer vaccination. In this review, we will discuss the current landscape of immuno-oncology research, with a focus on elements that influence immunotherapeutic outcomes. We will also highlight recent advances in basic aspects of tumor immunology, in particular, the role of the immunosuppressive cells within the tumor microenvironment in regulating antitumor immunity. Lastly, we will discuss how the understanding of basic tumor immunology can lead to the development of new immunotherapeutic strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Conventional antitumor drugs have limitations, including poor water solubility and lack of targeting capability, with consequent non-specific distribution, systemic toxicity, and low therapeutic index. Nanotechnology promises to overcome these drawbacks by exploiting the physical properties of diverse nanocarriers that can be linked to moieties with binding selectivity for cancer cells. The use of nanoparticles as therapeutic formulations allows a targeted delivery and a slow, controlled release of the drug(s), making them tunable modules for applications in precision medicine. In addition, nanoparticles are also being developed as cancer vaccines, offering an opportunity to increase both cellular and humoral immunity, thus providing a new weapon to beat cancer. Malignant tumors originate from a combination of genetic alterations, which induce activation of oncogenes and inactivation of oncosuppressor genes, ultimately resulting in uncontrolled growth and neoplastic transformation. Chemotherapy prevents the abnormal proliferation of cancer cells, but it also affects the entire cellular network in the human body with heavy side effects. For this reason, the ultimate aim of cancer therapy remains to selectively kill cancer cells while sparing their normal counterparts. Nanoparticle formulations have the potential to achieve this aim by providing optimized drug delivery to a pathological site with minimal accumulation in healthy tissues. In this review, we will first describe the characteristics of recently developed nanoparticles and how their physical properties and targeting functionalization are exploited depending on their therapeutic payload, route of delivery, and tumor type. Second, we will analyze how nanoparticles can overcome multidrug resistance based on their ability to combine different therapies and targeting moieties within a single formulation. Finally, we will discuss how the implementation of these strategies has led to the generation of nanoparticle-based cancer vaccines as cutting-edge instruments for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

We have proposed that safe and effective protection against the development of adult onset cancers may be achieved by vaccination against tissue-specific self-proteins that are "retired" from expression at immunogenic levels in normal tissues as we age, but are overexpressed in emerging tumors. α-Lactalbumin is an example of a "retired" self-protein because its expression in normal tissues is confined exclusively to the breast during late pregnancy and lactation, but is also expressed in the vast majority of human triple negative breast cancers (TNBC)--the most aggressive and lethal form of breast cancer and the predominant form that occurs in women at high genetic risk including those with mutated BRCA1 genes. In anticipation of upcoming clinical trials, here we provide preclinical data indicating that α-lactalbumin has the potential as a vaccine target for inducing safe and effective primary immunoprevention as well as immunotherapy against TNBC. [ABSTRACT FROM AUTHOR]

Therapeutic cancer vaccines have the potential to generate a long lasting immune response that will destroy tumor cells with specificity and safety, in contrast to many other current cancer therapies. Clinical success to date has been limited by a number of factors including choice of immunogenic cancer rejection antigens, optimization of vaccine platforms and immune adjuvants to effectively polarize the immune response, and incorporation of strategies to reverse cancer mediated immune suppression by utilization of effective adjuvant/immune modulators. WT-1 (Wilms' tumor gene 1) is a cancer antigen that is required for tumorigenesis, expressed in a high percentage of tumor cells and rarely expressed in adult normal cells. Moreover spontaneous immunity to WT-1 is seen in cancer patients and can be augmented with various therapeutic vaccine approaches. IRX-2 is an immune modulator with demonstrated preclinical and clinical pleiotropic immune activities including enhancement of the immune response to potential tumor antigens. This paper presents the rationale and preclinical data for utilizing the WT-1 tumor antigen in a novel vaccine platform consisting of a synthetic long peptide containing multiple class I and class II epitopes in combination with the IRX-2 immunomodulatory regimen to overcome immuno-suppressive pathways and enhance the anti-tumor response. [ABSTRACT FROM AUTHOR]

Intravesical instillation of bacillus Calmette Guérin (BCG) for the treatment of urothelial carcinoma (UC) of the bladder is based on the BCG-induced immune response, which eradicates and prevents bladder cancer. The results of recent studies have suggested that not only major histocompatibility complex (MHC)-nonrestricted immune cells such as natural killer cells, macrophages, neutrophils, etc., but also MHC-restricted CD8+ T cells play an important role and are one of the main effectors in this therapy. Better understanding of the mechanism of BCG immunotherapy supports the idea that active immunotherapy through its augmented T cell response can have great potential for the treatment of advanced UC. In this review, progress in immunotherapy for UC is discussed based on data from basic, translational and clinical studies. We also review the escape mechanism of cancer cells from the immune system, and down-regulation of MHC class I molecules. [ABSTRACT FROM AUTHOR]

Successful cancer immunotherapy is confounded by the magnitude of the tumor burden and the presence of immunoregulatory elements that suppress an immune response. To approach these issues, 26 patients with advanced treatment refractory cancer were enrolled in a safety/feasibility study wherein a conventional treatment modality, intensity modulated radiotherapy (IMRT), was combined with dendritic cell-based immunotherapy. We hypothesized that radiation would lower the tumor burdens, decrease the number/function of regulatory cells in the tumor environment, and release products of tumor cells that could be acquired by intratumoral injected immature dendritic cells (iDC). Metastatic lesions identified by CT (computed tomography) were injected with autologous iDC combined with a cytokine-based adjuvant and KLH (keyhole limpet hemocyanin), followed 24 h later by IV-infused T-cells expanded with anti-CD3 and IL-2 (AT). After three to five days, each of the injected lesions was treated with fractionated doses of IMRT followed by another injection of intratumoral iDC and IV-infused AT. No toxicity was observed with cell infusion while radiation-related toxicity was observed in seven patients. Five patients had progressive disease, eight demonstrated complete resolution at treated sites but developed recurrent disease at other sites, and 13 showed complete response at various follow-up times with an overall estimated Kaplan-Meier disease-free survival of 345 days. Most patients developed KLH antibodies supporting our hypothesis that the co-injected iDC are functional with the capacity to acquire antigens from their environment and generate an adaptive immune response. These results demonstrate the safety and effectiveness of this multimodality strategy combining immunotherapy and IMRT in patients with advanced malignancies. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite efforts to develop novel treatment strategies, human and canine osteosarcomas continue to have limited overall survival. Spontaneous canine osteosarcoma shares many molecular similarities with humans, and shows the same aggressive disease course, thereby rendering the dog an effective model for the human disease equivalent. In both species, surgery followed by chemotherapy represents the gold standard treatment. Immunotherapy represents a promising treatment modality. A peptide-based anticancer vaccine was administered to 20 dogs with non-metastatic osteosarcoma as an add-on therapy to standard treatment consisting of limb amputation and adjuvant chemotherapy. Endpoints were to evaluate the efficacy and safety of this combined therapeutic approach. By using a bacterial-based strategy for vaccine development, we report an efficacious induction of an immune response, ultimately translating in improved outcome compared with historical controls receiving standard-of-care treatment. The results of this clinical trial provide promising potential for future management in both humans and dogs with osteosarcoma. Despite efforts to develop novel treatment strategies, human and canine osteosarcomas continue to have poor prognosis and limited overall survival. The aim of this clinical trial was to test the antitumor effect and safety of multiple dermal administrations of a peptide-based anticancer vaccine in dogs with non-metastatic appendicular osteosarcoma undergoing standard of care (SOC), consisting of limb amputation and adjuvant chemotherapy. Salmonella-infected canine osteosarcoma cells were induced to release immunogenic peptides in the extracellular space via Cx43 hemichannels opening; the secretome was collected and constituted the vaccine. Dogs with non-metastatic appendicular osteosarcoma were eligible for recruitment. Following limb amputation and adjuvant carboplatin, dogs were vaccinated on a monthly basis for six times and followed up with serial thoracic radiographs. A population of dogs undergoing SOC treatment (amputation and adjuvant carboplatin) before the vaccine was available served as controls. Primary endpoints were time to metastasis (TTM) and tumor-specific survival (TSS). Secondary endpoints were feasibility, toxicity, T-cell and humoral immune responses. A total of 20 dogs were vaccinated along with SOC and 34 received SOC only. Vaccine-specific humoral and T-cell responses were observed; their amplitude correlated with TSS. Vaccine-associated toxicity was not recorded. TTM and TSS were significantly longer in vaccinated versus unvaccinated dogs (TTM: 308 vs. 240 days, respectively; p = 0.010; TSS: 621 vs. 278 days, respectively; p = 0.002). In dogs with non-metastatic osteosarcoma undergoing SOC, the addition of a bacteria-based vaccination strategy increased TTM, thereby prolonging survival, while maintaining a safe profile. Additionally, vaccinated dogs developed a long-term tumor-specific response, as documented by the immunomonitoring of these patients over time. These results hold promise for future management of canine osteosarcoma. [ABSTRACT FROM AUTHOR]