Peptide-based anticancer vaccination aims at stimulating an immune response against one or multiple tumor-associated antigens (TAAs) following immunization with purified, recombinant or synthetically engineered epitopes. Despite high expectations, the peptide-based vaccines that have been explored in the clinic so far had limited therapeutic activity, largely due to cancer cell-intrinsic alterations that minimize antigenicity and/or changes in the tumor microenvironment that foster immunosuppression. Several strategies have been developed to overcome such limitations, including the use of immunostimulatory adjuvants, the co-treatment with cytotoxic anticancer therapies that enable the coordinated release of damage-associated molecular patterns, and the concomitant blockade of immune checkpoints. Personalized peptide-based vaccines are also being explored for therapeutic activity in the clinic. Here, we review recent preclinical and clinical progress in the use of peptide-based vaccines as anticancer therapeutics.Abbreviations: CMP: carbohydrate-mimetic peptide; CMV: cytomegalovirus; DC: dendritic cell; FDA: Food and Drug Administration; HPV: human papillomavirus; MDS: myelodysplastic syndrome; MHP: melanoma helper vaccine; NSCLC: non-small cell lung carcinoma; ODD: orphan drug designation; PPV: personalized peptide vaccination; SLP: synthetic long peptide; TAA: tumor-associated antigen; TNA: tumor neoantigen.

• Klíčová slova
• CAR T cells, MAGEA3, NY-ESO-1, immune checkpoint blockers, mutational load, synthetic long peptides, tumor neoantigens,
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

The MAGNOLIA study, investigating the concept of perioperative immunotherapy in muscle- invasive bladder cancer, was prematurely terminated. The lessons learned that should be considered before initiating and conducting future clinical trials in this field are highlighted.

• MeSH
• adjuvantní chemoterapie MeSH
• antigeny nádorové terapeutické užití   MeSH
• cystektomie MeSH
• dvojitá slepá metoda MeSH
• imunoterapie * MeSH
• invazivní růst nádoru MeSH
• klinické zkoušky, fáze II jako téma MeSH
• lidé MeSH
• nádorové proteiny terapeutické užití   MeSH
• nádory močového měchýře farmakoterapie   patologie   chirurgie   MeSH
• předčasné ukončení klinických zkoušek MeSH
• randomizované kontrolované studie jako téma MeSH
• rekombinantní proteiny terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny nádorové MeSH
• MAGEA3 protein, human MeSH Prohlížeč
• nádorové proteiny MeSH
• rekombinantní proteiny MeSH

BACKGROUND: Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting. METHODS: DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 μg MAGE-A3 antigen plus 420 μg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT00796445. FINDINGS: Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28·0 months [IQR 23·3-35·5] in the MAGE-A3 group and 28·1 months [23·7-36·9] in the placebo group. Median disease-free survival was 11·0 months (95% CI 10·0-11·9) in the MAGE-A3 group and 11·2 months (8·6-14·1) in the placebo group (hazard ratio [HR] 1·01, 0·88-1·17, p=0·86). In the GS-positive population, median disease-free survival was 9·9 months (95% CI 5·7-17·6) in the MAGE-A3 group and 11·6 months (5·6-22·3) in the placebo group (HR 1·11, 0·83-1·49, p=0·48). Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 [3%] for MAGE-A3 vs four [<1%] for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment. INTERPRETATION: An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped. FUNDING: GlaxoSmithKline Biologicals SA.

• MeSH
• adjuvantní chemoterapie MeSH
• analýza přežití MeSH
• antigeny nádorové účinky léků   genetika   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• hodnocení rizik MeSH
• imunokonjugáty terapeutické užití   MeSH
• imunoterapie metody   MeSH
• injekce intramuskulární MeSH
• internacionalita MeSH
• invazivní růst nádoru patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• maligní melanom kůže MeSH
• melanom farmakoterapie   mortalita   patologie   chirurgie   MeSH
• nádorové proteiny účinky léků   genetika   MeSH
• nádory kůže farmakoterapie   mortalita   patologie   chirurgie   MeSH
• přežití bez známek nemoci MeSH
• prognóza MeSH
• senioři MeSH
• staging nádorů MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antigeny nádorové MeSH
• imunokonjugáty MeSH
• MAGEA3 protein, human MeSH Prohlížeč
• nádorové proteiny MeSH

Personalized peptide vaccination is a promising immunotherapeutic approach in prostate cancer (PCa). We therefore examined whether an approach, utilizing personalized multiple peptide-mediated ex vivo enrichment with effector T cells reactive to multiple tumor-associated antigens (TAAs), could be employed as a basis for the development of T cell immunotherapy of PCa. In this study, we used the non-adherent fraction (lymphocytes) of cryopreserved peripheral blood mononuclear cells from a leukapheretic product of biochemically recurrent (BR, n = 14) and metastatic hormone-refractory (HR, n = 12) PCa patients. The lymphocytes were primed with a pool of mixed overlapping peptides derived from 6 PCa TAAs-PSA, PAP, NY-ESO-1, MAGE-A1, MAGE-A3 and MAGE-A4. After 2 weeks of culture, the cells were stimulated with the peptides and T cell reactivity determined by externalization of CD107a. No TAAs-reactive effector T cells were detected in the patient's lymphocytes after their reconstitution. However, following their priming with the TAAs-derived peptides and 2-week culturing, the lymphocytes became enriched with polyclonal TAAs-reactive effector CD8+ T cells in 8 out of 14 BR and 5 out of 12 HR patients. No such reactive CD8+ T cells were detected in cultured lymphocytes without the peptide priming. Stimulation of the responding cultures with peptides derived from individual TAAs revealed a unique repertoire of the reactive CD8+ T cells. Our strategy revealed that the personalized multiple peptide-mediated ex vivo enrichment with multiple TAAs-reactive T cells in the PCa patient's lymphocytes is a viable approach for development of T cell immunotherapy of PCa.

• Klíčová slova
• CD107a externalization, Personalized T cell immunotherapy, Prostate cancer, Tumor-associated antigens,
• MeSH
• antigeny nádorové imunologie   MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• imunoterapie metody   MeSH
• individualizovaná medicína metody   MeSH
• kalikreiny imunologie   MeSH
• kultivované buňky MeSH
• leukocyty mononukleární imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• melanomové antigeny imunologie   MeSH
• membránové proteiny imunologie   MeSH
• nádorové proteiny imunologie   MeSH
• nádory prostaty imunologie   patologie   MeSH
• peptidy imunologie   MeSH
• prostatický specifický antigen imunologie   MeSH
• senioři MeSH
• T-lymfocyty imunologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny nádorové MeSH
• CTAG1B protein, human MeSH Prohlížeč
• kalikreiny MeSH
• KLK3 protein, human MeSH Prohlížeč
• MAGEA1 protein, human MeSH Prohlížeč
• MAGEA3 protein, human MeSH Prohlížeč
• MAGEA4 protein, human MeSH Prohlížeč
• melanomové antigeny MeSH
• membránové proteiny MeSH
• nádorové proteiny MeSH
• peptidy MeSH
• prostatický specifický antigen MeSH

INTRODUCTION: Monitoring of circulating melanoma cells in the peripheral blood is a promising method for identifying a subgroup of patients with minimal residual disease. OBJECTIVES: To evaluate the prognostic impact of melanoma-associated antigens by multimarker real-time RT-PCR for disease-specific survival time. METHODS: Five melanoma markers: Melan-A, gp 100, MAGE-3, MIA and tyrosinase were detected by a quantitative multimarker real-time reverse transcription-PCR (RT-PCR). We included 65 patients with resected melanoma in stage II-III. Peripheral blood samples were examined every 3 months for 2 years. The expression of melanoma markers in 2925 RT-PCR assays was correlated with clinical staging results in total of 5 years. RESULTS: Twenty-seven patients relapsed during the study period and 26 of them revealed positive markers. MAGE-3 was the most sensitive progression marker in single occurrence or in combination with MIA and gp 100. The time distribution of metastases during the screened period was as follows: progression in the first year was observed in 40.7% patients, second year in 25.9%, third year in 18.6%, fourth and fifth year in 7.4% equally. CONCLUSIONS: Statistically significant tumor marker elevation during the first 2 years after the surgical treatment correlates with a worse prognosis of patients. In contrast, the group showing negative real-time RT-PCR results in 24 months serial blood testing was associated with prolonged 5-year disease-specific survival. Therefore, quantitative detection of melanoma-specific molecular markers in the presented setting represents a useful tool for selecting patients in a higher risk of disease recurrence.

• MeSH
• antigeny nádorové genetika   MeSH
• antigeny sacharidové asociované s nádorem genetika   MeSH
• dospělí MeSH
• exprese genu genetika   MeSH
• leukocyty chemie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• MART-1 antigen genetika   MeSH
• melanom diagnóza   metabolismus   patologie   chirurgie   MeSH
• melanomové antigeny genetika   MeSH
• melanomový antigen gp100 genetika   MeSH
• mladý dospělý MeSH
• nádorové proteiny genetika   MeSH
• polymerázová řetězová reakce s reverzní transkripcí * MeSH
• přežití bez známek nemoci MeSH
• prognóza MeSH
• progrese nemoci MeSH
• senioři MeSH
• staging nádorů MeSH
• tyrosinasa genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny nádorové MeSH
• antigeny sacharidové asociované s nádorem MeSH
• MAGEA3 protein, human MeSH Prohlížeč
• MART-1 antigen MeSH
• melanomové antigeny MeSH
• melanomový antigen gp100 MeSH
• MIA antigen, human MeSH Prohlížeč
• MLANA protein, human MeSH Prohlížeč
• nádorové proteiny MeSH
• tyrosinasa MeSH

• Klíčová slova
• biomarker, circulating tumor cell, melanoma, targeted therapy,
• MeSH
• antigeny nádorové krev   MeSH
• biologické markery krev   MeSH
• cílená molekulární terapie * MeSH
• indoly terapeutické užití   MeSH
• lidé MeSH
• melanom krev   farmakoterapie   imunologie   mortalita   MeSH
• nádorové buněčné linie MeSH
• nádorové proteiny krev   MeSH
• protinádorové látky terapeutické užití   MeSH
• studie případů a kontrol MeSH
• sulfonamidy terapeutické užití   MeSH
• vemurafenib MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Názvy látek
• antigeny nádorové MeSH
• biologické markery MeSH
• indoly MeSH
• MAGEA3 protein, human MeSH Prohlížeč
• nádorové proteiny MeSH
• protinádorové látky MeSH
• sulfonamidy MeSH
• vemurafenib MeSH

BACKGROUND: Fewer than half of the patients with completely resected non-small-cell lung cancer (NSCLC) are cured. Since the introduction of adjuvant chemotherapy in 2004, no substantial progress has been made in adjuvant treatment. We aimed to assess the efficacy of the MAGE-A3 cancer immunotherapeutic in surgically resected NSCLC. METHODS: In this randomised, double-blind, placebo-controlled trial, we recruited patients aged at least 18 years with completely resected stage IB, II, and IIIA MAGE-A3-positive NSCLC who did or did not receive adjuvant chemotherapy from 443 centres in 34 countries (Europe, the Americas, and Asia Pacific). Patients were randomly assigned (2:1) to receive 13 intramuscular injections of recMAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic) or placebo during 27 months. Randomisation and treatment allocation at the investigator site was done centrally via internet with stratification for chemotherapy versus no chemotherapy. Participants, investigators, and those assessing outcomes were masked to group assignment. A minimisation algorithm accounted for the number of chemotherapy cycles received, disease stage, lymph node sampling procedure, performance status score, and lifetime smoking status. The primary endpoint was broken up into three co-primary objectives: disease-free survival in the overall population, the no-chemotherapy population, and patients with a potentially predictive gene signature. The final analyses included the total treated population (all patients who had received at least one treatment dose). This trial is registered with ClinicalTrials.gov, number NCT00480025. FINDINGS: Between Oct 18, 2007, and July 17, 2012, we screened 13 849 patients for MAGE-A3 expression; 12 820 had a valid sample and of these, 4210 (33%) had a MAGE-A3-positive tumour. 2312 of these patients met all eligibility criteria and were randomly assigned to treatment: 1515 received MAGE-A3 and 757 received placebo and 40 were randomly assigned but never started treatment. 784 patients in the MAGE-A3 group also received chemotherapy, as did 392 in the placebo group. Median follow-up was 38·1 months (IQR 27·9-48·4) in the MAGE-A3 group and 39·5 months (27·9-50·4) in the placebo group. In the overall population, median disease-free survival was 60·5 months (95% CI 57·2-not reached) for the MAGE-A3 immunotherapeutic group and 57·9 months (55·7-not reached) for the placebo group (hazard ratio [HR] 1·02, 95% CI 0·89-1·18; p=0·74). Of the patients who did not receive chemotherapy, median disease-free survival was 58·0 months (95% CI 56·6-not reached) in those in the MAGE-A3 group and 56·9 months (44·4-not reached) in the placebo group (HR 0·97, 95% CI 0·80-1·18; p=0·76). Because of the absence of treatment effect, we could not identify a gene signature predictive of clinical benefit to MAGE-A3 immunotherapeutic. The frequency of grade 3 or worse adverse events was similar between treatment groups (246 [16%] of 1515 patients in the MAGE-A3 group and 122 [16%] of 757 in the placebo group). The most frequently reported grade 3 or higher adverse events were infections and infestations (37 [2%] in the MAGE-A3 group and 19 [3%] in the placebo group), vascular disorders (30 [2%] vs 17 [3%]), and neoplasm (benign, malignant, and unspecified (29 [2%] vs 16 [2%]). INTERPRETATION: Adjuvant treatment with the MAGE-A3 immunotherapeutic did not increase disease-free survival compared with placebo in patients with MAGE-A3-positive surgically resected NSCLC. Based on our results, further development of the MAGE-A3 immunotherapeutic for use in NSCLC has been stopped. FUNDING: GlaxoSmithKline Biologicals SA.

• MeSH
• adjuvantní chemoterapie MeSH
• antigeny nádorové imunologie   metabolismus   MeSH
• dvojitá slepá metoda MeSH
• imunokonjugáty terapeutické užití   MeSH
• imunoterapie * MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   imunologie   metabolismus   patologie   MeSH
• míra přežití MeSH
• nádorové biomarkery metabolismus   MeSH
• nádorové proteiny imunologie   metabolismus   MeSH
• nádory plic farmakoterapie   imunologie   metabolismus   patologie   MeSH
• následné studie MeSH
• nemalobuněčný karcinom plic farmakoterapie   imunologie   metabolismus   patologie   MeSH
• prognóza MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• senioři MeSH
• staging nádorů MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antigeny nádorové MeSH
• imunokonjugáty MeSH
• MAGEA3 protein, human MeSH Prohlížeč
• nádorové biomarkery MeSH
• nádorové proteiny MeSH

BACKGROUND: Detection of melanoma cells in peripheral blood is a promising method for monitoring haematogenous spread of melanoma cells. It enables us to detect early metastasis and to better stratify candidates for adjuvant immunotherapy. Inconsistent data on the sensitivity and clinical relevance of this method have been reported. STUDY DESIGN: We developed a multimarker real-time reverse transcription-PCR (RT-PCR) for quantification of five melanoma markers: Melan-A, gp100, MAGE-3, MIA and tyrosinase. In this prospective study, 65 patients with resected cutaneous melanoma stage IIB-III were screened. Peripheral blood samples were collected every 3 months for the following 18 months, and circulating melanoma cells were examined and compared with clinical staging results. RESULTS: Eighteen patients relapsed during the trial and showed different types of melanoma progression. All these patients experienced statistically significant tumour marker elevation in the period from 0 to 9 months before the disease progression. MAGE-3 was the most sensitive progression marker. In patients with progression, we observed three concordant positive markers in 39% of cases, two concordant positive markers in 28%, and finally one marker in 33%. CONCLUSIONS: This report describes a multiple-marker real-time RT-PCR, which is able to provide quantitative data on melanoma markers in the peripheral blood of melanoma patients. Measurement of the studied molecular markers in our hands represents a prognostic factor and a useful method for early detection of metastasis and treatment response of melanoma patients.

• MeSH
• antigeny nádorové krev   genetika   MeSH
• antigeny sacharidové asociované s nádorem krev   genetika   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• MART-1 antigen MeSH
• melanom krev   patologie   MeSH
• melanomový antigen gp100 MeSH
• membránové glykoproteiny krev   genetika   MeSH
• messenger RNA krev   genetika   MeSH
• nádorové biomarkery krev   MeSH
• nádorové buněčné linie MeSH
• nádorové proteiny krev   genetika   MeSH
• nádory kůže krev   patologie   MeSH
• polymerázová řetězová reakce s reverzní transkripcí metody   MeSH
• progrese nemoci MeSH
• prospektivní studie MeSH
• senioři MeSH
• senzitivita a specificita MeSH
• staging nádorů MeSH
• tyrosinasa krev   genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky kontrolované MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny nádorové MeSH
• antigeny sacharidové asociované s nádorem MeSH
• MAGEA3 protein, human MeSH Prohlížeč
• MART-1 antigen MeSH
• melanomový antigen gp100 MeSH
• membránové glykoproteiny MeSH
• messenger RNA MeSH
• MIA antigen, human MeSH Prohlížeč
• MLANA protein, human MeSH Prohlížeč
• nádorové biomarkery MeSH
• nádorové proteiny MeSH
• PMEL protein, human MeSH Prohlížeč
• tyrosinasa MeSH