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1.
Adv Exp Med Biol ; 1295: 317-325, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33543466

RESUMO

In the last decades, viruses have gained great interest in the field of immuno-oncology (I-O) for their ability of interacting both with the immune system and the tumour microenvironment. Those pathogens have naturally evolved and been evolutionary to specifically infect hosts, replicate, deliver their genome, and spread. These properties, initially considered a disadvantage, have been investigated and edited to turn viruses into precious allies for molecular biology serving as gene therapy vectors, adjuvants for the immune system, drug cargos, and, lately, anticancer therapeutics. As anticancer drug, one interesting option is viral engineering. Modification of either the viral genome or the outer shell of viruses can change infectivity and tissue targeting and add new functions to the viral particle. Remarkably, in the field of cancer virotherapy, scientists realized that a specific viral genomic depletion would turn the normal tropism of viruses to conditionally replicate in cancer cells only. This category of viruses, named 'Oncolytic viruses', have been investigated and used for cancer treatment in the past decades resulting in the approval of the first oncolytic virus, a herpes simplex virus expressing a stimulating factor, named T-Vec, in 2015. As such, oncolytic viruses achieved positive outcome but still are not able to completely eradicate the disease. This has brought the scientific community to edit those agents, adding to their ability to directly lysate cancer cells, few modifications to mainly boost their interaction with the immune system. Viruses experienced then a renaissance not only as infecting agent but as nanoparticle and cancer vaccines too. These strategies bring new life to the concept of using viruses as viral particles for therapeutic applications.


Assuntos
Vacinas Anticâncer , Nanopartículas , Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Vacinas Anticâncer/uso terapêutico , Humanos , Neoplasias/terapia , Vírus Oncolíticos/genética , Simplexvirus , Microambiente Tumoral
2.
J Surg Oncol ; 123(3): 751-759, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33595893

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal cancer with an urgent need for better medical therapies. Efforts have been made to investigate the efficacy of immunotherapy, particularly given the hallmarks of immune suppression and exhaustion in PDAC tumors. Here, we review the molecular components responsible for the immune-privileged state in PDAC and provide an overview of the immunotherapeutic strategies for PDAC including vaccine therapy, checkpoint blockade, myeloid-targeted therapy, and immune agonist therapy.


Assuntos
Carcinoma Ductal Pancreático/terapia , Imunoterapia/métodos , Neoplasias Pancreáticas/terapia , Animais , Vacinas Anticâncer/uso terapêutico , Carcinoma Ductal Pancreático/imunologia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Humanos , Neoplasias Pancreáticas/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
Molecules ; 26(4)2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546290

RESUMO

Melanoma is one of the most aggressive forms of skin cancer, with few possibilities for therapeutic approaches, due to its multi-drug resistance and, consequently, low survival rate for patients. Conventional therapies for treatment melanoma include radiotherapy, chemotherapy, targeted therapy, and immunotherapy, which have various side effects. For this reason, in recent years, pharmaceutical and biomedical research has focused on new sito-specific alternative therapeutic strategies. In this regard, nanotechnology offers numerous benefits which could improve the life expectancy of melanoma patients with very low adverse effects. This review aims to examine the latest advances in nanotechnology as an innovative strategy for treating melanoma. In particular, the use of different types of nanoparticles, such as vesicles, polymers, metal-based, carbon nanotubes, dendrimers, solid lipid, microneedles, and their combination with immunotherapies and vaccines will be discussed.


Assuntos
Vacinas Anticâncer/uso terapêutico , Portadores de Fármacos/uso terapêutico , Melanoma/terapia , Nanopartículas/uso terapêutico , Neoplasias Cutâneas/terapia , Humanos , Nanotecnologia
4.
Mol Immunol ; 130: 1-6, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33340930

RESUMO

The capacity of α-galactosylceramide (α-GalCer) to act as an anti-cancer agent in mice through the specific stimulation of type I NKT (iNKT) cells has prompted extensive investigation to translate this finding to the clinic. However, low frequencies of iNKT cells in cancer patients and their hypo-responsiveness to repeated stimulation have been seen as barriers to its efficacy. Currently the most promising clinical application of α-GalCer, or its derivatives, is as stimuli for ex vivo expansion of iNKT cells for adoptive therapy, although some encouraging clinical results have recently been reported using α-GalCer pulsed onto large numbers of antigen presenting cells (APCs). In on-going preclinical studies, attempts to improve efficacy of injected iNKT cell agonists have focussed on optimising presentation in vivo, through encapsulation in particulate vectors, making structural changes that help binding to the presenting molecule CD1d, or injecting agonists covalently attached to recombinant CD1d. Variations on these same approaches are being used to enhance the APC-licencing function of iNKT cells in vivo to induce adaptive immune responses to associated tumour antigens. Looking ahead, a unique capacity of in vivo-activated iNKT cells to facilitate formation of resident memory CD8+ T cells is a new observation that could find a role in cancer therapy.


Assuntos
Galactosilceramidas/uso terapêutico , Imunoterapia/métodos , Ativação Linfocitária/efeitos dos fármacos , Células T Matadoras Naturais/efeitos dos fármacos , Neoplasias/terapia , Adjuvantes Imunológicos/uso terapêutico , Animais , Células Apresentadoras de Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/uso terapêutico , Galactosilceramidas/farmacologia , Humanos , Ativação Linfocitária/fisiologia , Células T Matadoras Naturais/fisiologia , Células T Matadoras Naturais/transplante , Neoplasias/imunologia
5.
Cancer Sci ; 112(3): 978-988, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33368875

RESUMO

Cancer is characterized by an accumulation of somatic mutations that represent a source of neoantigens for targeting by antigen-specific T cells. Head and neck squamous cell carcinoma (HNSCC) has a relatively high mutation burden across all cancer types, and cellular immunity to neoantigens likely plays a key role in HNSCC clinical outcomes. Immune checkpoint inhibitors (CPIs) have brought new treatment options and hopes to patients with recurrent and/or metastatic HNSCC. However, many patients do not benefit from CPI therapies, highlighting the need for novel immunotherapy or combinatorial strategies. One such approach is personalized cancer vaccination targeting tumor-associated antigens and tumor-specific antigens, either as single agents or in combination with other therapies. Recent advances in next-generation genomic sequencing technologies and computational algorithms have enabled efficient identification of somatic mutation-derived neoantigens and are anticipated to facilitate the development of cancer vaccine strategies. Here, we review cancer vaccine approaches against HNSCC, including fundamental mechanisms of a cancer vaccine, considerations for selecting appropriate antigens, and combination therapies.


Assuntos
Antígenos de Neoplasias/genética , Vacinas Anticâncer/uso terapêutico , Neoplasias de Cabeça e Pescoço/terapia , Medicina de Precisão/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Ensaios Clínicos como Assunto , Terapia Combinada/métodos , Análise Mutacional de DNA , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunogenicidade da Vacina , Mutação , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Resultado do Tratamento , Vacinas de DNA/genética , Vacinas de DNA/imunologia , Vacinas de DNA/uso terapêutico , Vacinas de Subunidades/genética , Vacinas de Subunidades/imunologia , Vacinas de Subunidades/uso terapêutico
6.
Nat Commun ; 11(1): 5696, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33173046

RESUMO

Poorly immunogenic tumors, including triple negative breast cancers (TNBCs), remain resistant to current immunotherapies, due in part to the difficulty of reprogramming the highly immunosuppressive tumor microenvironment (TME). Here we show that peritumorally injected, macroporous alginate gels loaded with granulocyte-macrophage colony-stimulating factor (GM-CSF) for concentrating dendritic cells (DCs), CpG oligonucleotides, and a doxorubicin-iRGD conjugate enhance the immunogenic death of tumor cells, increase systemic tumor-specific CD8 + T cells, repolarize tumor-associated macrophages towards an inflammatory M1-like phenotype, and significantly improve antitumor efficacy against poorly immunogenic TNBCs. This system also prevents tumor recurrence after surgical resection and results in 100% metastasis-free survival upon re-challenge. This chemo-immunotherapy that concentrates DCs to present endogenous tumor antigens generated in situ may broadly serve as a facile platform to modulate the suppressive TME, and enable in situ personalized cancer vaccination.


Assuntos
Materiais Biocompatíveis/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Imunoterapia/métodos , Neoplasias de Mama Triplo Negativas/terapia , Animais , Antígenos de Neoplasias/metabolismo , Biotecnologia/métodos , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Sistemas de Liberação de Medicamentos/métodos , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Humanos , Fatores Imunológicos/metabolismo , Fatores Imunológicos/uso terapêutico , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias de Mama Triplo Negativas/imunologia , Microambiente Tumoral/imunologia
7.
Urol Clin North Am ; 47(4): 443-456, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33008495

RESUMO

Cancer vaccines, cytokines, and checkpoint inhibitors are immunotherapeutic agents that act within the cancer immunity cycle. Prostate cancer has provided unique opportunities for, and challenges to, immunotherapy drug development, including low tumor mutational burdens, limited expression of PD-L1, and minimal T-cell intratumoral infiltrates. Nevertheless, efforts are ongoing to help prime prostate tumors by turning a "cold" prostate cancer "hot" and thus rendering them more susceptible to immunotherapy. Combination treatments, use of molecular biomarkers, and use of new immunotherapeutic agents provide opportunities to enhance the immune response to prostate tumors.


Assuntos
Vacinas Anticâncer/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Idoso , Biomarcadores Tumorais/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Neoplasias da Próstata/mortalidade , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento
8.
Artigo em Alemão | MEDLINE | ID: mdl-33034692

RESUMO

Therapeutic vaccines are intended for the treatment of established diseases by harnessing the patient's own immune system. In this article we discuss therapeutic areas that are of relevance for therapeutic vaccination, i.e., oncology and neurodegenerative diseases. Clinical and regulatory aspects related to the manufacture and clinical use of actively personalized cancer vaccines are thoroughly reviewed. This applies to the regulatory classification of genomic sequencing approaches to identify tumor-specific mutations, combination therapies with checkpoint inhibitors, clinical study designs, and the use of suitable adjuvants and drug substances. Huge amounts of data (big data) are increasingly being generated in the area of personalized therapies; we briefly address the impact and usability of big data in regulatory procedures.


Assuntos
Vacinas Anticâncer , Neoplasias , Doenças Neurodegenerativas , Vacinas Anticâncer/uso terapêutico , Alemanha , Humanos , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/prevenção & controle , Vacinação
9.
Artigo em Alemão | MEDLINE | ID: mdl-33034694

RESUMO

The physician and scientist Paul Ehrlich put forward the thesis that the immune system not only fights infections but can also fight cancer. The possible positive effects of a simultaneous infection on the course of cancer were reported in ancient Egypt around 2600 BC. However, it was not until the 1960s that it became apparent that the immune system could specifically fight cancer cells, and it was not until the 1990s that researchers slowly clarified how this happens.Against this background, the efforts over the last 30 years to develop therapeutic vaccines against cancers are briefly summarized, and their lack of success to date is highlighted. In addition, potentially promising future developments in this context are discussed. The available scientific literature as well as our own results are taken into account.Central questions arise, such as the following: How do cancer cells differ from normal cells? How can the immune system recognize these differences? What are tumor-specific antigens? Why do they need to be selected and applied in an individualized fashion? How can an efficient immune response be induced? Which pharmaceutical formulations, adjuvants, and vaccination routes are effective?Finally, we explain why it may still be worth pursuing peptide vaccination, which has so far been completely unsuccessful (when measured in terms of already approved therapeutics).


Assuntos
Vacinas Anticâncer , Neoplasias , Antígenos de Neoplasias , Vacinas Anticâncer/uso terapêutico , Alemanha , Humanos , Imunoterapia , Neoplasias/prevenção & controle , Vacinas de Subunidades/uso terapêutico
10.
Artigo em Alemão | MEDLINE | ID: mdl-33084926

RESUMO

Combination therapies of different drugs are an integral part of medicine. However, there is a scientific and regulatory need to understand the contribution of each drug to the overall effect, i.e., nonclinical and clinical development programs have to consider these aspects and need to be designed accordingly. Many drugs are currently under development that attempt to control malignant diseases in the long term by using and activating components of the patient's own immune system. The term immuno-oncology is often used in this context. Medicines that are developed and used for immuno-oncology can be assigned to completely different classes of medicines.This article provides an analysis of combination therapies in immuno-oncology with medicinal products produced by biotechnological manufacturing. This encompasses checkpoint inhibitors, genetically modified cell therapies, tumor vaccines, and oncolytic viruses. The challenges in clinical development are demonstrated on the basis of this heterogenous group of approved immuno-oncological drugs that have been investigated in combination therapies. Due to the different characteristics and number of combination partners, an individually tailored program must be designed for each development program and there is no standard solution.


Assuntos
Vacinas Anticâncer , Neoplasias , Vacinas Anticâncer/uso terapêutico , Terapia Combinada , Alemanha , Humanos , Imunoterapia , Neoplasias/tratamento farmacológico
12.
Br J Radiol ; 93(1113): 20200112, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32706978

RESUMO

Interventional oncology (IO) has proven to be highly efficient in the local therapy of numerous malignant tumors in addition to surgery, chemotherapy, and radiotherapy. Due to the advent of immune-oncology with the possibility of tumor control at the molecular and cellular levels, a system change is currently emerging. This will significantly rule oncology in the coming decades. Therefore, one cannot think about IO in the 21st century without considering immunology. For IO, this means paying much more attention to the immunomodulatory effects of the interventional techniques, which have so far been neglected, and to explore the synergistic possibilities with immuno-oncology. It can be expected that the combined use of IO and immuno-oncology will help to overcome the limitations of the latter, such as limited local effects and a high rate of side-effects. To do this, however, sectoral boundaries must be removed and interdisciplinary research efforts must be strengthened. In case of success, IO will face an exciting future.


Assuntos
Imunoterapia/tendências , Oncologia/tendências , Neoplasias/terapia , Vacinas Anticâncer/uso terapêutico , Quimioembolização Terapêutica/métodos , Quimioembolização Terapêutica/tendências , História do Século XXI , Humanos , Imunização Passiva/métodos , Imunomodulação , Imunoterapia/métodos , Imunoterapia Ativa/métodos , Neoplasias/imunologia , Radioterapia (Especialidade)/tendências , Ablação por Radiofrequência/métodos , Ablação por Radiofrequência/tendências , Radioisótopos de Ítrio/uso terapêutico
13.
Cancer Immunol Immunother ; 69(11): 2247-2257, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32500232

RESUMO

Cancer vaccines induce cancer-specific T-cells capable of eradicating cancer cells. The impact of cancer peptide vaccines (CPV) on the tumor microenvironment (TME) remains unclear. S-588410 is a CPV comprising five human leukocyte antigen (HLA)-A*24:02-restricted peptides derived from five cancer testis antigens, DEPDC1, MPHOSPH1, URLC10, CDCA1 and KOC1, which are overexpressed in esophageal cancer. This exploratory study investigated the immunologic mechanism of action of subcutaneous S-588410 emulsified with MONTANIDE ISA51VG adjuvant (median: 5 doses) by analyzing the expression of immune-related molecules, cytotoxic T-lymphocyte (CTL) response and T-lymphocytes bearing peptide-specific T-cell receptor (TCR) sequencing in tumor tissue or blood samples from 15 participants with HLA-A*24:02-positive esophageal cancer. Densities of CD8+, CD8+ Granzyme B+, CD8+ programmed death-1-positive (PD-1+) and programmed death-ligand 1-positive (PD-L1+) cells were higher in post- versus pre-vaccination tumor tissue. CTL response was induced in all patients for at least one of five peptides. The same sequences of peptide-specific TCRs were identified in post-vaccination T-lymphocytes derived from both tumor tissue and blood, suggesting that functional peptide-specific CTLs infiltrate tumor tissue after vaccination. Twelve (80%) participants had treatment-related adverse events (AEs). Injection site reaction was the most frequently reported AE (grade 1, n = 1; grade 2, n = 11). In conclusion, S-588410 induces a tumor immune response in esophageal cancer. Induction of CD8+ PD-1+ tumor-infiltrating lymphocytes and PD-L1 expression in the TME by vaccination suggests S-588410 in combination with anti-PD-(L)1 antibodies may offer a clinically useful therapy.Trial registration UMIN-CTR registration identifier: UMIN000023324.


Assuntos
Vacinas Anticâncer/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T Citotóxicos/imunologia , Idoso , Antígenos de Neoplasias/imunologia , Feminino , Antígeno HLA-A24/imunologia , Humanos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Linfócitos T Citotóxicos/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Vacinas de Subunidades/uso terapêutico
15.
Cochrane Database Syst Rev ; 5: CD013238, 2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32395825

RESUMO

BACKGROUND: Glioblastoma is an uncommon but highly aggressive type of brain tumour. Significant gains have been achieved in the molecular understanding and the pathogenesis of glioblastomas, however clinical improvements are difficult to obtain for many reasons. The current standard of care involves maximal safe surgical resection followed by chemoradiation and then adjuvant chemotherapy European Organisation for Research and Treatment of Cancer and the NCIC Clinical Trials Group (EORTC-NCIC) protocol with a median survival of 14.6 months. Successive phase III international randomised controlled studies have failed to significantly demonstrate survival advantage with newer drugs. Epidermal growth factor receptor (EGFR) is observed to be aberrant in 30% to 60% of glioblastomas. The receptor aberrancy is driven by abnormal gene amplification, receptor mutation, or both, in particular the extracellular vIII domain. EGFR abnormalities are common in solid tumours, and the advent of anti-EGFR therapies in non-small cell lung cancer and colorectal adenocarcinomas have greatly improved clinical outcomes. Anti-EGFR therapies have been investigated amongst glioblastomas, however questions remain about its ongoing role in glioblastoma management. This review aimed to report on the available evidence to date and perform a systematic analysis on the risks and benefits of use of anti-EGFR therapies in glioblastomas. OBJECTIVES: To evaluate the efficacy and harms of anti-EGFR therapies for glioblastoma in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, EBM Reviews databases, with supplementary handsearches to identify all available and relevant studies to 20 April 2020. SELECTION CRITERIA: All randomised controlled trials (RCTs) using anti-EGFR therapies in adults with glioblastoma were eligible for inclusion. Anti-EGFR therapies included tyrosine kinase inhibitors, monoclonal antibodies, or vaccines. The comparison included investigational product added to standard of care versus standard of care or placebo, or investigational product against standard of care or placebo. DATA COLLECTION AND ANALYSIS: The authorship team screened the search results and recorded the extracted data for analysis. We used standard Cochrane methodology to performed quantitative meta-analysis if two or more studies had appropriate and available data. Otherwise, we conducted a qualitative and descriptive analysis. We used the GRADE system to rate the certainty of the evidence. The analysis was performed along the two clinical settings: first-line (after surgery) and recurrent disease (after failure of first line treatment). Where information was available, we documented overall survival, progression-free survival, adverse events, and quality of life data from eligible studies. MAIN RESULTS: The combined searches initially identified 912 records (after removal of duplicates), and further screening resulted in 19 records for full consideration. We identified nine eligible studies for inclusion in the review. There were three first-line studies and six recurrent studies. Five studies used tyrosine kinase inhibitors (TKIs); two studies used monoclonal antibodies; and two studies used targeted vaccines. More recent studies presented greater detail in the conduct of their studies and thus had a lower risk of bias. We observed no evidence benefit in overall survival with the use of anti-EGFR therapy in the first-line or recurrent setting (hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.76 to 1.04; 3 RCTs, 1000 participants, moderate-certainty evidence; and HR 0.79, 95% CI 0.51 to 1.21, 4 RCTs, 489 participants, low-certainty evidence, respectively). All the interventions were generally well tolerated with low-certainty evidence for lymphopenia (odds ratio (OR) 0.97, 95% CI 0.19 to 4.81; 4 RCTs, 1146 participants), neutropenia (OR 1.29, 95% CI 0.82 to 2.03; 4 RCTs, 1146 participants), and thrombocytopenia (OR 3.69, 95% CI 0.51 to 26.51; 4 RCTs, 1146 participants). A notable toxicity relates to ABT-414, where significant ocular issues were detected. The addition of anti-EGFR therapy showed no evidence of an increase in progression-free survival (PFS) in the first-line setting (HR 0.94, 95% CI 0.81 to 1.10; 2 RCTs, 894 participants, low-certainty evidence). In the recurrent setting, there was an increase in PFS with the use of anti-EGFR therapy (HR 0.75, 95% CI 0.58 to 0.96, 3 RCTs, 275 participants, low-certainty evidence). The available quality of life assessment data showed that anti-EGFR therapies were neither detrimental or beneficial when compared to standard care (not estimable). AUTHORS' CONCLUSIONS: In summary, there is no evidence of a demonstrable overall survival benefit with the addition of anti-EGFR therapy in first-line and recurrent glioblastomas. Newer drugs that are specially designed for glioblastoma targets may raise the possibility of success in this population, but data are lacking at present. Future studies should be more selective in pursuing people displaying specific EGFR targets.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Glioblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Encefálicas/mortalidade , Vacinas Anticâncer/uso terapêutico , Progressão da Doença , Glioblastoma/mortalidade , Humanos , Linfopenia/etiologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Neutropenia/etiologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Ensaios Clínicos Controlados Aleatórios como Assunto , Trombocitopenia/etiologia
16.
Internist (Berl) ; 61(7): 690-698, 2020 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-32462251

RESUMO

Tumor cells always exhibit differences to normal cells. These differences can be recognized by the immune system, enabling the destruction of tumor cells by T cells, as was impressively demonstrated by the success of immune checkpoint inhibition, e.g., in malignant melanoma. Many cancers, however, do not respond to this kind of therapy. In these cases, vaccination against tumor antigens could be very helpful. Nevertheless, all of the efforts made in this respect during the past 30 years have been virtually futile. With current knowledge and technology there is new hope.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/uso terapêutico , Melanoma/imunologia , Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Humanos , Melanoma/prevenção & controle , Neoplasias/prevenção & controle , Neoplasias/terapia , Linfócitos T/imunologia , Vacinação
17.
Oncogene ; 39(22): 4323-4330, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32322001

RESUMO

Progress in cancer therapies has resulted in improved survival of patients with early stage breast cancer. However, mortality remains high in patients with distant recurrence of the disease after initially successful treatment of early stage breast cancer. To this end, tumor recurrences have been attributed to the presence of dormant tumor cells in breast cancer patients and cancer survivors. Current clinical practice guidelines recommend a "wait-and-watch" approach for tumor recurrence. This is because of our limited understanding of tumor dormancy. Dormant tumor cells are quiescent, and thus, do not respond to chemotherapies or radiation therapies, and they are not operable. Therefore, immunotherapy is the only option for the treatment of tumor dormancy. However, gaps in our knowledge as to dormancy-specific antigens prevent a relapse preventing vaccine design. Here, I provide a critical review of cancer immunotherapy, and discuss empirical evidence related to naturally occurring tumor dormancy and treatment-induced tumor dormancy at the site of primary tumor and in distant organs before and after cancer therapies. Finally, I suggest that personalized vaccines targeting dormancy-associated neoantigens, which can be given to patients with early stage disease after the completion of neoadjuvant therapies and tumor resection as well as to cancer survivors could eliminate relapse causing dormant cells and offer a cure for cancer.


Assuntos
Vacinas Anticâncer/uso terapêutico , Imunoterapia , Metástase Neoplásica/prevenção & controle , Neoplasias/terapia , Medicina de Precisão , Antígenos de Neoplasias/imunologia , Apoptose , Divisão Celular , Intervalo Livre de Doença , Previsões , Humanos , Modelos Imunológicos , Metástase Neoplásica/imunologia , Metástase Neoplásica/patologia , Neoplasias/imunologia , Neoplasias/patologia , Células-Tronco Neoplásicas/imunologia , Evasão Tumoral
18.
Vet Radiol Ultrasound ; 61(4): 471-480, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32323424

RESUMO

Canine oral melanoma (OM) is an aggressive cancer with a high rate of metastasis. Surgery and/or radiotherapy (RT) are effective local treatments, yet many dogs succumb to distant metastasis. Immunotherapy represents an attractive strategy for this potentially immunogenic tumor. The objective of this multi-institutional retrospective study was to examine the clinical outcome of dogs with OM treated with ONCEPT melanoma vaccine. Most dogs also underwent surgery and/or RT (8 Gy × four weekly fractions). Dogs with distant metastasis at diagnosis and those receiving concurrent chemotherapy were excluded. One hundred thirty-one dogs treated with ONCEPT were included: 62 had adequate local tumor control defined as complete tumor excision or irradiation of residual microscopic disease; 15 were treated in the microscopic disease setting following an incomplete excision without adjuvant RT; and 54 had gross disease. Median time to progression, median progression-free survival, and median tumor-specific overall survival were 304, 260, and 510 days, respectively. In multivariable analysis, presence of gross disease correlated negatively with all measures of clinical outcome. Other negative prognostic indicators were primary tumor ≥2 cm, higher clinical stage (stages 2 and 3), presence of lymph node metastasis at diagnosis, and caudal location in the oral cavity. Radiotherapy had a protective effect against tumor progression. To date, this is the largest reported series of dogs with OM treated with ONCEPT. Several previously reported prognostic indicators were confirmed.


Assuntos
Vacinas Anticâncer/uso terapêutico , Terapia Combinada/veterinária , Doenças do Cão/terapia , Melanoma/veterinária , Neoplasias Bucais/veterinária , Radioterapia Adjuvante/veterinária , Animais , Terapia Combinada/métodos , Cães , Feminino , Humanos , Metástase Linfática , Masculino , Melanoma/diagnóstico por imagem , Neoplasias Bucais/terapia , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
19.
Eur J Cancer ; 132: 43-52, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32325419

RESUMO

BACKGROUND: Immune-based strategies represent a promising approach in breast cancer (BC) treatment. The glycoprotein mucin-1 (MUC-1) is overexpressed in more than 90% of BC patients, and is targeted by the cancer vaccine tecemotide. We have investigated the efficacy and safety of tecemotide when added to neoadjuvant standard-of-care (SoC) treatment in early BC patients. PATIENTS AND METHODS: A total of 400 patients with HER2-early BC were recruited into this prospective, multicentre, randomised 2-arm academic phase II trial. Patients received preoperative SoC treatment (chemotherapy or endocrine therapy) with or without tecemotide. Postmenopausal women with oestrogen receptor (ER)+++, or ER++ and Ki67 < 14%, and G1,2 tumours ('luminal A' tumours) received 6 months of letrozole. Postmenopausal patients with triple-negative, ER-/+/++ and Ki67 ≥ 14%, and with G3 tumours, as well as premenopausal patients, received four cycles of epirubicin/cyclophosphamide plus four cycles of docetaxel. Primary end-point was residual cancer burden (RCB; 0/I versus II/III) at surgery. Secondary end-points included pathological complete response (pCR), safety, and quality of life. FINDINGS: We observed no significant difference in RCB 0/I rates between patients with (36.4%) and without (31.9%) tecemotide in the overall study population (p = 0.40) nor in endocrine and chemotherapy-treated subgroups (25.0% versus 13.3%, p = 0.17; 39.6% versus 37.8%, p = 0.75, respectively). The addition of tecemotide did not affect overall pCR rates (22.5% versus 17.4%, p = 0.23), MUC-1 expression, or tumour-infiltrating lymphocytes content. Tecemotide did not increase toxicity when compared to SoC therapy alone. INTERPRETATION: Neoadjuvant tecemotide is safe, but does not improve RCB or pCR rates in patients receiving standard neoadjuvant therapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Vacinas Anticâncer/uso terapêutico , Glicoproteínas de Membrana/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Segurança do Paciente , Prognóstico , Estudos Prospectivos , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo
20.
Oncogene ; 39(18): 3620-3637, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32157213

RESUMO

Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer-related death. The immune-rich contexture of the HCC microenvironment makes this tumour an appealing target for immune-based therapies. Here, we discuss how the functional characteristics of the liver microenvironment can potentially be harnessed for the treatment of HCC. We will review the evidence supporting a therapeutic role for vaccines, cell-based therapies and immune-checkpoint inhibitors and discuss the potential for patient stratification in an attempt to overcome the series of failures that has characterised drug development in this disease area.


Assuntos
Carcinoma Hepatocelular/terapia , Imunoterapia , Neoplasias Hepáticas/terapia , Microambiente Tumoral/imunologia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Carcinoma Hepatocelular/imunologia , Terapia Baseada em Transplante de Células e Tecidos/tendências , Humanos , Fígado/imunologia , Neoplasias Hepáticas/imunologia
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