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PURPOSE Next-generation sequencing (NGS) testing is being incorporated into routine standard of care for patients with cancer. Immune checkpoint inhibitors (CPIs) are approved for use in both tumor-specific and tumor-agnostic indications. We sought to determine tumor type–specific or tumor-agnostic correlations between mutations detected by NGS and response to CPIs. MATERIALS AND METHODS A retrospective analysis of 26,004 patient records with NGS data available was conducted. Time to treatment failure and overall survival analyses were performed. Hazard ratios and associated statistics were computed in the R programming language. The study was considered exempt from internal review board review and data were considered nonhuman subjects. RESULTS Response to CPIs varied between tumor types with melanoma and lung cancer performing relatively better on CPIs than other tumor types. Within tumor types, response to CPIs was stratified by mutations in specific genes. Tumor-agnostic markers including high tumor mutation burden and microsatellite instability-high were also associated with longer time to treatment failure on CPIs. Importantly, within the high tumor mutation burden and microsatellite instability-high groups, mutations in individual genes correlate with response to CPIs. CONCLUSION The results from commercial NGS panels may be used to stratify patients for response to CPIs. In tumors where CPIs show relatively low efficacy, there may be distinct patient populations—based on gene mutation status—that are predicted to have better response to CPIs. Likewise, there may be distinct patient populations who do relatively worse on CPIs within tumor types known to respond well to CPIs.

The present study reviews the use of tumor-specific antibodies conjugated to fluorescent dyes in preclinical and clinical studies to enhance visualization of primary tumors and metastases for fluorescence-guided surgery (FGS) in colorectal cancer (CRC). A search strategy was developed using the peer-reviewed National Center for Biotechnology Information (NCBI) database on PubMed. Studies using tumor-specific fluorescence imaging and FGS techniques on murine models of colorectal cell lines or patient-derived orthotopic xenograft (PDOX) colorectal cancer are reviewed. A total of 24 articles were identified that met the inclusion criteria, 21 preclinical and 3 clinical trials. The most widely used target antigen in preclinical and clinical trials was carcinoembryonic antigen (CEA). Mouse studies and clinical studies have demonstrated that the use of FGS in CRC can aid in decreased residual tumor and decreased rates of recurrence. As the mainstay of colorectal cancer treatment is surgery, the addition of intraoperative fluorescence imaging can help locate tumor margins, visualize occult micro-metastases, drive surgical decision making and improve patient outcomes.

Adoptive cell transfer (ACT) with tumor-infiltrating lymphocytes (TILs) can generate durable clinical responses in patients with metastatic melanoma and ongoing trials are evaluating efficacy in other advanced solid tumors. The aim of this study was to develop methods for the expansion of tumor-reactive TIL from resected soft tissue sarcoma to a degree required for the ACT. From 2015 to 2018, 70 patients were consented to an institutional review board-approved protocol, and fresh surgical specimens were taken directly from the operating room to the laboratory. Fragments of the tumor (1 mm(3)) or fresh tumor digest were placed in culture for a period of 4 weeks. Successfully propagated TIL from these cultures were collected and analyzed by flow cytometry. TIL were cocultured with autologous tumor and function was assessed by measurement of interferon-γ in the supernatant by enzyme-linked immunosorbent assay. Initial TIL cultures were further expanded using a rapid expansion protocol. Nearly all specimens generated an initial TIL culture (91% fragment method, 100% digest method). The phenotype of the TIL indicated a predominant CD3(+) population after culture (43% fragment, 52% digest) and TIL were responsive to the autologous tumor (56% fragment, 40% digest). The cultured TIL expanded to a degree required for clinical use following rapid expansion protocol (median: 490-fold fragment, 403-fold digest). The data demonstrate the feasibility of TIL culture from fresh soft tissue sarcoma. The derived TIL have tumor-specific reactivity and can be expanded to clinically relevant numbers. An active ACT clinical trial using the methods described in this report is now approved for patients with metastatic soft tissue sarcoma.

TSNAD is a one-stop software solution for predicting neoantigens from the whole genome/exome sequencing data of tumor-normal pairs. Here we present TSNAD v2.0 which provides several new features such as the function of RNA-Seq analysis including gene expression and gene fusion analysis, the support of different versions of the reference genome. Most importantly, we replace the NetMHCpan with DeepHLApan we developed previously, which considers both the binding between peptide and major histocompatibility complex (MHC) and the immunogenicity of the presented peptide-MHC complex (pMHC). TSNAD v2.0 achieves good performamce on a standard dataset. For better usage, we provide the Docker version and the web service of TSNAD v2.0. The source code of TSNAD v2.0 is freely available at https://github.com/jiujiezz/tsnad. And the web service of TSNAD v2.0 is available at http://biopharm.zju.edu.cn/tsnad/.

Purpose of the study. To determine the effectiveness of antiandrogenic therapy — 10-year General and tumor-specific survival (OV, OSV) depending on the type of hormone therapy, the stage of the disease, and the risk of progression.Patients and methods. The study was based on a retrospective analysis of 100 patients with localized, locally advanced, and metastatic prostate cancer over the period 2008–2018. The assessment was conducted in 2019. All patients received antiandrogenic treatment in the form of castration therapy (n=59) and combined (complex) treatment (n=41) in various variants and modes for more than 5 years. Patients had a 100% 5-year survival rate. The control point of the study was General and tumor- specific survival, as well as prognostic factors that determine this survival. Results. By the end of the study, 53 (53%) patients were alive, 8 (8%) died, and 39 (39%) patients were censored. The highest percentage of 10-year overall survival was achieved in localized stages of the disease and was 52% (31 patients) — stage 1, 38% (22 patients) — stage 2. Tumor specific survival rate (1–2 stages) — 62% (33 patients). At stage 3–30% (14 patients) and 51% (21 patients) and at stage 4–18% (1 patient) and 32% (2 patients), respectively. Depending on the risk of progression (Gleason index), high rates of both General and tumor- specific survival were achieved with low Gleason (2–5), and moderate risk of Gleason progression (6–7), and were 85% and 62%, respectively. The most effective method of treatment that determines the 10-year overall survival was combined (hormone radiation) therapy, which allowed to achieve results in 75% of patients. The tumor — specific survival rate was more than 80%.Conclusion. In real clinical practice, the use of antideprivation therapy in various variants and modes allows to obtain a 10-year General and tumor- specific survival rate in 75% and more than 80% of patients. Stratification of patients by risk groups forms a personalized approach to the treatment of each patient. Use of research treatment regimens in the work STAMPEDE, CHAARTED allows to increase the overall survival of patients with metastatic stage of the disease.

Gliomas are the most aggressive form of brain tumors responsible for the majority of brain cancer related deaths. Interleukin (IL)-6, 10 and tumor necrosis factor (TNF)- α are tumor specific proteins that are expressed in gliomas. This study aims to estimate the pre- and postoperative levels of serum markers of these cytokines to evaluate any bearing with its grade and volume.Prospective analysis of 80 patients of newly-diagnosed gliomas of any grade was carried out. Pre- and postoperative blood samples day one, one month and at 3rd month of surgery was taken and levels of IL-6, 10 and TNF- α measured and matched with 20 healthy controls.Of the 80 patients, 3 patients had pilocytic astrocytoma, 4 had ganglioglioma, 9 had oligodendroglioma, 17 had diffuse astrocytoma, 5 had anaplastic astrocytoma while 43 had glioblastoma. Preoperative levels of IL-6 and TNF- α was found to be markedly raised in high grade gliomas. Positive correlation was seen between IL-6 with the grade of tumor and high-grade tumors were seen to be more significantly correlated with IL-6. However, preoperative IL-10 in both low and high grade of gliomas did not show any correlation with the volume and grade of tumor.High level of IL-6 and TNF-α in peripheral blood in patients of high-grade gliomas provides clue to the invasiveness of the disease which can be useful for understanding the premorbid development of tumor and perhaps extrapolating to ongoing tumor response to treatment.

Cancer is one of the diseases that have the highest mortality, which threatens the human health. Chemotherapy functions as the most widely used strategy in clinic to treat cancer, still exists urgent problems, like lacking selectivity and causing severe side effects. According to detailed researches on the metabolism, functions and histology of cancer tissues, many different features of cancer are uncovered, like lower pH in microenvironment, abnormal redox level in intracellular compartments and elevated expression level of several enzymes and receptors. Recently, the development of smart nanoparticles that response to tumor specific microenvironment has lighted up hope for selective cancer therapy. Herein, this review mainly focuses on pH-sensitive nanoscale materials for anti-cancer drug delivery. We summarized the formation progress of acidic tumor microenvironment, the mechanism of pH-responsive drug delivery system and nanomaterials that responsive to acidic pH in tumor microenvironment.

Liquid biopsies can be a rapid, cost-effective and noninvasive alternative to tumor biopsies for detecting genetic mutations in somatic tumors. Genetic profiling of liquid biopsies can also be used to identify novel antigens for targeted therapy, provide updated information on disease prognosis and evaluate treatment efficacy. In this study, we aimed to examine mutations that could be identified in liquid biopsy and their potential implications for personalized dendritic cell immunotherapy using neoantigens. We analyzed the genomic profiles of 99 blood samples from 85 patients with 22 different types of cancer using two commercially available liquid biopsy tests before the patients underwent standard cancer treatment and dendritic cell immunotherapy. Nonsynonymous mutations were detected in more than 90% of the samples, with an average frequency of 3.6 mutations per sample. The tumor mutations were specific to each patient, as approximately 94.7% of the mutations were so unique that there was almost no duplication among the patients. Clonal evolution was observed in two patients just before or after chemotherapy, radiotherapy and immunotherapy. These findings indicate that liquid biopsy can be a potential surrogate for neoantigen-based immunotherapy and the importance of tailoring neoantigen-based immunotherapy in accordance with the liquid biopsy result in each treatment stage.

Simple Summary In recent years, many new therapeutic options for newly diagnosed, as well as relapsed and refractory multiple myeloma (MM) have been approved. They have dramatically improved progression-free and overall survival. Despite these advances, MM still remains incurable and eventually all cases will become refractory to standard treatments. Many new substances and drug classes have become available, which has greatly increased treatment options. However, the right sequencing of novel treatments has become the main challenge in MM therapy. Guidelines can provide helpful recommendations, but diversifying treatment patterns make a one-fits-all approach impossible. This review aims to summarize existing evidence regarding the sequencing of novel agents and will also focus on groups of special interest such as elderly and frail patients. Abstract The treatment landscape for relapsed multiple myeloma (RRMM) has experienced an unprecedented wave of innovation. Implementation of numerous new substances and drug classes with different modes of action is made possible in routine clinical practice. Next generation proteasome inhibitors, monoclonal antibodies, as well as first in class agents such as selinexor and venetoclax have widened the therapeutic spectrum. This has led to an increase in progression-free and overall survival. Consequently, new challenges for treating physicians in choosing the right treatment at the right stage of the disease have been generated. Several trials support the use of novel agents in the frontline treatment of newly diagnosed multiple myeloma. The use of lenalidomide or bortezomib as a backbone in the first-line setting, requires strategies for treatment once these patients relapse and are refractory to these drugs. Despite the variety of options, selecting the optimal treatment strategy is difficult, since multiple factors have to be considered: patient-specific factors such as age and co-morbidities, as well as myeloma/tumor specific factors such as cytogenetics and relapse kinetics. This review intends to summarize the existing data and guidelines regarding the optimal sequencing of treatments of RRMM using already approved agents as well as agents under investigation.

Intractable cancers such as osteosarcoma (OS) and oral cancer (OC) are highly refractory, recurrent, and metastatic once developed, and their prognosis is still disappointing. Tumor-targeted therapy eliminating cancers effectively and safely is the current clinical choice. Since aggressive tumors have inherent or acquired resistance to multidisciplinary therapies targeting apoptosis, tumor-specific induction of another cell death modality is a promising avenue to meet the goal. Here, we report that a cold atmospheric air plasma-activated medium (APAM) can induce cell death in OS and OC via a unique mitochondrial clustering. This event was named monopolar perinuclear mitochondrial clustering (MPMC) because of the characteristic unipolar mitochondrial perinuclear aggregation. APAM had potent antitumor activity both in vitro and in vivo. APAM caused apoptosis, necrotic cell death, and autophagy. APAM contained hydrogen peroxide and increased mitochondrial ROS (mROS), while the antioxidant N-acetylcysteine (NAC) prevented cell death. MPMC occurred following mitochondrial fragmentation coinciding with nuclear damages. MPMC was accompanied by the tubulin network remodeling and mitochondrial lipid peroxide (mLPO) accumulation and prevented by NAC and the microtubule inhibitor, Nocodazole. Increased Cardiolipin (CL) oxidation was also seen, and NAC and the peroxy radical scavenger Ferrostatin-1 prevented it. In contrast, in fibroblasts, APAM induced minimal cell death, mROS generation, mLPO accumulation, CL oxidation, and MPMC. These results suggest that MPMC is a tumor-specific cause of cell death via mitochondrial oxidative stress and microtubule-driven mitochondrial motility. MPMC might serve as a promising target for exerting tumor-specific cytotoxicity. Graphical abstract

Alterations to mismatch repair (MMR) pathways are a known cause of cancer, particularly colorectal and endometrial carcinomas. Recently, checkpoint inhibitors have been approved for use in MMR-deficient cancers of any type (Prasad et al. in JAMA Oncol 4:157-158, 2018). Functional studies in breast cancer have shown associations between MMR loss, resistance to aromatase inhibitors and sensitivity to palbociclib (Haricharan et al. in Cancer Discov 7:1168-1183, 2017). Herein, we investigate the clinical meaning of MMR deficiency in breast cancer by immunohistochemical assessment of MSH2, MSH6, MLH1 and PMS2 on a large series of breast cancers linked to detailed biomarker and long-term outcome data.Cases were classified as MMR intact when all four markers expressed nuclear reactivity, but MMR-deficient when at least one of the four biomarkers displayed loss of nuclear staining in the presence of positive internal stromal controls on the tissue microarray core.Among the 1635 cases with interpretable staining, we identified 31 (1.9%) as MMR-deficient. In our cohort, MMR deficiency was present across all major breast cancer subtypes, and was associated with high-grade, low-progesterone receptor expression and high tumor-infiltrating lymphocyte counts. MMR deficiency is significantly associated with inferior overall (HR 2.29, 95% CI 1.02-5.17, p = 0.040) and disease-specific survival (HR 2.71, 95% CI 1.00-7.35, p = 0.042) in the 431 estrogen receptor-positive patients who were uniformly treated with tamoxifen as their sole adjuvant systemic therapy.Overall, this study supports the concept that breast cancer patients with MMR deficiency as assessed by immunohistochemistry may be good candidates for alternative treatment approaches such as immune checkpoint or CDK4 inhibitors.

Objectives Progress in multiple myeloma treatment allows patients to achieve deeper responses, for which the assessment of minimal residual disease (MRD) is critical. Typically, bone marrow samples are used for this purpose; however, this approach is site‐limited. Liquid biopsy represents a minimally invasive and more comprehensive technique that is not site‐limited, but equally challenging. Methods While majority of current data comes from short‐term studies, we present a long‐term study on blood‐based MRD monitoring using tumor‐specific cell‐free DNA detection by ASO‐qPCR. One hundred and twelve patients were enrolled into the study, but long‐term sampling and analysis were feasible only in 45 patients. Results We found a significant correlation of quantity of tumor‐specific cell‐free DNA levels with clinically meaningful events [induction therapy (P = .004); ASCT (P = .012)]. Moreover, length of cfDNA fragments is associated with better treatment response of patients. Conclusions These results support the concept of tumor‐specific cell‐free DNA as a prognostic marker.

18F-Fluoro-deoxyglucose positron emission computed tomography (18F-FDG PET CT) is an established modality used mainly in oncology. Though it has widespread oncologic indications, it is not tumor specific. Apart from the physiological distribution, uptake of FDG may be seen in many benign conditions, including infection and inflammation in children and adults. Performing and acquiring a technically adequate PET CT study may be more challenging in children. Proper preparation and an acceptable imaging protocol will help to avoid re-acquisition and in minimizing the radiation exposure. Sound knowledge of the physiological variants and benign conditions that are specific to the pediatric population will aid in correct interpretation of the PET CT study. It is important that radiologists and Nuclear Medicine physicians who report these studies are well-acquainted with these pitfalls to avoid false positive studies.

Understanding the molecular mechanisms of cancer biology introduces targeted therapy as a complementary method along with other conventional therapies. Recombinant immunotoxins are tumor specific antibodies that their recognizing fragment is utilized for delivering modified toxins into tumor cells. These molecules have been considered as a targeted strategy in the treatment of human cancers. HER2 tumor biomarker is a transmembrane tyrosine kinase receptor that can be used for targeted therapies in the forms of anti-HER2 monoclonal antibodies, antibody–drug conjugates and immunotoxins. There have been many studies on HER2-based immunotoxins in recent years, however, little progress has been made in the clinical field which demanded more improvements. Here, we summarized the HER2 signaling and it’s targeting using immunotherapeutic agents in human cancers. Then, we specifically reviewed anti-HER2 immunotoxins, and their strengths and drawbacks to highlight their promising clinical impact.

Neutrophils are important for tumor immunosurveillance; yet their roles in tumorigenesis remain debating due to incomplete understanding of their heterogeneity and functional plasticity. Here we resolve at single-cell resolution the heterogeneity of neutrophils in tumor-bearing mice and patients with gastric cancer. Our results define CXCR2negCD44neg neutrophils as a tumor-specific (tsNeu) population with activated (CD14high) but atavistic phenotypes (CD53highCD63high). Human and mouse tsNeus can be further classified into four subsets according to their expression of CD54 and CD101. Importantly, the spatiotemporal evolution and anti-tumor function of tsNeu requires the Hippo pathway transcriptional co-activator YAP/TAZ. Deficiency of YAP/TAZ impairs the generation of effective tsNeus and therefore accelerates tumor progression. Remarkably, treatment with the Hippo antagonist phosphatidic acid (PA) turns blood neutrophils into tsNeus with enhanced abilities of direct killing tumor cells, as well as inducing adaptive anti-tumor immunity. Collectively, our work not only identified molecular makers for tsNeus, but also revealed key transcriptional programs for their fate determination and function; and further offers a strategy of targeting Hippo-YAP/TAZ for neutrophil therapy against gastric cancer.

PURPOSE: In chronic lymphocytic leukemia (CLL), the T-cell receptor (TCR) repertoire is skewed and tumor-derived antigens are hypothesized as drivers of oligoclonal expansion. Ibrutinib, a standard treatment for CLL, inhibits not only Bruton tyrosine kinase of the B-cell receptor signaling pathway, but also interleukin-2-inducible kinase of the TCR signaling pathway. T-cell polarization and activation are affected by ibrutinib, but it is unknown if T cells contribute to clinical response. EXPERIMENTAL DESIGN: High-throughput TCRß sequencing was performed in 77 longitudinal samples from 26 CLL patients treated with ibrutinib. TCRß usage in CD4(+) and CD8(+) T cells and granzyme B expression were assessed by flow cytometric analysis. Antitumor cytotoxicity of T cells expanded with autologous CLL cells or with antigen-independent anti-CD3/CD28/CD137 beads was tested. RESULTS: The clonality of the TCR repertoire increased at the time of response. With extended treatment, TCR clonality remained stable in patients with sustained remission and decreased in patients with disease progression. Expanded clonotypes were rarely shared between patients, indicating specificity for private antigens. Flow cytometry demonstrated a predominance of CD8(+) cells among expanded clonotypes. Importantly, bulk T cells from responding patients were cytotoxic against autologous CLL cells in vitro and selective depletion of major expanded clonotypes reduced CLL cell killing. CONCLUSIONS: In patients with CLL, established T-cell responses directed against tumor are suppressed by disease and reactivated by ibrutinib.

The identification of reliable and non-invasive oncology biomarkers remains a main priority in healthcare. There are only a few biomarkers that have been approved as diagnostic for cancer. The most frequently used cancer biomarkers are derived from either biological materials or imaging data. Most cancer biomarkers suffer from a lack of high specificity. However, the latest advancements in machine learning (ML) and artificial intelligence (AI) have enabled the identification of highly predictive, disease-specific biomarkers. Such biomarkers can be used to diagnose cancer patients, to predict cancer prognosis, or even to predict treatment efficacy. Herein, we provide a summary of the current status of developing and applying Magnetic resonance imaging (MRI) biomarkers in cancer care. We focus on all aspects of MRI biomarkers, starting from MRI data collection, preprocessing and machine learning methods, and ending with summarizing the types of existing biomarkers and their clinical applications in different cancer types.

PD-1 blockade exerts clinical efficacy against various types of cancer by reinvigorating T cells that directly attack tumor cells (tumor-specific T cells) in the tumor microenvironment (TME), and tumor-infiltrating lymphocytes (TILs) also comprise nonspecific bystander T cells. Here, we show that TILs include skewed T cell clonotypes, which are characterized by exhaustion (Tex) or nonexhaustion signatures (Tnon-ex), using single-cell sequencing. Among skewed clonotypes, those in the Tex, but not those in the Tnon-ex, cluster responded to autologous tumor cell lines. After PD-1 blockade, new tumor-specific clonotypes in the Tex cluster appeared in the TME. Tumor-draining lymph nodes (TDLNs) without metastasis harbor a considerable number of such clonotypes, whereas these clonotypes are rarely detected in peripheral blood. We propose that tumor-infiltrating skewed T cell clonotypes with an exhausted phenotype directly attack tumor cells and that PD-1 blockade can promote novel infiltration of tumor-specific T-cell clonotypes, mainly from TDLNs.

In 1970, shortly after joining Roswell Park Memorial Institute, the New York State institute for the study of malignant diseases, the author initiated investigations on the use of tumor cell products for diagnosis and therapy of cancer. Immunochemical approaches were used primarily to differentiate quantitatively or qualitatively normal cells from tumor cells. Prostate cancer was a major area of endeavor, with the goal to identify and characterize prostate tumor specific and associated antigens, and eventually to develop a simple but reliable blood test for prostate cancer. Prostate cancer research had not received much attention at the time this work was begun. The early studies focused upon, among others, prostatic acid phosphatase, alkaline phosphatase, and new prostate tumor markers. By the mid 1970s, three able investigators--Dr. Ching-Li Lee, Dr. Carl S. Killian, and Dr. Ming C. Wang--had joined the prostate cancer research team, and were invited to take charge of these three research projects, respectively.

This minireview highlights the recent advances in the therapeutic agents that aim to provide synergistic enhancements of focused ultrasound treatment of tumors. Even though focused ultrasound therapy itself can bring therapeutic effects in cancers, many biochemical agents have been reported in the literature to enhance the treatment efficacy significantly. Until now, many mechanisms have been researched to advance the therapy, such as sonodynamic-plus-chemo-therapy, microbubble-aided therapy, localized release or delivery of nanomaterials, and multimodal image-guided therapy. Here, the novel materials adopted in each mechanism are briefly reviewed to provide a trend in the field and encourage future research towards the successful deployment of focused ultrasound therapy in real clinical environments.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, as 90% of patients do not survive beyond five years from diagnosis. This dismal prognosis is largely due to the advanced stage of the disease at diagnosis, which precludes potentially curative surgical resection. Although early detection strategies hold significant promise for improving patient outcomes, there is still no accurate diagnostic tool to detect incipient PDAC. Here, we sought to develop antibodies for the early detection of PDAC by positron-emission tomography (PET) imaging. Accordingly, we establish a pipeline to generate novel tumor-specific monoclonal antibodies (mAbs) against cell-surface proteins of PDAC patient-derived organoids (PDOs). We identify a panel of 16 tumor organoid-binding antibodies (TOBi-bodies) that display high reactivity to human PDAC tissues but not to matched adjacent normal pancreas. We then employ biochemical, flow cytometric, mass spectrometric, and CRISPR/Cas9-mediated knockout methods to determine the cognate antigens of these TOBi-bodies. We identify two mAbs that bind to tumor-specific variants of the surface protein CEACAM6 and show minimal binding to normal tissues. PET imaging in mouse models using these TOBi-bodies enables the detection of incipient human organoid-derived PDAC tumors that are rather undetectable by palpation or high-resolution ultrasound imaging techniques. We propose that further development of these mAbs as PET radiotracers could facilitate the early detection and accurate staging of PDAC.

In epithelial ovarian cancer (EOC), the strongest prognostic factor is the completeness of surgery. Intraoperative molecular imaging that targets cell-surface proteins on tumor cells may guide surgeons to detect metastases otherwise not visible to the naked eye. Previously, we identified 29% more metastatic lesions during cytoreductive surgery using OTL-38, a fluorescent tracer targeting folate receptor-alpha (FR alpha). Unfortunately, eleven out of thirteen fluorescent lymph nodes were tumor negative. The current study evaluates the suitability of five biomarkers (EGFR, VEGF-A, L1CAM, integrin alpha v beta 6 and EpCAM) as alternative targets for molecular imaging of EOC metastases and included FR alpha as a reference. Immunohistochemistry was performed on paraffin-embedded tissue sections of primary ovarian tumors, omental, peritoneal and lymph node metastases from 84 EOC patients. Tumor-negative tissue specimens from these patients were included as controls. EGFR, VEGF-A and L1CAM were highly expressed in tumor-negative tissue, whereas alpha v beta 6 showed heterogeneous expression in metastases. The expression of EpCAM was most comparable to FR alpha in metastatic lesions and completely absent in the lymph nodes that were false-positively illuminated with OTL-38 in our previous study. Hence, EpCAM seems to be a promising novel target for intraoperative imaging and may contribute to a more reliable detection of true metastatic EOC lesions.

INTRODUCTION AND OBJECTIVE:Extracellular vesicles (EVs) are secreted by normal and tumor cells and are involved in cell-cell communication. Their molecular properties reflect in part the parental c...

Gliomas represent the majority of malignant central nervous system tumors, with the most aggressive subtype, glioblastoma, accounting for almost 57% of this entity. Type of glioma and its incidence can vary depending on the age of presentation. In turn, outcomes can vary significantly based on the actual type of glioma (histologically and molecularly) and age of the patient, as well as various tumor specific factors such as size, location, comorbidities, etc. In the last decade we have been able to identify key molecular features that have provided us with greater insight into the behavior of these tumors, but the spectrum of treatment options remains limited. In addition, ultimate causes of death in patients with gliomas are variable and stochastic in nature. Given these complicated factors, prognostication for gliomas remains extremely difficult. This review aims to discuss prognostication in low grade versus high grade gliomas, variability in treatment of these tumors, clinical features of poor prognosis, and differences in prognostic understanding between patients, caregivers, and providers. We will also make some general recommendations where appropriate on how to approach this subject from a palliative care perspective.

Introduction. Vulvar squamous cell carcinoma (VSCC) is a rare malignancy with an increasing incidence, especially in young women. Surgical treatment of VSCC is associated with significant morbidity and high recurrence rates, which is related to the limited ability to distinguish (pre)malignant from healthy tissue. There is a need for new tools for specific real-time detection of occult tumor lesions and localization of cancer margins in patients with VSCC. Several tumor-specific imaging techniques are developed to recognize malignant tissue by targeting tumor markers. We present a systematic review to identify, evaluate, and summarize potential markers for tumor-specific imaging of VSCC.Methods. Relevant papers were identified by a systematic cross-database literature search developed with assistance of an experienced librarian. Data were extracted from eligible papers and reported based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. VSCC-specific tumor markers were valued based on a weighted scoring system, in which each biomarker was granted points based on ranked eligibility criteria: I) percentage expression, II) sample size, and Ill) in vivo application.Results. In total 627 papers were included of which 22 articles met the eligibility criteria. Twelve VSCC-specific tumor markers were identified and of these 7 biomarkers were considered most promising: EGFR, CD44v6, GLUT1, MRP1, MUC1, CXCR-4 and VEGF-A.Discussion. This overview identified 7 potential biomarkers that can be used in the development of VSCCspecific tracers for real-time and precise localization of tumor tissue before, during, and after treatment. These biomarkers were identified in a small number of samples, without discriminating for VSCC-specific hallmarks such as HPV-status. Before clinical development, experimental studies should first aim at validation of these biomarkers using immunohistochemistry and cell line-based examination, discriminating for HPV-status and the expression rate in lymph nodes and precursor lesions. (C) 2019 Published by Elsevier Inc.

Immunotherapy has long been considered a potential therapy for malignant mesothelioma and is currently being pursued as such. Some of the early phase clinical trials involving immunomodulators have demonstrated encouraging results and numerous clinical trials are underway to further investigate this treatment approach in various treatment settings and larger patient cohorts. Areas covered: This review summarizes the current and emerging clinical evidence for checkpoint blockade and other immunotherapeutic strategies in mesothelioma. The mesothelioma tumor immune microenvironment and mutational landscape are also discussed, including their impact on treatment strategies. We also provide an evaluation of the current evidence for neoantigen targeted personalized immunotherapy. Expert opinion: Immune checkpoint inhibitors work by unleashing the host immune response against probable neoantigens. Despite impressive activity in a small subset of patients and the potential for prolonged responses, most patients experience treatment failure. Neoantigen vaccines provide a potential complementary therapeutic strategy by increasing the immunogenic antigen load, which can lead to an increased tumor specific immune response. Further research is needed explore this treatment option in mesothelioma and technological advances are required to translate this concept into clinical practice.

Aim Venous thromboembolism (VTE) is a major cause of morbidity and mortality in gynecologic malignant patients after surgery. We aimed to validate the Caprini risk assessment model (RAM) and elevated tumor-specific D-dimer as predictive marker of postoperative VTE for patients undergoing surgery of gynecologic malignancies. Methods Inpatients were divided into five groups (low: score = 0-1; moderate: score = 2; high: score = 3-4; higher: score = 5-7; sup-high: score > 7) and treated according to their risk level after the surgery during the hospitalization according to the Caprini RAM. D-dimer level was detected during the perioperative period. If D-dimer did not fall to normal reference range on the seventh day after operation, the use of low-molecular-weight heparin was prolonged to 28 days after surgery. Results The majority (853/974, 87.6%) of the patients was in the Caprini score ≥5, with an overall VTE incidence of 1.75%. The VTE group had significantly higher Caprini score, CA125, vascular invasion rate and lymph node metastasis rate. If 1.5 μg/mL was used as the D-dimer cut-off value to predicting VTE, the sensitivity was 87.5%, the specificity was 93.8% and the negative predictive value was 99.2%. The D-dimer level was a marker for prolonging the anticoagulants use during the perioperative period, especially for the sup-high group. Conclusion The Caprini RAM is an effective and reliable VTE risk prediction tool for patients undergoing gynecological malignant tumor surgery. The group (score ≥ 5) can be divided into two subgroups (higher: score = 5-7 and sup-high: score > 7), which may better predict the occurrence of VTE for malignant tumor patients. Great than 1.5 μg/mL D-dimer before operation should be given more attention for the presence of VTE.

OBJECTIVE. To examine survival of women who develop metachronous uterine malignancy after definitive pelvic radiotherapy for cervical cancer. METHODS. This retrospective observational study examined the Surveillance, Epidemiology, End Results Program between 1973 and 2013. Women with cervical cancer who received definitive radiotherapy without hysterectomy were examined for the diagnosis of metachronous uterine malignancy (n = 5277). Survival was compared between metachronous and non-metachronous uterine malignancies according to tumor factors. RESULTS. The 10- and 20-year cumulative incidences of metachronous uterine malignancy were 0.6% and 1.2%, respectively. When compared to non-metachronous uterine malignancy, metachronous tumor were more likely to be non-endometrioid and advanced-stage (both, P < 0.001). As a whole cohort, metachronous uterine malignancy was significantly associated with decreased overall survival (OS) compared to non-metachronous tumors (hazard ratio [HR] 4.22, P < 0.001). OS was significantly worse in metachronous compared to non-metachronous malignancies, although the magnitude of statistical significance was greater for endometrioid tumors (HRs for endometrioid versus non-endometrioid: 6.17 versus 1.92). For grade 1–2 endometrial cancer, metachronous cases had significantly decreased OS compared to non-metachronous cases, a larger difference than that seen in higher grade tumors (HRs for grade 1–2 versus 3: 7.79 versus 2.15). Similarly, in early-stage endometrial cancer, metachronous cases had significantly decreased OS, with a greater HR compared to advanced-stage disease (HRs for stage I–II versus III–IV: 5.29 versus 2.29). CONCLUSION. Radiotherapy-associated metachronous uterine malignancy after cervical cancer is rare but commonly presents with aggressive tumor characteristics. The impact on survival is considerably high when metachronous uterine malignancy is endometrioid, low-grade, and early-stage.

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. VIDEO ABSTRACT.

The foundations of basic T-cell immunology and an understanding of the roles for T cells in controlling cancer have led to the remarkable yet inconsistent success of cancer immunotherapy. Because of these advances in cancer treatment, the need is urgent for biomarkers that can predict the efficacy of these treatments and for new therapeutic strategies for cases where currently available approaches are ineffective. Although our ability to profile heterogeneous cell populations in human blood or tissue samples has vastly improved in the past decade, identifying the cell subsets relevant to diseases, and to cancer particularly, remains a challenge. Given strong evidence for the implication of T cells specific for tumor-expressed antigens in various forms of effective immunotherapy, here, we focus on the utility, challenges, and techniques for the identification and profiling of these important cells. We review recent techniques that allow identifying and profiling of tumor-specific T cells. As these methods improve, we can expect more rapid progress in the rational design of novel cancer biomarkers and therapies based on antigen-specific T cells. Cancer Immunol Res; 6(1); 2–9. ©2018 AACR.

The specific coagulation in the tumor vasculature has the potential for the ablation of solid tumors by cutting off the blood supply. However, the safe delivery of effective vessel occluding agents in the tumor-specific embolization therapy remains challenging. Herein, it is reported that the photothermal responsive tumor-specific embolization therapy based on thrombin (Thr) is delivered by intravenous injection via the phase-change materials (PCM)-based nanoparticles. The wax sealing profile of PCM enables safe delivery and prevents the preleakage of Thr in the blood circulation. While in the tumor site, the thermal effect induced by IR780 triggers the melting of PCM and rapidly releases Thr to generate coagulation in the tumor blood vessels. Based on the safe delivery and controllable release of Thr, thermal responsive tumor-specific embolization therapy could be achieved with high efficiency and no significant damage to normal organs and tissues. The safe administration of Thr to induce vascular infarction in tumors based on PCM nanoparticles in this work shows a promising strategy for improving the therapeutic specificity and efficacy of coagulation-based tumor therapy.

BackgroundBispecific antibodies (BsAbs) are gaining momentum in several immunotherapeutic1 2 3 and immuno-oncology settings.4 Certain designs of BsAbs enable tumor-specific targeting when two targets are concurrently expressed on tumor but not normal tissue. Judicious choice of bispecific immunotherapeutic targeting enables separate effects that are simultaneously beneficial and specific against tumor cells. This provides a multi-modal approach to the previously intractable problem of counteracting Efflux Pump (EP) mediated drug resistance in tumors. EP mediated drug resistance (EPMDR) adversely impacts a broad range of therapeutics including antineoplastics, TKIs, ADC-toxins and others. Elevated EP activity can also promote cancer cell growth by expelling catabolites and inhibitory substances from tumor cells. Prior efforts to combat EPMDR have focused on small molecule antagonists to EP intracellular domains; although some showed early promise5 6 these ultimately failed mainly for lack of tumor specificity and off-target toxicity. In contrast, BsAbs targeting extracellular domains of efflux pumps together with other tumor associated antigens (TAA ) provide for: a) Tumor specific targeting b) Specific masking or antagonizing of the TAA target c) Concurrent counteraction of tumor cell efflux mechanismsd) Invoking an Fc-mediated immune attack on tumor cells Use of the Kenjockety BASE PlatformTM (Bispecific Antibodies Specific to Efflux Pumps) has yielded BsAbs that have successfully targeted four different EPs together with several TAAs.MethodsMonoclonal antibodies to EPs have been raised and engineered into BsAbs with a common light chain7 8 in IgG frameworks. These concurrently target an EP and a TAA. By design, each arm of the antibody binds with relatively weak affinity to its target on normal tissue. However, when both targets are displayed together on tumor cells, their concurrent engagement results in stronger, efficacious binding.ResultsA prototype BsAb that concurrently targets CD47 and the EP, P-glycoprotein, provided compelling, dose-dependent proofs of concept in various in vitro studies and in drug-resistant hematologic and solid tumor xenograft models. Efficacy was shown with and without additional therapeutics. In cynomolgus studies the BsAb also demonstrated a lack of off-tumor toxicities typically associated with each target.ConclusionsBsAbs concurrently targeting EPs and TAAs (including immuno-oncology targets) provide promising new tumor-specific therapies for treatment of patients with drug resistant cancers.ReferencesSheridan C. 2021. Despite slow progress, bispecifics generate buzz. Nat Biotechnol 2016; 34:12;1215–1217.Huang S, van Duijnhoven A, Sijts A, van Elsas A. Bispecific antibodies targeting dual tumor-associated antigens in cancer therapy. J Cancer Res Clin Oncol 2020;146:3111–3122.Ma J, Mo Y, Tang M, et al. Bispecific antibodies: from research to clinical application. Front Immunol 2021;12:626–616.Dheilly E, Moine V, Broyer L et al. Selective blockade of the ubiquitous checkpoint receptor CD47 is enabled by dual-targeting bispecific antibodies. Mol Ther 2017;25:523–533.Amiri-Kordestani L, Basseville A, Kurdziel K, et al. Targeting MDR in breast and lung cancer: discriminating its potential importance from the failure of drug resistance reversal studies. Drug Resist Update 2012;15:50–61.Robey R, Pluchino M, Hall M, et al. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat Rev Cancer 2018;18:452–464.Speiss C, Zhai Q, Carter P. Alternative molecular formats and therapeutic applications for bispecific antibodies. Mol Immunol 2015;67:95–106.Labrijn A, Janmaat M, Reichert J et al. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov 2019;18:585–608.

BackgroundNexImmune is developing highly differentiated immunotherapies to target, activate and expand tumor antigen-specific T cells using the proprietary Artificial Immune Modulation (AIM™) nanotechnology platform. The AIM nanoparticle (AIM-np) technology functions as synthetic dendritic cells capable of directing a specific T cell-mediated immune response. By mimicking natural T cell biology, NexImmune’s cellular therapy product candidates (AIM ACT) are designed to combine the attributes of cellular precision, potency, and persistence with reduced potential for undesired toxicities. Human papilloma virus (HPV) is responsible for >45,000 cancers yearly in the United States, according to the CDC. From 2013–2017 an estimate 79% of cervical, vulva, penis, vaginal, anus, and oropharyngeal cancers were attributed to HPV and of these about 80% were associated with high-risk HPV types 16 and 18. Although multivalent vaccines against high-risk HPV infections exist, significant clinical challenges remain. A limited vaccination rate means many remain vulnerable and vaccination does not treat pre-existing HPV infections or malignancies.MethodsTherefore, NexImmune is employing its AIM-np technology to generate an adoptive cell therapy (ACT) using its proprietary enrichment and expansion (E+E) ex vivo process to expand clinically relevant numbers of CD8+ T cells that recognize the HPV16 and HPV18 oncogenic antigens (i.e., E6 and E7) expressed by malignant cells of head and neck, cervical, and anal cancers. Using the Immune Epitope Database and Analysis Resource (IEDB), 44 HLA-A2 restricted peptides were identified as potential immunogenic targets for preclinical screening. Using PBMCs from healthy donor-derived apheresis material, different combinations of these peptides were used in the E+E process to expand HPV-cancer specific CD8+ T cells.ResultsAfter multiple E+E experiments were concluded, 5 peptides were identified that consistently elicited the strongest T cell responses. Furthermore, these CD8+ T cells were predominantly from the central memory (CD62L+CD45RA-) and effector memory (CD62L-CD45RA-) phenotype (sum total 82.18 ± 8.29 [Mean ± SEM]) suggesting their in vivo functionality and persistence will combine anti-tumor activity with long-term immunologic memory.ConclusionsA similar E+E screening is being conducted with PBMCs isolated from HPV+ cancer patients. A comparison of the CD8+ T cell responses from healthy donor and cancer patient cells will provide critical preclinical data to support a planned FIH trial for HPV-associated malignancies. The current study demonstrates the ability for high-throughput peptide screening to identify clinically relevant peptide cocktails capable of expanding multi-antigen tumor-specific CD8+ T cell populations within 2 weeks.

BackgroundVaccines have little chance of destroying heterogeneous tumor cells since they rarely induce polyclonal T-cell responses against the tumor. The main challenge is the accurate identification of tumor targets recognizable by T cells. Presently, 6–8% of neoepitopes selected based on the patients‘ tumor biopsies are confirmed as real T cell targets.1 2. To overcome this limitation, we developed a computational platform called Personal Antigen Selection Calculator (PASCal) that identifies frequently presented immunogenic peptide sequences built on HLA-genetics and tumor profile of thousands of real individuals.3 Here we show the performance of PASCal for the identification of both shared and personalized tumor targets in metastatic colorectal cancer (mCRC) and breast cancer subjects.MethodsExpression frequency of the tumor-specific antigens (TSAs) ranked in PASCal’s database (based on 7,548 CRC specimen) was compared to the RNA-sequencing data of CRC tumors obtained from TCGA. Using PASCal, 12 shared PEPIs (epitopes restricted to at least 3 HLA class I alleles of a subject from an in silico cohort) derived from 7 TSAs were selected as frequent targets (calculated probability: average 2.5 [95%CI 2.4–2.8] TSAs/patient). Spontaneous immune responses against each of the twelve 9mer peptides were determined by ELISpot using PBMCs of 10 mCRC subjects who participated in the OBERTO-101 study.4 PEPIs selected for a breast cancer subject based on her HLA genotype were also tested.ResultsEach of the 106 tumors analyzed expressed at least 13, average 15 of the 20 top-ranked TSAs in PASCal’s database confirming their prevalence in CRC. 7/10 subjects had spontaneous CD8+ T-cell responses against at least one peptide selected with PASCal. Each peptide (12/12) was recognized by at least one patient. Patients‘ T-cells reacted with average 3.6/12 (30%) peptides confirming the expression of average 2.8 [95%CI 1.0–4.6] TSAs (n=10). After HLA-matching, among the subjects for whom we could select at least 4 PEPIs (average 5) from the list of 12 peptides (n=6), average 2.5 (50%) peptides were positive. Of the 12 PEPIs selected with PASCal for a breast cancer subject, we detected spontaneous T-cell responses against 9 PEPIs, indicating that at least 75% of the selected peptides were present in the subject’s tumor and were recognized by T-cells.ConclusionsPASCal platform accommodates both tumor- and patient heterogeneity and identifies non-mutated tumor targets that may trigger polyclonal cytotoxic T-cell responses. It is a rapid tool for the design of both off-the-shelf and personalized cancer vaccines negating the need for tumor biopsy.ReferencesWells DK, van Buuren MM, Dang KK, et al. Key parameters of tumor epitope immunogenicity revealed through a consortium approach improve neoantigen prediction. Cell 2020:183(3):818–34.e13.Bulik-Sullivan B, Busby J, Palmer CD, et al. Deep learning using tumor HLA peptide mass spectrometry datasets improves neoantigen identification. Nat Biotech 2018:37:55–63.Somogyi E, Csiszovszki Z, Lorincz O, et al. 1181PDPersonal antigen selection calculator (PASCal) for the design of personal cancer vaccines. Annal Oncol 2019:30(Supplement_5):v480-v81.Hubbard J, Cremolini C, Graham R, et al. P329 PolyPEPI1018 off-the shelf vaccine as add-on to maintenance therapy achieved durable treatment responses in patients with microsatellite-stable metastatic colorectal cancer patients (MSS mCRC). J ImmunoTher Cancer 2019:7(1):282.

BackgroundDespite the broad success of immune checkpoint inhibition (ICI e.g. anti-Programmed Death Ligand-1 [PD-L1]) in cancer treatment, tumor-intrinsic factors leading to intrinsic and acquired resistance are poorly understood. Tumor specific MHC-I expression is indispensable for anti-PD-1/L1 response as complete loss of MHC-I via B2M deletion results in inability of CD8+ T cells to recognize tumor-associated antigens. However, MHC-I is heterogeneously downregulated or lost in many tumor types. Tumor cell destruction can also occur through non-synaptic mechanisms, in a so-called ‘field effect’. Therefore, we modeled heterogeneous loss of MHC-I expression in breast cancer and experimentally evaluated how heterogeneous MHC-I loss affects response to anti-PD-L1 therapy.MethodsWe performed quantitative immunofluorescence for MHC-I and Pan-CK on breast cancer tumors (n=410). To determine the functional effect of MHC-I heterogeneity on anti-PD-L1 response, we used an immunocompetent EMT6 orthotopic mammary tumor model which ubiquitously expresses MHC-I at baseline. Using CRISPR/Cas9, we engineered EMT6 cells with B2m loci excision resulting in complete knockout of MHC-I on the cell surface. We then orthotopically implanted B2m-comtetent and B2m-KO cells at varying inoculum ratios (100:0, 90:10, 50:50, 10:90, 0:100) into syngeneic Balb/C mice and assessed immune responsiveness and efficacy of checkpoint inhibition. Additionally, to look at how loss of MHC-I affects the tumor microenvironment we will use the PanCancer Immune NanoString panel (n=770 genes) to evaluate gene expression patterns in tumor cells and infiltrating immune cells.ResultsIn patient samples, we identified high diversity in MHC-I expression across all clinical subtypes, with triple negative breast cancer (TNBC) having the highest MHC-I expression. Chemotherapy-treated tumors had higher MHC-I levels than untreated tumors. In mice when 10% of cells were B2m-KO, we observed a 50% reduction in complete eradication of EMT6 tumors with aPD-L1 treatment and reduced disease-stabilization and no complete responses when a 50% mixture of MHC-I deficient cells. An increasing percentage of B2m KO leads to worse outcomes overall and a decrease in infiltrating T cells.ConclusionsOur work suggests that there is an ICI-responsive phenotype that is driven by heterogeneity in MHC-I expression levels. As little as 10% of tumor specific MHC-I loss can lead to therapeutic resistance and a decrease in complete responders. This represents that early TNBC may be less responsive to single-agent PD-L1 due to specific percentages of MHC-I loss. MHC-I expression can influence therapy outcomes and potentially lead to novel observations of how to overcome lack of, or limited, MHC-I expression.

Ferroptosis-based nanomedicine has drawn increasing attention in antitumor therapy because of the advantages of this unconventional mode of apoptosis, but the difficulties of delivery to the tumor site and surface-to-core penetration after arrival seriously hinder further clinical transformation and application. Herein, we propose an unprecedented strategy of injecting magnetic nanodroplets (MNDs) to solve these two longstanding problems. MNDs are nanocarriers that can carry multifunctional drugs and imaging materials. MNDs can effectively accumulate in the tumor site by active tumor targeting (multifunctional drugs) and passive tumor targeting (enhanced permeability and retention effect), allowing diffusion of the MNDs from the surface to the core through mild-temperature magnetic fluid hyperthermia (MHT) under multimodal imaging guidance. Finally, the ferroptosis pathway is activated deep within the tumor site through the drug release. This approach was inspired by the ability of mild-temperature MHT to allow MNDs to quickly pass through the blood vessel-tumor barrier and deeply penetrate the tumor tissue from the surface to the core to amplify the antitumor efficacy of ferroptosis. This strategy is termed as "thermoferroptosis sensitization". Importantly, this behavior can be performed under the guidance of multimodal imaging, making the design of MNDs for cancer therapy safer and more reasonable.

In this article, targeted and controlled anticancer drug delivery and release with magneto-electric nanoparticles, published in 2016, rodzinski et al., explain how magneto-electric nanoparticles abbreviated as (mens) can be used to monitor the delivery of drugs and their release into cancer cells. They go further to explain how they use this automated drug delivery system to eradicate cancerous tumor cells. &nbsp

Our understanding of the involvement of the immune system in cancer control has increased over recent years. However, the development of cancer vaccines intended to reverse tumor-induced immune tolerance remains slow as most current vaccine candidates exhibit limited clinical efficacy. The skin is particularly rich with multiple subsets of dendritic cells (DCs) that are involved to varying degrees in the induction of robust immune responses. Transcutaneous administration of cancer vaccines may therefore harness the immune potential of these DCs, however, this approach is hampered by the impermeability of the stratum corneum. Innovative vaccine formulations including various nanoparticles, such as liposomes, are therefore needed to properly deliver cancer vaccine components to skin DCs. Areas covered: The recent insights into skin DC subsets and their functional specialization, the potential of nanoparticle-based vaccines in transcutaneous cancer vaccination and, finally, the most relevant clinical trial advances in liposomal and in cutaneous cancer vaccines will be discussed. Expert commentary: To define the optimal conditions for mounting protective skin DC-induced anti-tumor immune responses, investigation of the cellular and molecular interplay that controls tumor progression should be pursued in parallel with clinical development. The resulting knowledge will then be translated into improved cancer vaccines that better target the most appropriate immune players. journal article review research support, non-u.s. gov't 2017 11 imported

Pituitary tumors develop within a macroenvironment and microenvironment that favor their overall survival. Given the pituitary gland's unique anatomic, histological, and physiological properties, the role of the TME in the pituitary tumors is central. This chapter summarizes the body of literature investigating the role of each component of the TME in relation to tumors of the pituitary and its intimate association with tumorigenesis, maintenance, and progression.

Cancer cells divide continuously without any control, rendering immortal cells. These changes cause the dynamic instability in their genomes. Therefore each cancer cell in a tumor mass has various changes for specific tumor types. Their differences should be diagnosed on the basis of mutated genes and/or proteins. After the detection of alterations in cancer cells based on the techniques and instruments of biomedicine, personalized therapy continues with preexisting drug implementations. Personalized therapy broadens the borders with circulating tumor cells causing the metastasis in distant regions, developing specific gene therapies, novel targeted drugs, and immunotherapeutics for eliminating cancerous cells precisely. Within this context, biomedicine helps humankind to merge the biological and physiological knowledge to clinical practice. In this chapter, we aimed to clarify attitudes in biomedicine from molecular changes from single tumor cells to in vivo studies to find the best therapy for a cancer patient.