Project description:The aim of neoadjuvant treatment in non-small cell lung cancer (NSCLC) is to eliminate micrometastatic disease to facilitate surgical resection. Neoadjuvant chemotherapy (ChT) in localised NSCLC has numerous advantages over other therapeutic modalities and is considered standard treatment in resectable disease. Treatment with immune checkpoint inhibitors (ICI) improves long-term survival in advanced disease and has a better toxicity profile than conventional therapies. These immunotherapy agents (anti-PD1/PD-L1), administered with or without ChT, are currently being evaluated in the preoperative setting, with initial results showing better pathological response rates and more long-term benefits. Importantly, these drugs do not appear to increase the rate of severe adverse effects and/or postoperative complications. However, several questions still need to be resolved, including the identification of predictive biomarkers; comparative studies of immunotherapy alone vs combined treatment with ChT and/or radiotherapy; the optimal duration of treatment; the timing of surgery; the need for adjuvant treatment; appropriate radiologic evaluation and mediastinal staging; and the correlation between pathological response and survival outcomes. Here we review the current evidence for immunotherapy from a multidisciplinary perspective and discuss current and future controversies.
Project description:Lung carcinoma is associated with a high mortality worldwide, being the leading cause of cancer death. It is mainly classified into squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, and small cell lung cancer. However, such malignancy has been increasingly subdivided into histological and molecular subtypes to guide treatment. Therapies can be used in adjuvant and palliative settings. Regarding immunotherapy, it has been widely tested in both first or subsequent palliative lines. In this sense, drugs such as pembrolizumab, nivolumab, atezolizumab, ipilimumab, avelumab, and durvalumab have been assessed in large studies. Some of these trials have also studied these medicines in adjuvant and in maintenance therapy. In recent years, advances in immunotherapy have raised the hope that the unfavorable prognosis observed in several affected individuals can be changed. Immunotherapy has increased the overall survival in squamous NSCLC, non-squamous NSCLC, and small cell lung cancer. However, it has added to the oncology practice some side effects that are unusual in standard chemotherapy and require special clinical support. In order to show how immunotherapy is being applied in the treatment of lung carcinoma, we reviewed the main studies in adjuvant and palliative scenarios. What is the better scheme? What is the better combination? What is the better dose? When should we use immunotherapy? Does programmed cell death ligand 1 expression significantly interfere in immunotherapy efficiency? Some of these questions have already been answered, while others require more investigations.
Project description:BackgroundIn the recent years, immunotherapeutics and specifically immunecheckpoints inhibitors have marked a significant shift in the diagnostic and therapeutic algorithm of Non-Small Cell Lung Cancer (NSCLC), allowing us to use immunotherapeutics alone or combined with chemotherapy for a great subset of patients. However, new interesting approaches are being presently investigated, markedly immunotherapy combinations, that is, the use of two or more immunotherapeutics combined.MethodsIn particular, the combination of anti-PD-1 nivolumab and anti-CTLA-4 ipilimumab has already provided groundbreaking positive results in the advanced NSCLC and other combinations are currently under investigation.ResultsTherefore, this paper aims to provide a comprehensive state-of-the-art review about immunotherapy combination, along with suggestions about future directions. A comprehensive literature search was carried out to identify eligible studies from MEDLINE/PubMed and ClinicalTrials.gov.ConclusionNivolumab plus ipilimumab represent the most promising immunotherapy combination for the treatment of advanced NSCLC patients; safety, tolerability and efficacy of new immunotherapeutics (in monotherapy and in immunotherapy combinations) must be further assessed in future studies.
Project description:Prostate cancer (PC) is the most common type of tumor in men. In the early stage of the disease, it is sensitive to androgen deprivation therapy. In patients with metastatic castration-sensitive prostate cancer (mHSPC), chemotherapy and second-generation androgen receptor therapy have led to increased survival. However, despite advances in the management of mHSPC, castration resistance is unavoidable and many patients develop metastatic castration-resistant disease (mCRPC). In the past few decades, immunotherapy has dramatically changed the oncology landscape and has increased the survival rate of many types of cancer. However, immunotherapy in prostate cancer has not yet given the revolutionary results it has in other types of tumors. Research into new treatments is very important for patients with mCRPC because of its poor prognosis. In this review, we focus on the reasons for the apparent intrinsic resistance of prostate cancer to immunotherapy, the possibilities for overcoming this resistance, and the clinical evidence and new therapeutic perspectives regarding immunotherapy in prostate cancer with a look toward the future.
Project description:Cancer is the second leading cause of death globally and its incidence and mortality are rapidly increasing worldwide. The dynamic interaction of immune cells and tumor cells determines the clinical outcome of cancer. Immunotherapy comes to the forefront of cancer treatments, resulting in impressive and durable responses but only in a fraction of patients. Thus, understanding the characteristics and profiles of immune cells in the tumor microenvironment (TME) is a necessary step to move forward in the design of new immunomodulatory strategies that can boost the immune system to fight cancer. Histamine produces a complex and fine-tuned regulation of the phenotype and functions of the different immune cells, participating in multiple regulatory responses of the innate and adaptive immunity. Considering the important actions of histamine-producing immune cells in the TME, in this review we first address the most important immunomodulatory roles of histamine and histamine receptors in the context of cancer development and progression. In addition, this review highlights the current progress and foundational developments in the field of cancer immunotherapy in combination with histamine and pharmacological compounds targeting histamine receptors.
Project description:Immune checkpoint inhibitors (ICIs) have shown remarkable benefit in the treatment of patients with non-small-cell lung cancer (NSCLC) and have emerged as an effective treatment option even in the first-line setting. ICIs can block inhibitory pathways that restrain the immune response against cancer, restoring and sustaining antitumor immunity. Currently, there are 4 PD-1/PD-L1 blocking agents available in clinics, and immunotherapy-based regimen alone or in combination with chemotherapy is now preferred option. Combination trials assessing combination of ICIs with chemotherapy, targeted therapy and other immunotherapy are ongoing. Controversies remain regarding the use of ICIs in targetable oncogene-addicted subpopulations, but their initial treatment recommendations remained unchanged, with specific tyrosine kinase inhibitors as the choice. For the majority of patients without targetable driver oncogenes, deciding between therapeutic options can be difficult due to lack of direct cross-comparison studies. There are continuous efforts to find predictive biomarkers to find those who respond better to ICIs. PD-L1 protein expressions by immunohistochemistry and tumor mutational burden have emerged as most well-validated biomarkers in multiple clinical trials. However, there still is a need to improve patient selection, and to establish the most effective concurrent or sequential combination therapies in different NSCLC clinical settings. In this review, we will introduce currently used ICIs in NSCLC and analyze most recent trials, and finally discuss how, when and for whom ICIs can be used to provide promising avenues for lung cancer treatment.
Project description:Despite the marked success of molecular targeted therapy in lung cancer in this era of personalized medicine, its efficacy has been limited by the presence of resistance mechanisms. The prognosis of patients with lung cancer remains poor, and there is an unmet need to develop more effective therapies to improve clinical outcomes. The increasing insight into the human immune system has led to breakthroughs in immunotherapy and has prompted research interest in employing immunotherapy to treat lung cancer. Natural killer (NK) cells, which serve as the first line of defense against tumors, can induce the innate and adaptive immune responses. Therefore, the use of NK cells for the development of novel lung‑cancer immunotherapy strategies is promising. A growing number of novel approaches that boost NK cell antitumor immunity and expand NK cell populations ex vivo now provide a platform for the development of antitumor immunotherapy. The present review outlined the biology of NK cells, summarized the role of NK cells in lung cancer and the effect of the tumor microenvironment on NK cells, highlighted the potential of NK cell‑based immunotherapy as an effective therapeutic strategy for lung cancer and discussed future directions.
Project description:Different immunotherapeutic approaches have proved to be of significant clinical value to many patients with different types of advanced cancer. However, we need more precise immunotherapies and predictive biomarkers to increase the successful response rates. The advent of next generation sequencing technologies and their applications in immuno-oncology has helped us tremendously towards this aim. We are now moving towards the realization of personalized medicine, thus, significantly increasing our expectations for a more successful management of the disease. Here, we discuss the current immunotherapeutic approaches against cancer, including immune checkpoint blockade with an emphasis on anti-PD-L1 and anti-CTLA-4 monoclonal antibodies. We also analyze a growing list of other co-inhibitory and co-stimulatory markers and emphasize the mechanism of action of the principal pathway for each of these, as well as on drugs that either have been FDA-approved or are under clinical investigation. We further discuss recent advances in other immunotherapies, including cytokine therapy, adoptive cell transfer therapy and therapeutic vaccines. We finally discuss the modulation of gut microbiota composition and response to immunotherapy, as well as how tumor-intrinsic factors and immunological processes influence the mutational and epigenetic landscape of progressing tumors and response to immunotherapy but also how immunotherapeutic intervention influences the landscape of cancer neoepitopes and tumor immunoediting.
Project description:The advent of immunotherapy has transformed the treatment paradigm of several solid tumors and is expected to influence the therapeutic algorithm even more in the future following the results of numerous ongoing clinical trials in a wide range of malignancies. Exploiting the anti-cancer effect of the immune system with the use of vaccines, viral vectors, and more lately with immune check-point inhibitors and chimeric antigen receptor modification, has been proven a successful therapeutic strategy in a broad spectrum of tumors. In particular, immune check-point inhibition in melanoma, non-small-cell lung cancer and renal cancer, peptide vaccination in prostate cancer and glioblastoma, and oncolytic immunotherapy in melanoma are well-established therapeutic modalities that have obtained approval by regulatory authorities and are already in clinical use. A large number of ongoing clinical trials involving thousands of patients are currently seeking to define the appropriate tumor type, therapeutic setting, treatment combination and patient populations in order to maximize clinical benefit from immunotherapeutic agents. In this context, identification of the patients whose tumors are most likely to respond to immunotherapy by the use of appropriate biomarkers will be crucial for the optimal implementation of immunotherapy into the therapeutic armamentarium.
Project description:Survival rates for metastatic lung cancer including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are poor with 5-year survival of less than 5%. The use of molecular targeted therapies has improved median overall survival (OS) in a limited group of NSCLC patients whose tumors harbor specific genetic alterations. However for a large group of NSCLC and SCLC molecular alterations are not available to lead to direct targeted therapies. Recent favorable results of newer trials of therapeutic vaccines and checkpoint inhibitors have proven against the common belief that lung cancer is nonimmunogenic. In particular, the checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed death-1 (PD-1) pathway have shown durable clinical responses with manageable toxicity. Several phase II and III clinical trials testing the association of different schedule of chemotherapy and immunotherapy or immunotherapy alone are ongoing in lung cancer and important results are expected in the near future. However, more studies are needed to understand the optimal combination of immunotherapeutic agents with chemotherapy and radiation therapy for the treatment of NSCLC and SCLC.