New Era Of Immunotherapy Research Articles

Revolutionizing Cancer Treatment: Unleashing the Power of Viral Vaccines, Monoclonal Antibodies, and Proteolysis-Targeting Chimeras in the New Era of Immunotherapy.

In the realm of cancer immunotherapy, a profound evolution has ushered in sophisticated strategies that encompass both traditional cancer vaccines and emerging viral vaccines. This comprehensive Review offers an in-depth exploration of the methodologies, clinical applications, success stories, and future prospects of these approaches. Traditional cancer vaccines have undergone significant advancements utilizing diverse modalities such as proteins, peptides, and dendritic cells. More recent innovations have focused on the physiological mechanisms enabling the human body to recognize and combat precancerous and malignant cells, introducing specific markers like peptide-based anticancer vaccines targeting tumor-associated antigens. Moreover, cancer viral vaccines, leveraging engineered viruses to stimulate immune responses against specific antigens, exhibit substantial promise in inducing robust and enduring immunity. Integration with complementary therapeutic methods, including monoclonal antibodies, adjuvants, and radiation therapy, has not only improved survival rates but also deepened our understanding of viral virulence. Recent strides in vaccine design, encompassing oncolytic viruses, virus-like particles, and viral vectors, mark the frontier of innovation. While these advances hold immense potential, critical challenges must be addressed, such as strategies for immune evasion, potential off-target effects, and the optimization of viral genomes. In the landscape of immunotherapy, noteworthy innovations take the spotlight from the use of immunomodulatory agents for the enhancement of innate and adaptive immune collaboration. The emergence of proteolysis-targeting chimeras (PROTACs) as precision tools for cancer therapy is particularly exciting. With a focus on various cancers, from melanoma to formidable solid tumors, this Review critically assesses types of cancer vaccines, mechanisms, barriers in vaccine therapy, vaccine efficacy, safety profiles, and immune-related adverse events, providing a nuanced perspective on the underlying mechanisms involving cytotoxic T cells, natural killer cells, and dendritic cells. The Review also underscores the transformative potential of cutting-edge technologies such as clinical studies, molecular sequencing, and artificial intelligence in advancing the field of cancer vaccines. These tools not only expedite progress but also emphasize the multidimensional and rapidly evolving nature of this research, affirming its profound significance in the broader context of cancer therapy.

Chimeric antigen receptor T cells targeting the GM3(Neu5Gc) ganglioside.

Chimeric antigen receptor (CAR) T cell technology has ushered in a new era of immunotherapy, enabling the targeting of a broad range of surface antigens, surpassing the limitations of traditional T cell epitopes. Despite the wide range of non-protein tumor-associated antigens, the advancement in crafting CAR T cells for these targets has been limited. Owing to an evolutionary defect in the CMP-Neu5Ac hydroxylase (CMAH) that abolishes the synthesis of CMP-Neu5Gc from CMP-Neu5Ac, Neu5Gc is generally absent in human tissues. Despite this, Neu5Gc-containing antigens, including the ganglioside GM3(Neu5Gc) have consistently been observed on tumor cells across a variety of human malignancies. This restricted expression makes GM3(Neu5Gc) an appealing and highly specific target for immunotherapy. In this study, we designed and evaluated 14F7-28z CAR T cells, with a targeting unit derived from the GM3(Neu5Gc)-specific murine antibody 14F7. These cells exhibited exceptional specificity, proficiently targeting GM3(Neu5Gc)-expressing murine tumor cells in syngeneic mouse models, ranging from B cell malignancies to epithelial tumors, without compromising safety. Notably, human tumor cells enhanced with murine Cmah were effectively targeted and eliminated by the 14F7 CAR T cells. Nonetheless, despite the detectable presence of GM3(Neu5Gc) in unmodified human tumor xenografts, the levels were insufficient to trigger a tumoricidal T-cell response with the current CAR T cell configuration. Overall, our findings highlight the potential of targeting the GM3(Neu5Gc) ganglioside using CAR T cells across a variety of cancers and set the stage for the optimization of 14F7-based therapies for future human clinical application.

Using Combination therapy to overcome diverse challenges of Immune Checkpoint Inhibitors treatment.

Immune checkpoint inhibitors (ICIs) have heralded a new era in immunotherapy, representing a pivotal breakthrough in cancer treatment. Their impact is profound, with ICIs standing as some of the most prescribed anticancer therapies today. Notably, their ability to induce long-term remission even after treatment cessation provides genuine hope for achieving durable cures. However, despite these strides, challenges persist in the landscape of oncology, including resistance phenomena, immune-related adverse events, and suboptimal response rates. In response to these challenges, combination therapy emerges as a promising approach, poised to enhance treatment outcomes and address limitations inherent to single-agent ICI therapy. By synergistically targeting multiple pathways, combination therapy holds the potential to augment therapeutic efficacy while mitigating toxicity and impeding the emergence of resistance mechanisms. Understanding the intricacies underlying resistance development and adverse events is paramount in devising novel and refined combination strategies. A timeline showing FDA approvals of ICIs combination is shown in Figure 1. This review aims to provide a comprehensive and up-to-date examples of different combined therapy strategies that can be used to overcome various challenges regarding ICI treatment. Through the exploration of innovative therapeutic combinations, we aim to provide clinicians and researchers with actionable knowledge to optimize patient outcomes and propel the field of immuno-oncology forward.

Management of metastatic endometrial cancer: physicians' choices beyond the first line after approval of checkpoint inhibitors.

Endometrial cancer (EC) represents 3.4% of all newly diagnosed cancer cases and is responsible for 2.1% of all cancer-related deaths. Approximately 10%-15% of women with EC are diagnosed with advanced-stage disease, resulting in a reported 5-year survival rate of only 17% for those with distant metastases. A better understanding of its molecular features has ushered in a new era of immunotherapy for the treatment of EC, allowing for alternative therapeutic approaches, even in cases of advanced disease. We administered a multi-choice online survey for Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) members. The questionnaire was available for 2 months, starting in October 2022. Our objective was to evaluate the current attitude of incorporating molecular characterization of EC into routine clinical practice, appraise the implementation of newly available therapies, and compare the outcomes with the previous survey conducted in April-May 2021 to ascertain the actual changes that have transpired during this recent time period. The availability of molecular classification in Italian centers has changed in 1 year. Seventy-five percent of centers performed the molecular classification compared with 55.6% of the previous survey. Although this percentage has increased, only 18% performed all the tests. Significant changes have occurred in the administration of new treatments in EC patients in MITO centers. In 2022, 82.1% of the centers administrated dostarlimab in recurrent or advanced MMR-deficient (dMMR) EC experiencing disease progression after platinum-based chemotherapy regimens, compared to only 24.4% in 2021. In 2022, 85.7% of the centers already administrated the pembrolizumab plus lenvatinib combination as a second-line therapy for MMR-proficient (pMMR) patients with advanced or recurrent EC who had progressed from first-line platinum-based therapy. Both the therapeutic and diagnostic scenarios have changed over the last couple of years in MITO centers, with an increased prescription of immune checkpoint inhibitors and use of the molecular classification.

Facts and Hopes in Colorectal Cancer Immunotherapy.

Although a minority of colorectal cancers exhibit mismatch repair deficiency and associated sensitivity to immune checkpoint inhibitors (ICI), the vast majority of colorectal cancers arise in a tolerogenic microenvironment with mismatch repair proficiency, low tumor-intrinsic immunogenicity, and negligible immunotherapy responsiveness. Treatment strategies to augment tumor immunity with combination ICIs and chemotherapy have broadly failed in mismatch repair-proficient tumors. Similarly, although several small single-arm studies have shown that checkpoint blockade plus radiation or select tyrosine kinase inhibition may show improved outcomes compared with historical controls, this finding has not been clearly validated in randomized trials. An evolving next generation of intelligently engineered checkpoint inhibitors, bispecific T-cell engagers, and emerging CAR-T cell therapies may improve immunorecognition of colorectal tumors. Across these modalities, ongoing translational efforts to better define patient populations and biomarkers associated with immune response, as well as combine biologically sound and mutually amplifying therapies, show promise for a new era of immunotherapy in colorectal cancer.

Vista of the Future: Novel Immunotherapy Based on the Human V-Set Immunoregulatory Receptor for Digestive System Tumors.

While gastrointestinal tumors remain a multifactorial and prevalent group of malignancies commonly treated surgically in combination with chemotherapy and radiotherapy, advancements regarding immunotherapeutic approaches continue to occur. Entering a new era of immunotherapy focused on overcoming resistance to preceding therapies caused the emergence of new therapeutic strategies. A promising solution surfaces with a V-domain Ig suppressor of T-cell activation (VISTA), a negative regulator of a T-cell function expressed in hematopoietic cells. Due to VISTA's ability to act as both a ligand and a receptor, several therapeutic approaches can be potentially developed. A broad expression of VISTA was discovered on various tumor-growth-controlling cells, which proved to increase in specific tumor microenvironment (TME) conditions, thus serving as a rationale behind the development of new VISTA-targeting. Nevertheless, VISTA's ligands and signaling pathways are still not fully understood. The uncertain results of clinical trials suggest the need for future examining inhibitor agents for VISTA and implicating a double immunotherapeutic blockade. However, more research is needed before the breakthrough can be achieved. This review discusses perspectives and novel approaches presented in the current literature. Based on the results of the ongoing studies, VISTA might be considered a potential target in combined therapy, especially for treating gastrointestinal malignancies.

Recent progress and current challenges of immunotherapy in advanced/metastatic esophagogastric adenocarcinoma

The new era of immunotherapy is successfully implemented in the treatment of metastatic/locally advanced esophagogastric adenocarcinoma (EGAC), as it has been investigated in combinations with/without chemotherapy in human epidermal growth factor receptor 2 (Her2)-positive and Her2-negative tumors. Recent approvals of immune checkpoint inhibitors (ICI) enrich the therapeutic landscape in nearly every therapeutic line. Based on CHECKMATE-649, the combination of nivolumab and chemotherapy in first-line therapy of programmed cell death protein 1 (PD-L1)-positive patients with advanced gastroesophageal junction cancer (GEJC), esophageal cancer (EC), and gastric cancer (GC) was approved in Europe for PD-L1 combined positivity score (CPS) ≥ 5 patients and independently from PD-L1 score in the USA and Asia. Based on KEYNOTE-590, patients with advanced GEJC and EC qualify for the combination of pembrolizumab plus chemotherapy in Europe (CPS ≥ 10) and the USA. For Her2-positive patients, trastuzumab with first-line chemotherapy plus pembrolizumab has beneficial response rates and resulted in approval in the USA (KEYNOTE-811). In third-line therapy, superior overall survival (OS) was achieved by the administration of nivolumab (approval in Japan, ATTRACTION-02), and pembrolizumab shows a positive effect on the duration of response (KEYNOTE-059). Questions of resistance to immunotherapy or the role of gender in response to ICI need to be clarified. This review provides an overview of the current approvals of ICI in advanced EGAC and reflects results of relevant phase II/III trials with focus on possible biomarkers, including PD-L1 CPS and microsatellite-instability (MSI) status.

Progress and Prospect of Immunotherapy for Triple-Negative Breast Cancer.

Breast cancer is the most commonly diagnosed cancer (estimated 2.3 million new cases in 2020) and the leading cause of cancer death (estimated 685,000 deaths in 2020) in women globally. Breast cancers have been categorized into four major molecular subtypes based on the immunohistochemistry (IHC) expression of classic hormone and growth factor receptors including the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), as well as a proliferation marker Ki-67 protein expression. Triple-negative breast cancer (TNBC), a breast cancer subtype lacking ER, PR, and HER2 expression, is associated with a high metastatic potential and poor prognosis. TNBC accounts for approximately only 15%–20% of new breast cancer diagnoses; it is responsible for most breast cancer–related deaths due to the lack of targeted treatment options for this patient population, and currently, systemic chemotherapy, radiation, and surgical excision remain the major treatment modalities for these patients with TNBC. Although breast cancer patients in general do not have a robust response to the immunotherapy, a subset of TNBC has been demonstrated to have high tumor mutation burden and high tumor-infiltrating lymphocytes, resembling the features observed on melanoma or lung cancers, which can benefit from the treatment of immune checkpoint inhibitors (ICIs). Therefore, the immunogenic nature of this aggressive disease has presented an opportunity for the development of TNBC-targeting immunotherapies. The recent US Food and Drug Administration approval of atezolizumab in combination with the chemotherapeutic agent nab-paclitaxel for the treatment of PD-L1-positive unresectable, locally advanced, or metastatic TNBC has led to a new era of immunotherapy in TNBC treatment. In addition, immunotherapy becomes an active research area, both in the cancer biology field and in the oncology field. In this review, we will extend our coverage on recent discoveries in preclinical research and early results in clinical trials from immune molecule-based therapy including cytokines, monoclonal antibodies, antibody–drug conjugates, bi-specific or tri-specific antibodies, ICIs, and neoantigen cancer vaccines; oncolytic virus-based therapies and adoptive immune cell transfer–based therapies including TIL, chimeric antigen receptor-T (CAR-T), CAR-NK, CAR-M, and T-cell receptor-T. In the end, we will list a series of the challenges and opportunities in immunotherapy prospectively and reveal novel technologies such as high-throughput single-cell sequencing and CRISPR gene editing-based screening to generate new knowledges of immunotherapy.

Platinum-free chemotherapy in the new era of immunotherapy: A phase II study of camrelizumab combined with apatinib and albumin paclitaxel in advanced non-squamous NSCLC (CAPAP-lung).

9034 Background: Cytotoxic chemotherapy and anti-angiogenic therapy may enhance the therapeutic efficacy of immune checkpoint inhibitors (ICIs). Platinum-containing dual-agent chemotherapy combined with ICIs is the standard first-line treatment for non-small cell lung cancer (NSCLC), however, the optimal combination regimen remains unclear. The adverse effects of platinum-based chemotherapy are relatively serious, whether platinum chemotherapy can be eliminated in the first-line treatment of non-small cell lung cancer is a hotspot and difficulty in current research. Based on these results, we initiated CAPAP-lung study, which is a single-arm, multicenter Phase II trial to evaluate the efficacy and safety of Camrelizumab in combination with apatinib and albumin paclitaxel without platinum as the first-line therapy for non-squamous non-small cell lung cancer. Methods: Patients diagnosed with ⅢB-IV non-squamous NSCLC without EGFR and ALK sensitive mutations received Camrelizumab (200mg/3w) in combination with Albumin Paclitacxel (135mg/m2, d1, d8/3w, 4-6 cycles) and Apatinib (250mg Qd po for 5 days, resting for 2 days every week). From August 2020 to February 2022, 54 of the planned 63 patients have been enrolled. The primary endpoint is progression-free survival(PFS), and secondary endpoints were overall survival (OS), duration of Response (DOR), objective response rate (ORR), and disease control rate (DCR) assessed by RECIST v1.1. This study is registered with ClinicalTrials.gov, NCT04459078 (follow-up is ongoing). Results: The data for a total of 38 patients out of 54 enrolled patients were evaluable. Median PFS was 10.97 mo (95%CI 7.1-NR).The objective response rate (ORR) and disease control rate (DCR) were 71.1% (27/38, 95%CI 53.9-84.0) and 97.4% (37/38, 95%CI 84.6-99.9), respectively. The incidence of grade 3 and worse treatment-related adverse events was acceptable, with grade 3 events in 25(46.3%) patients and grade 4 events in 3(5.6%) patients. The most common grade 3 treatment-related adverse events were decreased neutrophil count (8 [14.8%]), liver function damage (9 [16.7%]), rash (3 [5.6%]), and decreased white blood cell count (3 [5.6%]). Conclusions: Camrelizumab combined with albumin paclitaxel and apatinib showed encouraging antitumor activity with an acceptable safety profile for the first-line treatment of advanced lung adenocarcinoma. Clinical trial information: NCT04459078.

The Long-Term and Short-Term Efficacy of Immunotherapy in Non-Small Cell Lung Cancer Patients With Brain Metastases: A Systematic Review and Meta-Analysis.

BackgroundAlthough immunotherapy has been widely used, there is currently no research comparing immunotherapy for non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). This meta-analysis addresses a gap in the comparison of immunotherapy efficacy, including immune checkpoint inhibitors (ICIs), chemotherapy (CT), radiotherapy (RT), and ICI combined CT or RT.MethodsA search of Pubmed, Cochrane, EMBASE, and ClinicalTrial.gov was conducted to identify studies which enrolled NSCLC patients with BM treated with ICIs. The outcomes consisted of intracerebral overall response rate (iORR), intracerebral disease control rate (iDCR), extracranial overall response rate (EORR), distant brain failure (DBF), local control (LC), progression-free survival (PFS), and overall survival (OS).ResultsA total of 3160 participants from 46 trials were included in the final analysis. Patients treated with immunotherapy were associated with a longer PFS (0.48, 95%CI: 0.41-0.56), and a longer OS (0.64, 95%CI: 0.60-0.69) compared with immunotherapy-naive patients. In prospective studies, dual ICI combined CT and ICI combined CT achieved a better OS. The hazard ratio (HR) of dual ICI combined CT versus dual ICI was 0.61, and the HR of ICI combined CT versus ICI monotherapy was 0.58. Moreover, no statistical difference in PFS, OS, EORR, iORR, iDCR, and EDCR was found between patients with ICI monotherapy and ICI combined cranial radiotherapy. Concurrent ICI combined RT was shown to decrease the rate of DBF (OR = 0.15, 95% CI: 0.03-0.73) compared with RT after ICI. Patients treated with WBRT might have an inferior efficacy than those with SRS because the iORR of SRS was 0.75 (0.70, 0.80) and WBRT was 0. Furthermore, no obvious difference in PFS and OS was observed among the three different types of ICI, which targets PD-1, PD-L1, and CTLA-4, respectively.ConclusionsPatients treated with ICI got superior efficacy to those without ICI. Furthermore, dual ICI combined CT and ICI combined CT seemed to be optimal for NSCLC patients with BM. In terms of response and survival, concurrent administration of SRS and ICI led to better outcomes for patients with BMs than non-concurrent or non-SRS.Importance of the StudyIn the new era of immunotherapy, our meta-analysis validated the importance of immunotherapy for non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). By comparing the long-term and short-term impacts of various regimens, all immunotherapy treatments had superior efficacy to immunotherapy-naive. At the same time, through pairwise comparison in immunotherapy, our findings can help clinicians to make treatment decisions for NSCLC patients with BMs.Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=269621, identifier CRD42021269621.

Ushering in a New Era of Immunotherapy

Genetic Engineering & Biotechnology NewsVol. 42, No. 5 Sponsored ContentUshering in a New Era of ImmunotherapyNovel approaches to CAR T-cell therapy discovery and development addresses patient relapse in hematological cancersPublished Online:10 May 2022https://doi.org/10.1089/gen.42.05.07AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetails Volume 42Issue 5May 2022 Information© 2022 by GEN PublishingTo cite this article:Ushering in a New Era of Immunotherapy.Genetic Engineering & Biotechnology News.May 2022.20-21.http://doi.org/10.1089/gen.42.05.07Published in Volume: 42 Issue 5: May 10, 2022PDF download

The New Era of Immunotherapy in Gastric Cancer.

Simple SummaryAdvanced gastric cancer remains a malignancy with a poor prognosis, with a median survival of about 12–15 months. In recent years, immune checkpoint inhibitors have emerged as a new standard of care for several malignancies, including advanced gastric cancer, and have demonstrated good clinical benefit in some populations. In this review paper, we describe the current status of immunotherapy in gastric cancer, with a focus on molecular and immunological profiles, biomarkers, major clinical trials, and novel immunotherapies.Immune checkpoint inhibitors (ICIs) such as anti-programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) monoclonal antibodies have prolonged survival in various types of malignancies, including advanced gastric cancer (AGC). Nivolumab, a monoclonal anti-PD-1 antibody, showed an improvement in overall survival at a later-line therapy in unselected AGC patients in the ATTRACTION-2 study or in combination with chemotherapy as first-line therapy in the global CheckMate-649 study. Another monoclonal anti-PD-1 antibody, pembrolizumab, showed single agent activity in tumors with high microsatellite instability or high tumor mutational burden. Furthermore, a recent KEYNOTE-811 study demonstrated significant improvement in response rate with pembrolizumab combined with trastuzumab and chemotherapy for HER2-positive AGC. Based on these results, ICIs are now incorporated into standard treatment for AGC patients. As a result of pivotal clinical trials, three anti-PD-1 antibodies were approved for AGC: nivolumab combined with chemotherapy as first-line treatment or nivolumab monotherapy as third- or later-line treatment in Asian countries; pembrolizumab for previously treated microsatellite instability-high (MSI-H) or tumor mutational burden-high AGC, or pembrolizumab combined with trastuzumab and chemotherapy for HER2-positive AGC in the United States; and dostarlimab for previously treated MSI-H AGC in the United States. However, a substantial number of patients have showed resistance to ICIs, highlighting the importance of the better selection of patients or further combined immunotherapy. This review focused on molecular and immunological profiles, pivotal clinical trials of ICIs with related biomarkers, and investigational immunotherapy for AGC.

Epigenetic Priming of Bladder Cancer Cells With Decitabine Increases Cytotoxicity of Human EGFR and CD44v6 CAR Engineered T-Cells.

BackgroundTreatment of B-cell malignancies with CD19-directed chimeric antigen receptor (CAR) T-cells marked a new era in immunotherapy, which yet has to be successfully adopted to solid cancers. Epigenetic inhibitors of DNA methyltransferases (DNMTi) and histone deacetylases (HDACi) can induce broad changes in gene expression of malignant cells, thus making these inhibitors interesting combination partners for immunotherapeutic approaches.MethodsUrothelial carcinoma cell lines (UCC) and benign uroepithelial HBLAK cells pretreated with the DNMTi decitabine or the HDACi romidepsin were co-incubated with CAR T-cells directed against EGFR or CD44v6, and subsequent cytotoxicity assays were performed. Effects on T-cell cytotoxicity and surface antigen expression on UCC were determined by flow cytometry. We also performed next-generation mRNA sequencing of inhibitor-treated UCC and siRNA-mediated knockdown of potential regulators of CAR T-cell killing.ResultsExposure to decitabine but not romidepsin enhanced CAR T-cell cytotoxicity towards all UCC lines, but not towards the benign HBLAK cells. Increased killing could neither be attributed to enhanced target antigen expression (EGFR and CD44v6) nor fully explained by changes in the T-cell ligands PD-L1, PD-L2, ICAM-1, or CD95. Instead, gene expression analysis suggested that regulators of cell survival and apoptosis were differentially induced by the treatment. Decitabine altered the balance between survival and apoptosis factors towards an apoptosis-sensitive state associated with increased CAR T-cell killing, while romidepsin, at least partially, tilted this balance in the opposite direction. Knockdown experiments with siRNA in UCC confirmed BID and BCL2L1/BCLX as two key factors for the altered susceptibility of the UCC.ConclusionOur data suggest that the combination of decitabine with CAR T-cell therapy is an attractive novel therapeutic approach to enhance tumor-specific killing of bladder cancer. Since BID and BCL2L1 are essential determinants for the susceptibility of a wide variety of malignant cells, their targeting might be additionally suitable for combination with immunotherapies, e.g., CAR T-cells or checkpoint inhibitors in other malignancies.

CTNNB1 Alternation Is a Potential Biomarker for Immunotherapy Prognosis in Patients With Hepatocellular Carcinoma.

BackgroundThe emergence of immune checkpoint inhibitors (ICIs) marks the beginning of a new era of immunotherapy for hepatocellular carcinoma (HCC), however, not all patients respond successfully to this treatment. A major challenge for HCC immunotherapy is the development of ways to screen for those patients that would benefit from this type of treatment and determine the optimal treatment plan for individual patients. Therefore, it is important to find a biomarker which allows for the stratification of HCC patients, which distinguishes responders from non-responders, thereby further improving the clinical benefits for those undergoing immunotherapy.MethodsWe used univariate and multivariate Cox risk proportional regression models to evaluate the relationship between non-synonymous mutations with a mutation frequency greater than 10%. We made a prognosis of an immunotherapy HCC cohort using mutation and prognosis data. An additional three HCC queues from the cbioportal webtool were used for further verification. The CIBERSORT, IPS, quanTIseq, and MCPcounter algorithms were used to evaluate the immune cells. PCA and z-score algorithm were used to calculate immune-related signature with published gene sets. Gene set enrichment analysis (GSEA) was used to compare the differences in the pathway-based enrichment scores of candidate genes between mutant and wild types.ResultsUnivariate and multivariate Cox results showed that only CTNNB1-Mutant(CTNNB1-MUT) was associated with progression-free survival (PFS) of HCC patients in the immunotherapy cohort. After excluding the potential bias introduced by other clinical features, it was found that CTNNB1-MUT served as an independent predictor of the prognosis of HCC patients after immunotherapy (P < 0.05; HR > 1). The results of the tumor immune microenvironment (TIME) analysis showed that patients with CTNNB1-MUT had significantly reduced activated immune cells [such as T cells, B cells, M1-type macrophages, and dendritic cells (DCs)], significantly increased M2-type macrophages, a significantly decreased expression of immunostimulating molecules, low activity of the immune activation pathways (cytokine pathway, immune cell activation and recruitment) and highly active immune depletion pathways (fatty acid metabolism, cholesterol metabolism, and Wnt pathway).ConclusionsIn this study, we found CTNNB1-MUT to be a potential biomarker for HCC immunotherapy patients, because it identified those patients are less likely to benefit from ICIs.

Strengthening the CAR-T cell therapeutic application using CRISPR/Cas9 technology.

Adoptive cell immunotherapy with chimeric antigen receptor T (CAR-T) cell has brought a revolutionary means of treatment for aggressive diseases such as hematologic malignancies and solid tumors. Over the last decade, the United States Food and Drug Administration (FDA) approved five types of CAR-T cell therapies for hematologic malignancies, including Idecabtagene vicleucel (Abecma), Lisocabtagene maraleucel (Breyanzi), Brexucabtagene autoleucel (Tecartus), Tisagenlecleucel (Kymriah), and Axicabtagene ciloleucel (Yescarta). Despite outstanding results gained from different clinical trials, CAR-T cell therapy is not free from side effects and toxicities, and needs careful investigations and improvements. Gene-editing technology, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system, has emerged as a promising tool to address some of the CAR-T therapy hurdles. Using CRISPR/Cas9 technology, CAR expression as well as other cellular pathways can be modified in various ways to enhance CAR-T cells antitumor function and persistence in immunosuppressive tumor microenvironment. CRISPR/Cas9 technology can also be used to decrease CAR-T cell toxicities and side effects. Hereby, we discussed the practical challenges and hurdles related to the accuracy, efficiency, efficacy, safety, and delivery of CRISPR/Cas9 technology to the genetically engineered-T cells. Combining of these two state-of-the-art technologies, CRISPR/Cas9 and CAR-T cells, the field of oncology has an extraordinary opportunity to enter a new era of immunotherapy, which offers novel therapeutic options for different types of tumors.

Nivolumab: 5 years from the day of international registration of immunotherapy of metastatic kidney cancer

Five years ago, on November 23, 2015, the US Food and Drug Administration (FDA) approved nivolumab for the treatment of metastatic renal cell carcinoma, thus ushering in a new era of immunotherapy for this tumor. The purpose of this review is to systematize the accumulated results of studies of nivolumab in monotherapy and in combinations.

Nivolumab: 5 Years Since FDA Approval of the First Checkpoint Inhibitor for Renal Cell Carcinoma

On November 23, 2015, the US Food and Drug Administration (FDA) approved nivolumab for the treatment of metastatic renal cell carcinoma (RCC), thus opening a new era of immunotherapy for this tumor. This review summarizes the 5-year experience of studying and using nivolumab in RCC patients.

Evolving Treatment of Advanced Hepatocellular Carcinoma in the Asia-Pacific Region: A Review and Multidisciplinary Expert Opinion.

Simple SummaryFor years, the systemic therapies sorafenib and lenvatinib have represented standard of care for first-line treatment of advanced hepatocellular carcinoma (HCC). The recent approval of atezolizumab in combination with bevacizumab heralded the arrival of immunotherapy for first-line treatment of advanced HCC, and the field is growing, with other combination immunotherapies under investigation. Focusing on the Asia–Pacific region, where drug availability and reimbursement systems differ widely, this article reviews the evolving treatment landscape and summarises the authors’ expert opinion on therapeutic decision-making to optimise outcomes in advanced HCC.Hepatocellular carcinoma (HCC) is the fourth most common driver of cancer-related death globally, with an estimated 72% of cases in Asia. For more than a decade, first-line systemic treatments for advanced or unresectable HCC were limited to the multi-targeted kinase inhibitors sorafenib and, more recently, lenvatinib. Now, treatment options have expanded to include immunotherapy, as exemplified by the immune checkpoint inhibitor (ICI) atezolizumab combined with the antiangiogenic agent bevacizumab. Additional combinations of ICIs with kinase inhibitors, other ICIs, or antiangiogenic agents are under investigation, further supporting the new era of immunotherapy for first-line treatment of advanced or unresectable HCC. We describe this evolving landscape and provide expert opinion on therapeutic best practices in the Asia–Pacific region, where different costs of, and patient access to, treatment are a challenge. With the combination of atezolizumab plus bevacizumab likely to become the clinical standard of care, optimising treatment sequence and ensuring patient access to newer therapies remain priorities. Cost containment and treatment sequencing may be facilitated by characterisation of predictive positive and negative biomarkers. With these considerations in mind, this review and expert opinion focused on advanced HCC in the Asia–Pacific region offers perspectives of multiple stakeholders, including physicians, payer systems, and patients.

Immunology and Immunotherapeutic Approaches for Advanced Renal Cell Carcinoma: A Comprehensive Review.

Renal cell carcinoma (RCC) is a malignant tumor associated with various tumor microenvironments (TMEs). The immune system is activated by the development of cancer and drives T cell anti-tumor response. CD8 T cells are known to improve clinical outcomes and sensitivity to immunotherapy, and play a crucial role against tumors. In contrast, tumor-associated macrophages (TAMs) suppress immunity against malignancy and lead to tumor progression. TAMs are promoted from damaged TMEs and mount proinflammatory responses to pathogens. Initial immunotherapy consists of interferon-α and interleukin-2. However, response to such therapy is unclear in most patients, and it is associated with high levels of toxicity. Immune checkpoint inhibitors (ICIs), which up-regulate immune responses by blocking the programed cell death protein 1 (PD-1) receptor, the ligand of PD-1, or cytotoxic T-lymphocyte-associated protein 4 T cells, have led to a new era of immunotherapy. Furthermore, combination strategies with ICIs have proven effective through several randomized controlled trials. We expect the next generation of immunotherapy to lead to better outcomes based on ongoing trials and inspire new therapeutic strategies.

Cortical inflammation and brain signs of high-risk atherosclerosis in a non-human primate model.

Atherosclerosis is a chronic systemic inflammatory disease, inducing cardiovascular and cerebrovascular acute events. A role of neuroinflammation is suspected, but not yet investigated in the gyrencephalic brain and the related activity at blood−brain interfaces is unknown. A non-human primate model of advanced atherosclerosis was first established using longitudinal blood samples, multimodal imaging and gene analysis in aged animals. Non-human primate carotid lesions were compared with human carotid endarterectomy samples. During the whole-body imaging session, imaging of neuroinflammation and choroid plexus function was performed. Advanced plaques were present in multiple sites, premature deaths occurred and downstream lesions (myocardial fibrosis, lacunar stroke) were present in this model. Vascular lesions were similar to in humans: high plaque activity on PET and MRI imaging and systemic inflammation (high plasma C-reactive protein levels: 42 ± 14 µg/ml). We also found the same gene association (metabolic, inflammatory and anti-inflammatory markers) as in patients with similar histological features. Metabolic imaging localized abnormal brain glucose metabolism in the frontal cortex. It corresponded to cortical neuro-inflammation (PET imaging) that correlated with C-reactive protein level. Multimodal imaging also revealed pronounced choroid plexus function impairment in aging atherosclerotic non-human primates. In conclusion, multimodal whole-body inflammation exploration at the vascular level and blood−brain interfaces identified high-risk aging atherosclerosis. These results open the way for systemic and central inflammation targeting in atherosclerosis in the new era of immunotherapy.