Cancer vaccine: learning lessons from immune checkpoint inhibitors.
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ABSTRACT:
SUBMITTER: Ye Z
PROVIDER: S-EPMC5771333 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
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Project description:BackgroundCancer patients are at a higher risk for developing influenza (flu)- related complications. It is unclear if the flu vaccine exacerbates immune events in patients treated with immune checkpoint inhibitors (ICIs).MethodsWe conducted an institutional review board-IRB-approved retrospective review of advanced cancer patients on ICIs who received the flu vaccine during three 3 consecutive seasons: 2014-2015, 2015-2016, and 2016-2017. The primary outcome assessed was any "new onset" immune-related adverse event (IRAE). A subset analysis of vaccinated patients newly treated with anti-programmed cell death protein 1 (PD-1) agents (nivolumab or pembrolizumab) was conducted to assess overall IRAE rates for comparison with published clinical trials.ResultsDuring the three 3 seasons, 370 patients met criteria for ICI and vaccination within ~ twoapproximately 2 months (65 days). The most common underlying cancers were lung (46%) and melanoma (19%); 61% of patients received an anti-PD-1 agent only. In the entire cohort, 20% experienced an IRAE (any grade); incidence of grade 3 or 4 toxicity was 8%. No grade 5 events occurred. In the subset of 170 patients newly treated with anti-PD-1 agents, the overall IRAE rate was 18% and, grade 3/4 events occurred in 7.6%. Influenza was diagnosed in 2 patients.ConclusionsNo increase in incidence or severity of IRAEs was detected in patients on ICIs who received the inactivated influenza vaccine within ~ approximately 2 months of ICI. For newly treated patients on anti-PDI-1 agents, IRAE rates were comparable to those from published clinical trials and did not vary with order of administration. Routine seasonal flu vaccination is encouraged in patients on ICIs.
| S-EPMC6938975 | biostudies-literature
Project description:In recent years immune checkpoint inhibitors have garnered attention as being one of the most promising types of immunotherapy on the horizon. There has been particular focus on the immune checkpoint molecules, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) which have been shown to have potent immunomodulatory effects through their function as negative regulators of T cell activation. CTLA-4, through engagement with its ligands B7-1 (CD80) and B7-2 (CD86), plays a pivotal role in attenuating the activation of naïve and memory T cells. In contrast, PD-1 is primarily involved in modulating T cell activity in peripheral tissues via its interaction with PD-L1 and PD-L2. The discovery of these negative regulators of the immune response was crucial in the development of checkpoint inhibitors. This shifted the focus from developing therapies that targeted activation of the host immune system against cancer to checkpoint inhibitors, which aimed to mediate tumor cell destruction through the removal of coinhibitory signals blocking anti-tumor T cell responses.
| S-EPMC6163118 | biostudies-literature
Project description:Malignant cells have the capacity to rapidly grow exponentially and spread in part by suppressing, evading, and exploiting the host immune system. Immunotherapy is a form of oncologic treatment directed towards enhancing the host immune system against cancer. In recent years, manipulation of immune checkpoints or pathways has emerged as an important and effective form of immunotherapy. Agents that target cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1) are the most widely studied and recognized. Immunotherapy, however, extends beyond immune checkpoint therapy by using new molecules such as chimeric monoclonal antibodies and antibody drug conjugates that target malignant cells and promote their destruction. Genetically modified T cells expressing chimeric antigen receptors are able to recognize specific antigens on cancer cells and subsequently activate the immune system. Native or genetically modified viruses with oncolytic activity are of great interest as, besides destroying malignant cells, they can increase anti-tumor activity in response to the release of new antigens and danger signals as a result of infection and tumor cell lysis. Vaccines are also being explored, either in the form of autologous or allogenic tumor peptide antigens, genetically modified dendritic cells that express tumor peptides, or even in the use of RNA, DNA, bacteria, or virus as vectors of specific tumor markers. Most of these agents are yet under development, but they promise to be important options to boost the host immune system to control and eliminate malignancy. In this review, we have provided detailed discussion of different forms of immunotherapy agents other than checkpoint-modifying drugs. The specific focus of this manuscript is to include first-in-human phase I and phase I/II clinical trials intended to allow the identification of those drugs that most likely will continue to develop and possibly join the immunotherapeutic arsenal in a near future.
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Project description:Metastatic prostate cancer is a lethal disease with limited treatment options. Immune checkpoint inhibitors have dramatically changed the treatment landscape of multiple cancer types but have met with limited success in prostate cancer. In this review, we discuss the preclinical studies providing the rationale for the use of immunotherapy in prostate cancer and underlying biological barriers inhibiting their activity. We discuss the predictors of response to immunotherapy in prostate cancer. We summarize studies evaluating immune checkpoint inhibitors either as a single agent or in combination with other checkpoint inhibitors or with other agents such as inhibitors of androgen axis, poly ADP-ribose polymerase (PARP), radium-223, radiotherapy, cryotherapy, tumor vaccines, chemotherapy, tyrosine kinase inhibitors, and granulocyte-macrophage colony-stimulating factor. We thereafter review future directions including the combination of immune checkpoint blockade with inhibitors of adenosine axis, bispecific T cell engagers, PSMA directed therapies, adoptive T-cell therapy, and multiple other miscellaneous agents.
| S-EPMC8125096 | biostudies-literature
Project description:To date, clinical trials of various vaccine therapies using autologous tumor antigens or tumor-associated/specific antigen peptide with adjuvants have been performed to treat patients with high-grade gliomas (HGG). Furthermore, immune checkpoint pathway-targeted therapies including anti- programmed cell death 1 (PD-1) antibody have been remarkably effective in other neoplasms, and various clinical trials with anti-PD-1 antibody in patients with HGG have started to date. It is possible that up-regulation of immune checkpoint molecules in tumor tissues after vaccine therapy may be one of the mechanisms of vaccine failure. Multiple preclinical studies indicate that combination therapy with vaccination and immune checkpoint blockade is effective for the treatment of malignant tumors including HGG. Thus, immunotherapy, especially combination therapy with vaccine and immune checkpoint inhibitors, may be a promising strategy for treatment of patients with HGG.
| S-EPMC5566705 | biostudies-other
Project description:Machine learning (ML) may enhance the efficiency of developing accurate prediction models for survival, which is critical in informing disease prognosis and care planning. This study aimed to develop an ML prediction model for survival outcomes in patients with urothelial cancer-initiating atezolizumab and to compare model performances when built using an expert-selected (curated) versus an all-in list (uncurated) of variables. Gradient-boosted machine (GBM), random forest, Cox-boosted, and penalised, generalised linear models (GLM) were evaluated for predicting overall survival (OS) and progression-free survival (PFS) outcomes. C-statistic (c) was utilised to evaluate model performance. The atezolizumab cohort in IMvigor210 was used for model training, and IMvigor211 was used for external model validation. The curated list consisted of 23 pretreatment factors, while the all-in list consisted of 75. Using the best-performing model, patients were stratified into risk tertiles. Kaplan-Meier analysis was used to estimate survival probabilities. On external validation, the curated list GBM model provided slightly higher OS discrimination (c = 0.71) than that of the random forest (c = 0.70), CoxBoost (c = 0.70), and GLM (c = 0.69) models. All models were equivalent in predicting PFS (c = 0.62). Expansion to the uncurated list was associated with worse OS discrimination (GBM c = 0.70; random forest c = 0.69; CoxBoost c = 0.69, and GLM c = 0.69). In the atezolizumab IMvigor211 cohort, the curated list GBM model discriminated 1-year OS probabilities for the low-, intermediate-, and high-risk groups at 66%, 40%, and 12%, respectively. The ML model discriminated urothelial-cancer patients with distinctly different survival risks, with the GBM applied to a curated list attaining the highest performance. Expansion to an all-in approach may harm model performance.
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Project description:Lung cancer is predominantly a disease of the elderly with about 50% of diagnoses in patients aged ?70 years and about 14% in those older than 80. Medical and physiological characteristics of elderly cancer patients make the choice of their better treatment more challenging. Furthermore, aging is accompanied by the so called "immunosenescence" phenomenon, the age-related decline in the immune system that is one of the potential reasons of increase of the incidence and prevalence of most cancers. There is a growing interest in understanding of immunosenescence and how it may correlate with the use of immune checkpoint inhibitors in elderly non-small cell lung cancer (NSCLC) patients. The survival benefit achieved by immunotherapy in all histologies and therapy line settings, added to its manageable toxicity profile, has dramatically changed the scenario of advanced NSCLC treatment. At subgroup analyses of randomized clinical trials, elderly NSCLC population seems to benefit from anti-programmed death-1 (anti-PD-1)/anti-programmed death ligand-1 (anti-PD-L1) agents' treatment. These efficacy data were also confirmed by studies in real-life setting. The key-points of aging and immunosenescence are described, focusing on the role of immune checkpoint inhibitors in elderly NSCLC population.
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Project description:Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, only some patients respond to ICIs, and current biomarkers for ICI efficacy have limited performance. Here, we devised an interpretable machine learning (ML) model trained using patient-specific cell-cell communication networks (CCNs) decoded from the patient's bulk tumor transcriptome. The model could (i) predict ICI efficacy for patients across four cancer types (median AUROC: 0.79) and (ii) identify key communication pathways with crucial players responsible for patient response or resistance to ICIs by analyzing more than 700 ICI-treated patient samples from 11 cohorts. The model prioritized chemotaxis communication of immune-related cells and growth factor communication of structural cells as the key biological processes underlying response and resistance to ICIs, respectively. We confirmed the key communication pathways and players at the single-cell level in patients with melanoma. Our network-based ML approach can be used to expand ICIs' clinical benefits in cancer patients.
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Project description:Immune checkpoint inhibitors (ICIs) have recently revolutionized cancer treatment, providing unprecedented clinical benefits. However, primary or acquired therapy resistance can affect up to two-thirds of patients receiving ICIs, underscoring the urgency to elucidate the mechanisms of treatment resistance and to design more effective therapeutic strategies. Conventional cancer treatments, including cytotoxic chemotherapy, radiation therapy, and targeted therapy, have immunomodulatory effects in addition to direct cancer cell-killing activities. Their clinical utilities in combination with ICIs have been explored, aiming to achieve synergetic effects with improved and durable clinical response. Here, we will review the immunomodulatory effects of chemotherapy, targeted therapy, and radiation therapy, in the setting of ICI, and their clinical implications in reshaping modern cancer immunotherapy.
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Project description:Immune checkpoint inhibitors, mainly drugs targeting the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA4) pathways, represent a remarkable advance in lung cancer treatment. Immune checkpoint inhibitors targeting PD-1 and PD-L1 are approved for the treatment of patients with non-small-cell lung cancer, with impressive clinical activity and durable responses in some patients. This review will summarize the mechanism of action of these drugs, the clinical development of these agents and the current role of these agents in the management of patients with lung cancer. In addition, the review will discuss the role of predictive biomarkers for optimal patient selection for immunotherapy and management of autoimmune side effects of these agents.
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