Dendritic cells (DCs) have received considerable attention as potential targets for the development of novel cancer immunotherapies. However, the clinical efficacy of DC-based vaccines remains suboptimal, largely reflecting local and systemic immunosuppression at baseline. An autologous DC-based vaccine (DCVAC) has recently been shown to improve progression-free survival and overall survival in randomized clinical trials enrolling patients with lung cancer (SLU01, NCT02470468) or ovarian carcinoma (SOV01, NCT02107937), but not metastatic castration-resistant prostate cancer (SP005, NCT02111577), despite a good safety profile across all cohorts. We performed biomolecular and cytofluorometric analyses on peripheral blood samples collected prior to immunotherapy from 1000 patients enrolled in these trials, with the objective of identifying immunological biomarkers that may improve the clinical management of DCVAC-treated patients. Gene signatures reflecting adaptive immunity and T cell activation were associated with favorable disease outcomes and responses to DCVAC in patients with prostate and lung cancer, but not ovarian carcinoma. By contrast, the clinical benefits of DCVAC were more pronounced among patients with ovarian carcinoma exhibiting reduced expression of T cell-associated genes, especially those linked to TH2-like signature and immunosuppressive regulatory T (TREG) cells. Clinical responses to DCVAC were accompanied by signs of antitumor immunity in the peripheral blood. Our findings suggest that circulating signatures of antitumor immunity may provide a useful tool for monitoring the potency of autologous DC-based immunotherapy.

• Klíčová slova
• Cancer immunotherapy, anti-PD-1, circulating biomarkers, epithelial ovarian carcinoma, metastatic castrate-resistant prostate cancer, non-small cell lung carcinoma,
• MeSH
• dendritické buňky metabolismus   MeSH
• epiteliální ovariální karcinom farmakoterapie   MeSH
• lidé MeSH
• nádory plic * farmakoterapie   terapie   MeSH
• nádory vaječníků * genetika   terapie   MeSH
• protinádorové vakcíny * terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• protinádorové vakcíny * MeSH

Personalized cancer vaccines targeting patient-specific neoantigens are a promising cancer treatment modality; however, neoantigen physicochemical variability can present challenges to manufacturing personalized cancer vaccines in an optimal format for inducing anticancer T cells. Here, we developed a vaccine platform (SNP-7/8a) based on charge-modified peptide-TLR-7/8a conjugates that are chemically programmed to self-assemble into nanoparticles of uniform size (~20 nm) irrespective of the peptide antigen composition. This approach provided precise loading of diverse peptide neoantigens linked to TLR-7/8a (adjuvant) in nanoparticles, which increased uptake by and activation of antigen-presenting cells that promote T-cell immunity. Vaccination of mice with SNP-7/8a using predicted neoantigens (n = 179) from three tumor models induced CD8 T cells against ~50% of neoantigens with high predicted MHC-I binding affinity and led to enhanced tumor clearance. SNP-7/8a delivering in silico-designed mock neoantigens also induced CD8 T cells in nonhuman primates. Altogether, SNP-7/8a is a generalizable approach for codelivering peptide antigens and adjuvants in nanoparticles for inducing anticancer T-cell immunity.

• MeSH
• adjuvancia imunologická chemie   MeSH
• antigeny nádorové imunologie   MeSH
• CD8-pozitivní T-lymfocyty metabolismus   MeSH
• individualizovaná medicína MeSH
• melanom experimentální farmakoterapie   imunologie   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nanočástice MeSH
• primáti MeSH
• protinádorové vakcíny aplikace a dávkování   imunologie   MeSH
• toll-like receptor 7 imunologie   MeSH
• toll-like receptor 8 imunologie   MeSH
• vakcinace MeSH
• vakcíny konjugované MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• adjuvancia imunologická MeSH
• antigeny nádorové MeSH
• protinádorové vakcíny MeSH
• toll-like receptor 7 MeSH
• toll-like receptor 8 MeSH
• vakcíny konjugované MeSH

BACKGROUND: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. OBJECTIVE: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. DESIGN: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts before voting during a consensus conference. SETTING: Online Delphi survey and consensus conference. PARTICIPANTS: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). RESULTS AND LIMITATIONS: Overall, 116 statements were included in the Delphi survey. Of these, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease and the evolving role of checkpoint inhibitor therapy in metastatic disease. CONCLUSIONS: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time where further evidence is available to guide our approach.

• Klíčová slova
• Delphi, bladder cancer, consensus, diagnosis, follow-up, treatment,
• MeSH
• delfská metoda MeSH
• konsensus * MeSH
• lékařská onkologie metody   normy   MeSH
• lidé MeSH
• mezinárodní spolupráce MeSH
• močový měchýř patologie   MeSH
• nádory močového měchýře patologie   terapie   MeSH
• průzkumy a dotazníky MeSH
• směrnice pro lékařskou praxi jako téma * MeSH
• společnosti lékařské normy   MeSH
• staging nádorů MeSH
• účast zainteresovaných stran MeSH
• urologie metody   normy   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH

• Publikační typ
• komentáře MeSH
• úvodníky MeSH

Patients with inadequate anti-cancer T cell responses experience limited benefit from immune checkpoint inhibitors and other immunotherapies that require T cells. Therefore, treatments that induce de novo anti-cancer T cell immunity are needed. One strategy - referred to as in situ vaccination - is to deliver chemotherapeutic or immunostimulatory drugs into tumors to promote cancer cell death and provide a stimulatory environment for priming T cells against antigens already present in the tumor. However, achieving sufficient drug concentrations in tumors without causing dose-limiting toxicities remains a major challenge. To address this challenge, nanomedicines based on nano-sized carriers ('nanocarriers') of chemotherapeutics and immunostimulants are being developed to improve drug accumulation in tumors following systemic (intravenous) administration. Herein, we present the rationale for using systemically administrable nanomedicines to induce anti-cancer T cell immunity via in situ vaccination and provide an overview of synthetic nanomedicines currently used clinically. We also describe general strategies for improving nanomedicine design to increase tumor uptake, including use of micelle- and star polymer-based nanocarriers. We conclude with perspectives for how nanomedicine properties, host factors and treatment combinations can be leveraged to maximize efficacy.

• Klíčová slova
• Chemotherapeutic and immunostimulant, Immunogenic cell death, Nanomedicine and biomaterials, Nanoparticle and microparticle, Pattern recognition receptor,
• MeSH
• adjuvancia imunologická aplikace a dávkování   MeSH
• imunoterapie metody   MeSH
• lidé MeSH
• nádory farmakoterapie   imunologie   terapie   MeSH
• nanomedicína metody   MeSH
• protinádorové vakcíny aplikace a dávkování   imunologie   MeSH
• T-lymfocyty účinky léků   imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• adjuvancia imunologická MeSH
• protinádorové vakcíny MeSH

BACKGROUND: Great progress has recently been made in the treatment of metastatic renal cell carcinoma, including the introduction of nivolumab, an immune checkpoint inhibitor. Despite promising results, this treatment brings a completely new spectrum of adverse events, distinct from those experienced with small-molecule kinase inhibitors. Neurologic immune-related adverse events may be serious and potentially life-threatening complications requiring immediate immunosuppressive therapy. Only a few cases of immune-related encephalitis induced by checkpoint inhibitors have been described and the data regarding the management of this serious adverse event are limited. CASE PRESENTATION: We report the case of a 63-year-old white man with metastatic renal cancer who developed severe chorea-like dyskinesia during nivolumab therapy. The findings on brain magnetic resonance imaging and flow cytometry of cerebrospinal fluid, and the positivity of anti-paraneoplastic antigen Ma2 immunoglobuline G class autoantibodies were consistent with a diagnosis of immune-related encephalitis. High-dose intravenous corticosteroid therapy was started immediately, with no signs of improvement, even when infliximab was added. Our patient refused further hospitalization and was discharged. Three weeks later, he presented with signs of severe urosepsis. Despite intensive treatment, he died 4 days after admission. CONCLUSIONS: The management of less frequent immune-related adverse events has not been fully established and more information is required to provide uniform recommendations. Immune-related encephalitis is a severe and potentially fatal complication requiring immediate hospital admission and extensive immunosuppressive therapy. The examination of cerebrospinal fluid for paraneoplastic antibodies, such as anti-N-methyl-D-aspartate receptor and anti-Ma2 antibodies, in order to distinguish autoimmune etiology from other possible causes is essential and highly recommended.

• Klíčová slova
• Case report, Encephalitis, Immune-related adverse event, Nivolumab, Renal cancer,
• MeSH
• encefalitida chemicky indukované   MeSH
• karcinom z renálních buněk farmakoterapie   sekundární   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory ledvin farmakoterapie   patologie   MeSH
• nivolumab škodlivé účinky   MeSH
• protinádorové látky imunologicky aktivní škodlivé účinky   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• nivolumab MeSH
• protinádorové látky imunologicky aktivní MeSH

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

Immune checkpoint blockers (ICBs) are literally revolutionizing the clinical management of an ever more diversified panel of oncological indications. Although considerable attention persists around the inhibition of cytotoxic T lymphocyte-associated protein 4 (CTLA4) and programmed cell death 1 (PDCD1, best known as PD-1) signaling, several other co-inhibitory T-cell receptors are being evaluated as potential targets for the development of novel ICBs. Moreover, substantial efforts are being devoted to the identification of biomarkers that reliably predict the likelihood of each patient to obtain clinical benefits from ICBs in the absence of severe toxicity. Tailoring the delivery of specific ICBs or combinations thereof to selected patient populations in the context of precision medicine programs constitutes indeed a major objective of the future of ICB-based immunotherapy. Here, we discuss recent preclinical and clinical advances on the development of ICBs for oncological indications.

• Klíčová slova
• Atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab, pembrolizumab,
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH