Nejvíce citovaný článek - PubMed ID 24357284
Despite enormous progress, advanced cancers are still one of the most serious medical problems in current society. Although various agents and therapeutic strategies with anticancer activity are known and used, they often fail to achieve satisfactory long-term patient outcomes and survival. Recently, immunotherapy has shown success in patients by harnessing important interactions between the immune system and cancer. However, many of these therapies lead to frequent side effects when administered systemically, prompting treatment modifications or discontinuation or, in severe cases, fatalities. New therapeutic approaches like intratumoral immunotherapy, characterized by reduced side effects, cost, and systemic toxicity, offer promising prospects for future applications in clinical oncology. In the context of locally advanced or metastatic cancer, combining diverse immunotherapeutic and other treatment strategies targeting multiple cancer hallmarks appears crucial. Such combination therapies hold promise for improving patient outcomes and survival and for promoting a sustained systemic response. This review aims to provide a current overview of immunotherapeutic approaches, specifically focusing on the intratumoral administration of drugs in patients with locally advanced and metastatic cancers. It also explores the integration of intratumoral administration with other modalities to maximize therapeutic response. Additionally, the review summarizes recent advances in intratumoral immunotherapy and discusses novel therapeutic approaches, outlining future directions in the field.
- Klíčová slova
- advanced and metastatic cancer, cancer, combination therapy, immunotherapy, intratumoral,
- MeSH
- imunoterapie * metody MeSH
- kombinovaná terapie MeSH
- lidé MeSH
- metastázy nádorů MeSH
- nádorové mikroprostředí imunologie MeSH
- nádory * terapie imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: T cell density in colorectal cancer (CRC) has proven to be of high prognostic importance. Here, we evaluated the influence of a hyperfractionated preoperative short-term radiation protocol (25 Gy) on immune cell density in tumor samples of rectal cancer (RC) patients and on patient survival. In addition, we assessed spatial tumor heterogeneity by comparison of analogue T cell quantification on full tissue sections with digital T cell quantification on a virtually established tissue microarray (TMA). METHODS: A total of 75 RC patients (60 irradiated, 15 treatment-naïve) were defined for retrospective analysis. RC samples were processed for immunohistochemistry (CD3, CD8, PD-1, PD-L1). Analogue (score 0-3) as well as digital quantification (TMA: 2 cores vs. 6 cores, mean T cell count) of marker expression in 2 areas (central tumor, CT; invasive margin, IM) was performed. Survival was estimated on the basis of analogue as well as digital marker densities calculated from 2 cores (Immunoscore: CD3/CD8 ratio) and 6 cores per tumor area. RESULTS: Irradiated RC samples showed a significant decrease in CD3 and CD8 positive T cells, independent of quantification mode. T cell densities of 6 virtual cores approximated to T cell densities of full tissue sections, independent of individual core density or location. Survival analysis based on full tissue section quantification demonstrated that CD3 and CD8 positive T cells as well as PD-1 positive tumor infiltrating leucocytes (TILs) in the CT and the IM had a significant impact on disease-free survival (DFS) as well as overall survival (OS). In addition, CD3 and CD8 positive T cells as well as PD-1 positive TILs in the IM proved as independent prognostic factors for DFS and OS; in the CT, PD-1 positive TILs predicted DFS and CD3 and CD8 positive T cells as well as PD-1 positive TILs predicted OS. Survival analysis based on virtual TMA showed no impact on DFS or OS. CONCLUSION: Spatial tumor heterogeneity might result in inadequate quantification of immune marker expression; however, if using a TMA, 6 cores per tumor area and patient sample represent comparable amounts of T cell densities to those quantified on full tissue sections. Consistently, the tissue area used for immune marker quantification represents a crucial factor for the evaluation of prognostic and predictive biomarker potential.
- Klíčová slova
- Immunoscore, Irradiated rectal cancer, digital pathology, tissue microarray (TMA), virtual microscopy,
- Publikační typ
- časopisecké články MeSH
Toll-like receptor (TLR) agonists demonstrate therapeutic promise as immunological adjuvants for anticancer immunotherapy. To date, three TLR agonists have been approved by US regulatory agencies for use in cancer patients. Additionally, the potential of hitherto experimental TLR ligands to mediate clinically useful immunostimulatory effects has been extensively investigated over the past few years. Here, we summarize recent preclinical and clinical advances in the development of TLR agonists for cancer therapy.
- Klíčová slova
- Ampligen®, Hiltonol®, SD-101, bacillus Calmette-Guérin, imiquimod, motolimod,
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND: Locoregionally advanced, recurrent, and metastatic squamous cell carcinomas of the head and neck (SCCHN) remain difficult to treat disease entities, in which systemic treatment often forms an integral part of their management. Immunotherapy is based on functional restoration of the host immune system, helping to counteract various tumour evasion strategies. Broadly, immunotherapeutic approaches encompass tumour-specific antibodies, cancer vaccines, cytokines, adoptive T-cell transfer, and immune-modulating agents. Until 2015, the epidermal growth factor receptor inhibitor cetuximab, a tumour-specific antibody, represented the only Food and Drug Administration (FDA)-approved targeted therapy for SCCHN. Subsequently, in 2016, the results from two prospective trials employing the immune-modulating antibodies nivolumab and pembrolizumab heralded a new era of anticancer treatment. DISCUSSION: Nivolumab and pembrolizumab are monoclonal antibodies against programmed cell death protein-1 (PD-1), an 'immune checkpoint' receptor. Found on the surface of T-cells, PD-1 negatively regulates their activation and can thus be exploited during carcinogenesis. The second-line phase III trial CheckMate-141 randomly assigned 361 patients with recurrent and/or metastatic SCCHN in a 2:1 ratio to receive either single-agent nivolumab (3 mg/kg intravenously every 2 weeks) or standard monotherapy (methotrexate, docetaxel, or cetuximab). Nivolumab improved the objective response rate (13% versus 6%) and median overall survival (OS; 7.5 versus 5.1 months, p = 0.01) without increasing toxicity. Exploratory biomarker analyses indicated that patients treated with nivolumab had longer OS than those given standard therapy, regardless of tumour PD-1 ligand (PD-L1) expression or p16 status. In the non-randomised, multicohort phase Ib study KEYNOTE-012, treatment with pembrolizumab achieved comparable results. Importantly, most of the responding patients had a long-lasting response. CONCLUSION: Based on recent results, nivolumab and pembrolizumab have been approved by the FDA as new standard-of-care options for the second-line treatment of recurrent and/or metastatic SCCHN. Generally well tolerated, these novel drugs demonstrated modest response rates, with tumour regressions usually being durable, even in platinum-resistant/refractory cases. The next step will be to extend the observed benefit to first-line treatment, currently dominated by the EXTREME regimen (platinum/5-fluorouracil/cetuximab), and to the locoregionally advanced setting, where concurrent chemoradiation with cisplatin is standard. Regimens combining immunotherapy with other modalities will probably further improve outcomes.
- Klíčová slova
- Biomarkers, Cetuximab, Combination regimen, Head and neck cancer, Immunotherapy, Metastatic, Nivolumab, Pembrolizumab, Recurrent, Targeted therapy,
- MeSH
- dlaždicobuněčné karcinomy hlavy a krku MeSH
- imunoterapie * metody MeSH
- lidé MeSH
- nádory hlavy a krku terapie MeSH
- prospektivní studie MeSH
- spinocelulární karcinom terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
One type of anticancer vaccine relies on the administration of DNA constructs encoding one or multiple tumor-associated antigens (TAAs). The ultimate objective of these preparations, which can be naked or vectored by non-pathogenic viruses, bacteria or yeast cells, is to drive the synthesis of TAAs in the context of an immunostimulatory milieu, resulting in the (re-)elicitation of a tumor-targeting immune response. In spite of encouraging preclinical results, the clinical efficacy of DNA-based vaccines employed as standalone immunotherapeutic interventions in cancer patients appears to be limited. Thus, efforts are currently being devoted to the development of combinatorial regimens that allow DNA-based anticancer vaccines to elicit clinically relevant immune responses. Here, we discuss recent advances in the preclinical and clinical development of this therapeutic paradigm.
- Klíčová slova
- AFP, α-fetoprotein, APC, antigen-presenting cell, CDR, complementarity-determining region, CEA, carcinoembryonic antigen, CIN, cervical intraepithelial neoplasia, CTLA4, cytotoxic T lymphocyte protein 4, DAMP, damage-associated molecular pattern, DC, dendritic cell, FDA, Food and Drug Administration, GM-CSF, granulocyte macrophage colony-stimulating factor, GX-188E, HCC, hepatocellular carcinoma, HNSCC, head and neck squamous cell carcinoma, HPV, human papillomavirus, IL, interleukin, OS, overall survival, OVA, ovalbumin, PAP, prostate acid phosphatase, SCGB2A2, secretoglobin, family 2A, member 2, SOX2, SRY (sex determining region Y)-box 2, T, brachyury homolog, TAA, tumor-associated antigen, TLR, Toll-like receptor, TRA, tumor rejection antigen, Treg, regulatory T cell, VGX-3100, WT1, Wilms tumor 1, adjuvants, dendritic cell, electroporation, mucosal immunity,
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Immunomodulatory monoclonal antibodies (mAbs) differ from their tumor-targeting counterparts because they exert therapeutic effects by directly interacting with soluble or (most often) cellular components of the immune system. Besides holding promise for the treatment of autoimmune and inflammatory disorders, immunomodulatory mAbs have recently been shown to constitute a potent therapeutic weapon against neoplastic conditions. One class of immunomodulatory mAbs operates by inhibiting safeguard systems that are frequently harnessed by cancer cells to establish immunological tolerance, the so-called "immune checkpoints." No less than 3 checkpoint-blocking mAbs have been approved worldwide for use in oncological indications, 2 of which during the past 12 months. These molecules not only mediate single-agent clinical activity in patients affected by specific neoplasms, but also significantly boost the efficacy of several anticancer chemo-, radio- or immunotherapies. Here, we summarize recent advances in the development of checkpoint-blocking mAbs, as well as of immunomodulatory mAbs with distinct mechanisms of action.
- Klíčová slova
- CRC, colorectal carcinoma, CTLA4, cytotoxic T lymphocyte-associated protein 4, FDA, Food and Drug Administration, IL, interleukin, KIR, killer cell immunoglobulin-like receptor, MEDI4736, MPDL3280A, NK, natural killer, NSCLC, non-small cell lung carcinoma, PD-1, programmed cell death 1, RCC, renal cell carcinoma, TGFβ1, transforming growth factor β1, TLR, Toll-like receptor, TNFRSF, tumor necrosis factor receptor superfamily, Treg, regulatory T cell, ipilimumab, mAb, monoclonal antibody, nivolumab, pembrolizumab, urelumab,
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.
