Final pre-specified analysis of the phase II trial of the AE37+GM-CSF vaccine in high risk breast cancer patients to prevent recurrence.
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Reinstating endogenous antitumor immunity: The concept of therapeutic management of cancer
There is now increasing evidence to suggest that adaptive immunity plays a major role in regulating the growth of tumour cells. T cells play a major role in coordinating the immune response against tumourspecific antigens during tumour progression. While T cell activation depends on the initial tumour antigen-specific signal provided to the T cell receptors via the antigenloaded major histocompatibility complex (MHC) complex on dendritic cells (DCs), additional signals provided by costimulatory molecules fine-tune this response, determining its strength, nature and duration. To this end, the discovery of receptors regulating T cell activation against the autologous tumour was of paramount importance for understanding how cancer progresses under immunosurveillance. The CD28 co-receptor acts as a strong positive costimulatory receptor, and CTL antigen-4 (CTLA-4) as a potent co-inhibitory receptor. The programmed death 1 (PD-1) receptor: PD-Ligand (PD-L) pathway is another major receptor-ligand network that functions primarily to provide a co-inhibitory signal. PD1: PD-L interactions maintain peripheral tolerance and are exploited by tumours to evade immune eradication by memory T cells specifically recognizing tumour peptides [1]. As such, this pathway has emerged as a potential therapeutic target for enhancing the immune response. A second important discovery, which also sheds light to our understanding of tumour evolution, is presented by the "immunoediting" theory. According to this theory, the immune system "edits" the tumour immunogenicity, resulting in the promotion or suppression of tumour growth, a phenomenon [2]. As a result of its capacity to shape tumour immunogenicity, an additional role for the immune system has emerged, namely that of prognostic indicator. Studies by Galon et al. [3], initiated almost a decade ago, have demonstrated that the quantity, quality and spatial distribution of immune cells within the tumour has a greater prognostic value than the standard tumour staging based on tumour burden, infiltration of draining and regional lymph nodes by tumour cells, and evidence of metastases. This so-called "immunoscore" came to complete the immunoediting theory by increasing the knowledge of the immune events inside the tumours, and by better understanding, the immune architecture of these tumours, as well as the functional programs of their constituents, all of which complete the idea of how tumours evade from immunosurveillance. Forum of Clinical OncologyReinstating endogenous antitumor immunity: The concept of therapeutic management of cancer * E-mail: nfpist73@yahoo.gr However, a lot of cancer patients will fail to respond and therefore, it becomes crucial to identify biomarkers to predict who of the patients will most likely benefit from these therapies. Abstract: © De Gruyter Open Keywords: Cancer immunotherapy • Tumor infiltrating lymphocytes • Immunoscore • Cancer vaccines • Checkpoint inhibitors
Reinstating endogenous antitumor immunity: The concept of therapeutic management of cancer
There is now increasing evidence to suggest that adaptive immunity plays a major role in regulating the growth of tumour cells. T cells play a major role in coordinating the immune response against tumourspecific antigens during tumour progression. While T cell activation depends on the initial tumour antigen-specific signal provided to the T cell receptors via the antigenloaded major histocompatibility complex (MHC) complex on dendritic cells (DCs), additional signals provided by costimulatory molecules fine-tune this response, determining its strength, nature and duration. To this end, the discovery of receptors regulating T cell activation against the autologous tumour was of paramount importance for understanding how cancer progresses under immunosurveillance. The CD28 co-receptor acts as a strong positive costimulatory receptor, and CTL antigen-4 (CTLA-4) as a potent co-inhibitory receptor. The programmed death 1 (PD-1) receptor: PD-Ligand (PD-L) pathway is another major receptor-ligand network that functions primarily to provide a co-inhibitory signal. PD1: PD-L interactions maintain peripheral tolerance and are exploited by tumours to evade immune eradication by memory T cells specifically recognizing tumour peptides [1]. As such, this pathway has emerged as a potential therapeutic target for enhancing the immune response. A second important discovery, which also sheds light to our understanding of tumour evolution, is presented by the "immunoediting" theory. According to this theory, the immune system "edits" the tumour immunogenicity, resulting in the promotion or suppression of tumour growth, a phenomenon [2]. As a result of its capacity to shape tumour immunogenicity, an additional role for the immune system has emerged, namely that of prognostic indicator. Studies by Galon et al. [3], initiated almost a decade ago, have demonstrated that the quantity, quality and spatial distribution of immune cells within the tumour has a greater prognostic value than the standard tumour staging based on tumour burden, infiltration of draining and regional lymph nodes by tumour cells, and evidence of metastases. This so-called "immunoscore" came to complete the immunoediting theory by increasing the knowledge of the immune events inside the tumours, and by better understanding, the immune architecture of these tumours, as well as the functional programs of their constituents, all of which complete the idea of how tumours evade from immunosurveillance. Forum of Clinical OncologyReinstating endogenous antitumor immunity: The concept of therapeutic management of cancer * E-mail: nfpist73@yahoo.gr However, a lot of cancer patients will fail to respond and therefore, it becomes crucial to identify biomarkers to predict who of the patients will most likely benefit from these therapies. Abstract: © De Gruyter Open Keywords: Cancer immunotherapy • Tumor infiltrating lymphocytes • Immunoscore • Cancer vaccines • Checkpoint inhibitors
Triple-negative breast cancer (TNBC) is the subtype of breast cancer with the poorest outcomes, and is associated with a high risk of relapse and metastasis. The treatment choices for this malignancy have been confined to conventional chemotherapeutic agents, due to a lack of expression of the canonical molecular targets. Immunotherapy has been recently changing the treatment paradigm for many types of tumors, and the approach of evoking active immune responses in the milieu of breast tumors through cancer vaccines has been introduced as one of the most novel immunotherapeutic approaches. Accordingly, a number of vaccines for the treatment or prevention of recurrence have been developed and are currently being studied in TNBC patients, while none have yet received any approvals. To elucidate the efficacy and safety of these vaccines, we performed a systematic review of the available literature on the topic. After searching the PubMed, Scopus, Web of Science, Embase, Cochrane CENTRAL, and Google Scholar databases, a total of 5701 results were obtained, from which 42 clinical studies were eventually included based on the predefined criteria. The overall quality of the included studies was acceptable. However, due to a lack of reporting outcomes of survival or progression in some studies (which were presented as conference abstracts) as well as the heterogeneity of the reported outcomes and study designs, we were not able to carry out a meta-analysis. A total of 32 different vaccines have so far been evaluated in TNBC patients, with the majority belonging to the peptide-based vaccine type. The other vaccines were in the cell or nucleic acid (RNA/DNA)-based categories. Most vaccines proved to be safe with low-grade, local adverse events and could efficiently evoke cellular immune responses; however, most trials were not able to demonstrate significant improvements in clinical indices of efficacy. This is in part due to the limited number of randomized studies, as well as the limited TNBC population of each trial. However, due to the encouraging results of the currently published trials, we anticipate that this strategy could show its potential through larger, phase III randomized studies in the near future.
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