Retinoblastom je nejčastějším nitroočním maligním nádorem v dětském věku. Zásadní parametr určující stupeň retinoblastomu dle mezinárodní klasifikace retinoblastomu představuje seeding, neboli disperze nádorových partikulí do přilehlých kompartmentů. V článku jsme se zaměřili na vitreální seeding, jeden z hlavních limitujících faktorů úspěšné léčby retinoblastomu, při níž je zachován bulbus tzv. „eye-preservation treatment“. Článek shrnuje přehled vývoje léčby vitreálního seedingu retinoblastomu, zavedených postupů a zároveň seznamuje s novinkami na úrovni výzkumu. Zavedení systémové chemoterapie v léčbě retinoblastomu koncem 90. let znamenalo významný přelom, který umožnil postupné opuštění externí radioterapie s jejími vedlejšími účinky. Docílené koncentrace chemoterapeutik ve sklivcovém prostoru při systémové chemoterapii však nejsou pro léčbu vitreálního seedingu dostatečné a toxické účinky systémově podávaných chemoterapeutik nejsou zanedbatelné. Významnou změnou byl nástup chemoterapie in situ s cíleným podáváním chemoterapeutik, a to intraarteriálně a intravitreálně, což přispělo k definitivní eradikaci externí radioterapie a omezení systémové chemoterapie. Ačkoliv vitreální seeding zůstává nejčastějším důvodem selhání intraarteriální chemoterapie, tato technika výrazně ovlivnila původní léčebné schéma retinoblastomových dětí. Nejvíce se však zasloužila o zvýšení pravděpodobnosti zachování oka i zrakových funkcí u pacientů s pokročilým nálezem intravitreální chemoterapie. Nadále probíhá mnoho prací na vývoji nových terapeutických technik, a to s použitím periokulární aplikace chemoterapeutika, imunoterapie, genové terapie či onkolytických virů, z nichž se některé jeví jako slibné, ale k rutinnímu využití nejsou zatím dokončeny klinické studie.
Retinoblastoma is the most common primary malignant intraocular tumor in children. Seeding, specifically the dispersion of the tumor into the adjacent compartments, represents a major parameter determining the degree of retinoblastoma according to the International Classification of Retinoblastoma. In this article we focused on vitreous seeding, one of the main limiting factors in the successful “eye preservation treatment” of retinoblastoma. This article presents an overview of the history of vitreous seeding of retinoblastoma, established treatment procedures and new-research modalities. The introduction of systemic chemotherapy in the treatment of retinoblastoma at the end of the 1990s represented a significant breakthrough, which enabled the progressive abandonment of radiotherapy with its attendant side effects. However, the attained concentrations of chemotherapeutics in the vitreous space during systemic chemotherapy are not sufficient for the treatment of vitreous seeding, and the toxic effects of systemic chemotherapy are not negligible. A significant change came with the advent of chemotherapy in situ, with the targeted administration of chemotherapeutic drugs, namely intra-arterial and intravitreal injections, contributing to the definitive eradication of external radiotherapy and a reduction of systemic chemotherapy. Although vitreous seeding remains the most common reason for the failure of intra-arterial chemotherapy, this technique has significantly influenced the original treatment regimen of children with retinoblastoma. However, intravitreal chemotherapy has made the greatest contribution to increasing the probability of preservation of the eyeball and visual functions in patients with advanced findings. Novel local drug delivery modalities, gene therapy, oncolytic viruses and immunotherapy from several ongoing preclinical and clinical trials may represent promising approaches in the treatment of vitreous retinoblastoma seeding, though no clinical trials have yet been completed for routine use.
- Keywords
- intravitreální chemoterapie,
- MeSH
- Drug Therapy classification methods MeSH
- Intravitreal Injections classification methods MeSH
- Organ Sparing Treatments classification methods MeSH
- Humans MeSH
- Retinoblastoma * diagnosis drug therapy complications MeSH
- Neoplasm Seeding * MeSH
- Vitreous Body pathology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
PURPOSE: The combination of talimogene laherparepvec (T-VEC) and pembrolizumab previously demonstrated an acceptable safety profile and an encouraging complete response rate (CRR) in patients with advanced melanoma in a phase Ib study. We report the efficacy and safety from a phase III, randomized, double-blind, multicenter, international study of T-VEC plus pembrolizumab (T-VEC-pembrolizumab) versus placebo plus pembrolizumab (placebo-pembrolizumab) in patients with advanced melanoma. METHODS: Patients with stage IIIB-IVM1c unresectable melanoma, naïve to antiprogrammed cell death protein-1, were randomly assigned 1:1 to T-VEC-pembrolizumab or placebo-pembrolizumab. T-VEC was administered at ≤ 4 × 106 plaque-forming unit (PFU) followed by ≤ 4 × 108 PFU 3 weeks later and once every 2 weeks until dose 5 and once every 3 weeks thereafter. Pembrolizumab was administered intravenously 200 mg once every 3 weeks. The dual primary end points were progression-free survival (PFS) per modified RECIST 1.1 by blinded independent central review and overall survival (OS). Secondary end points included objective response rate per mRECIST, CRR, and safety. Here, we report the primary analysis for PFS, the second preplanned interim analysis for OS, and the final analysis. RESULTS: Overall, 692 patients were randomly assigned (346 T-VEC-pembrolizumab and 346 placebo-pembrolizumab). T-VEC-pembrolizumab did not significantly improve PFS (hazard ratio, 0.86; 95% CI, 0.71 to 1.04; P = .13) or OS (hazard ratio, 0.96; 95% CI, 0.76 to 1.22; P = .74) compared with placebo-pembrolizumab. The objective response rate was 48.6% for T-VEC-pembrolizumab (CRR 17.9%) and 41.3% for placebo-pembrolizumab (CRR 11.6%); the durable response rate was 42.2% and 34.1% for the arms, respectively. Grade ≥ 3 treatment-related adverse events occurred in 20.7% of patients in the T-VEC-pembrolizumab arm and in 19.5% of patients in the placebo-pembrolizumab arm. CONCLUSION: T-VEC-pembrolizumab did not significantly improve PFS or OS compared with placebo-pembrolizumab. Safety results of the T-VEC-pembrolizumab combination were consistent with the safety profiles of each agent alone.
- MeSH
- Double-Blind Method MeSH
- Humans MeSH
- Herpesvirus 1, Human * MeSH
- Melanoma * drug therapy MeSH
- Oncolytic Virotherapy * methods MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase I MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
Východiska: Každý rok jsou milionům lidí diagnostikována nádorová onemocnění a jejich léčba představuje pro plátce zdravotní péče finanční zátěž. V oblasti nádorových onemocnění byl učiněn velký pokrok; jednou z nejnovějších metod je využití onkolytických virů. Cílem této studie bylo hodnocení vliv divokých kmenů onkolytického viru Newcastleské choroby (Newcastle disease virus wild-type strains – NDV-WTS) na imunitní systém. Materiál a metody: Čtyřicet myší bylo rozděleno do čtyř skupin (10 zvířat v každé skupině). Kontrolní skupině byl aplikován fosfátový pufr a experimentálním skupinám 1 (NDV-WTS 1), 2 (NDV-WTS 2) a 3 (NDV-WTS 3) byl 0., 14. a 28. den aplikován Newcastleský virus v titrech 10–1, 10–2 a 10–3. Třicátý první den bylo zvířatům do levého chodidla vpíchnuto 100 μl Newcastleského viru. Po 48 hodinách byla měřena přecitlivělost oddáleného typu (delayed-type hypersensitivity – DTH). Třicátý třetí den byly izolovány peritoneální makrofágy. Pak byla měřena proliferace buněk pomocí methyl-thiazolyl-tetrazolium (MTT) testu. Rovněž bylo hodnoceno vychytávání neutrální červeně a respirační vzplanutí makrofágů. Data byla analyzována pomocí statistického software SPSS, verze 19. Výsledky: Výsledky DTH testu ukázaly otok chodidla u kontrolní skupiny a ve skupinách NDV-WTS 1, NDV-WTS 2 a NDV-WTS 3 z 23,5 %, 23,5 %, 23,6 % a 23,6 %. V tomto ohledu nebyly mezi jednotlivými skupinami významné rozdíly (p > 0,05). Negativní nitroblue tetrazolium (NBT) test jakožto indikátor respiračního vzplanutí makrofágů neprokázal mezi skupinami významné rozdíly (p > 0,05). Vychytávání neutrální červeně a MTT test rovněž neukázaly mezi skupinami významné rozdíly (p > 0,05). Závěr: Výsledky této studie svědčí o tom, že DV-WTS v dávkách 10–1, 10–2 a 10–3 nemají na normální zdravé buňky žádné vedlejší účinky.
Background: Millions of people are diagnosed with cancer each year, and fighting it puts a heavy financial burden on communities and governments. Numerous advances have been made in the field of cancer; one of the newest methods is using oncolytic viruses. This study aimed to evaluate the effect of oncolytic Newcastle disease virus wild-type strains (NDV-WTS) on the immune system. Material and methods: Forty mice were divided into four groups (10 animals in each group). The control group received phosphate buffered saline, and experimental group 1 (NDV-WTS 1), experimental group 2 (NDV-WTS 2), and experimental group 3 (NDV-WTS 3) received 10–1, 10–2, and 10–3 titers of Newcastle virus on 0, 14th, and 28th days. On the 31st day, 100 μL of Newcastle virus was injected into the left footpads of animals. After 48 hours, delayed-type hypersensitivity (DTH) reactions were measured. On the 33rd day, peritoneal macrophages were isolated. Then proliferation of the cells was measured by the methyl-thiazolyl-tetrazolium (MTT) test. Neutral red uptake and respiratory burst of peritoneal macrophages were also assessed. Data were analyzed using statistical software SPSS, version 19. Results: The results of the DTH test showed that footpad swelling in control, NDV-WTS 1, NDV-WTS 2, and NDV-WTS 3 groups were 23.5%, 23.5%, 23.6% and 23.6%. No significant differences were seen between the groups in this regard (P > 0.05). A negative nitroblue tetrazolium (NBT) reduction test as an indicator of macrophage‘s respiratory burst, showed no significant difference between the groups (P > 0.05). The neutral red uptake assay and MTT test showed no significant differences between the groups (P > 0.05). Conclusion: The results of this study showed that NDV-WTS in doses of 10–1, 10–2, and 10–3 have no adverse effects on healthy normal cells.
Východiska: Ve srovnání s normálními tkáněmi je jednou ze základních odlišností nádorového bujení vznik mikroprostředí se sníženou nebo zcela vymizelou imunogenicitou. Jedním z hlavních úkolů onkolytických virů je vytvoření situace, která v tomto prostředí povede k obnovení imunitních procesů a ke ztrátě životnosti nádorových buněk. Onkolytické viry jsou v tomto smyslu neustále vylepšovány, a lze je tedy jednoznačně považovat za možnou adjuvantní imunomodulační protinádorovou terapii. Nezbytným předpokladem pro úspěch této protinádorové léčby je specificita onkolytických virů, které se replikují jen v buňkách nádoru, ale nepůsobí na normální buňky. Práce nejen představuje strategie, jakými se onkolytické viry optimalizují pro získání nádorové specifity a zvýšení účinnosti, ale také rekapituluje nejzajímavější poznatky vyplývající z proběhlých preklinických a klinických testů. Cíl: Předkládaný přehled podává informace o současném stavu vývoje a použití onkolytických virů jako součásti biologického léčení nádorů.
Background: The fundamental difference between tumor and normal tissue growth is the emergence of the microenvironment with diminished or extinguished immunogenicity. One of the main functions of oncolytic viruses is the formation of such a microenvironment, which leads to a revival of immunological processes and loss of viability of cancer cells. Oncolytic viruses are being continuously improved and should be considered as a possible adjuvant immunomodulatory cancer treatment. A key requirement for the success of this cancer therapy is the specificity of the oncolytic viruses, which replicate only in tumor cells but do not affect normal cells. In this review, optimization strategies to achieve cancer specificity with increased efficacy are discussed and the most interesting results from preclinical and clinical trials are presented. Purpose: This review provides information on the current status of the development and use of oncolytic viruses as part of the biological treatment of cancer.
- MeSH
- Molecular Targeted Therapy MeSH
- Immunotherapy methods MeSH
- Humans MeSH
- Tumor Microenvironment MeSH
- Neoplasms immunology therapy MeSH
- Oncolytic Virotherapy * methods MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Oncolytic virotherapies (OV) hold immense clinical potential. OV based on human adenoviruses (HAdV) derived from HAdV with naturally low rates of pre-existing immunity will be beneficial for future clinical translation. We generated a low-seroprevalence HAdV-D10 serotype vector incorporating an αvβ6 integrin-selective peptide, A20, to target αvβ6-positive tumor cell types. HAdV-D10 has limited natural tropism. Structural and biological studies of HAdV-D10 knob protein highlighted low-affinity engagement with native adenoviral receptors CAR and sialic acid. HAdV-D10 fails to engage blood coagulation factor X, potentially eliminating "off-target" hepatic sequestration in vivo. We engineered an A20 peptide that selectively binds αvβ6 integrin into the DG loop of HAdV-D10 fiber knob. Assays in αvβ6+ cancer cell lines demonstrated significantly increased transduction mediated by αvβ6-targeted variants compared with controls, confirmed microscopically. HAdV-D10.A20 resisted neutralization by neutralizing HAdV-C5 sera. Systemic delivery of HAdV-D10.A20 resulted in significantly increased GFP expression in BT20 tumors. Replication-competent HAdV-D10.A20 demonstrated αvβ6 integrin-selective cell killing in vitro and in vivo. HAdV-D10 possesses characteristics of a promising virotherapy, combining low seroprevalence, weak receptor interactions, and reduced off-target uptake. Incorporation of an αvβ6 integrin-selective peptide resulted in HAdV-D10.A20, with significant potential for clinical translation.
- Publication type
- Journal Article MeSH
LTX-315 is a nonameric oncolytic peptide in early clinical development for the treatment of solid malignancies. Preclinical and clinical evidence indicates that the anticancer properties of LTX-315 originate not only from its ability to selectively kill cancer cells, but also from its capacity to promote tumor-targeting immune responses. Here, we investigated the therapeutic activity and immunological correlates of intratumoral LTX-315 administration in three syngeneic mouse models of breast carcinoma, with a focus on the identification of possible combinatorial partners. We found that breast cancer control by LTX-315 is accompanied by a reconfiguration of the immunological tumor microenvironment that supports the activation of anticancer immunity and can be boosted by radiation therapy. Mechanistically, depletion of natural killer (NK) cells compromised the capacity of LTX-315 to limit local and systemic disease progression in a mouse model of triple-negative breast cancer, and to extend the survival of mice bearing hormone-accelerated, carcinogen-driven endogenous mammary carcinomas. Altogether, our data suggest that LTX-315 controls breast cancer progression by engaging NK cell-dependent immunity.
- MeSH
- Killer Cells, Natural MeSH
- Immunotherapy MeSH
- Humans MeSH
- Mice MeSH
- Tumor Microenvironment MeSH
- Oligopeptides * MeSH
- Triple Negative Breast Neoplasms * therapy MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Rotaviruses infect cells by binding to specific cell surface molecules including gangliosides, heat shock protein cognate protein 70 (Hsc70), and some integrins. The characterization of cell surface receptors defining viral tropism is crucial for inhibiting entry into the normal cells or the cancer cells. In the present work, several tumor cell-adapted rotavirus isolates were tested for their interaction with some heat shock proteins (HSPs) present in the U-937 cells, derived from a human pleural effusion (histiocytic lymphoma monocyte). This interaction was examined by virus overlay protein-binding (VOPB), immunochemistry, immuno-dot blot assays, and flow cytometry. The results indicated that the rotavirus isolates studied were able to infect U937 cells by interacting with Hsp90, Hsp70, Hsp60, Hsp40, Hsc70, protein disulfide isomerase (PDI), and integrin β3, which are implicated in cellular proliferation, differentiation, and cancer development. Interestingly, these cellular proteins were found to be associated in lipid microdomains (rafts), facilitating in this way eventual sequential interactions of the rotavirus particles with the cell surface receptors. The rotavirus tropism for U937 cells through the use of these cell surface proteins made this rotavirus isolates an attractive target for the development of oncolytic strategies in the context of alternative and complementary treatment of cancer.
- MeSH
- Immune Checkpoint Inhibitors * pharmacology therapeutic use MeSH
- Protein Kinase Inhibitors therapeutic use MeSH
- Interferon alpha-2 therapeutic use MeSH
- Ipilimumab therapeutic use MeSH
- Controlled Clinical Trials as Topic MeSH
- Drug Therapy, Combination MeSH
- Humans MeSH
- Herpesvirus 1, Human MeSH
- Melanoma * drug therapy radiotherapy therapy MeSH
- Neoplasm Metastasis therapy MeSH
- Brain Neoplasms secondary MeSH
- Neoadjuvant Therapy methods MeSH
- Nivolumab therapeutic use MeSH
- Oncolytic Virotherapy methods MeSH
- Prognosis MeSH
- Proto-Oncogene Proteins B-raf antagonists & inhibitors MeSH
- Recurrence MeSH
- Check Tag
- Humans MeSH
Největším pokrokem v onkologii v posledním desetiletí bylo zavedení imunoterapie do běžné klinické praxe. Kombinace standardní terapie a moderních léčebných modalit nám již umožňuje docílit zvýšení míry léčebných odpovědí a prodloužení mediánu celkového přežití. Stále však hledáme odpovědi na řadu klíčových otázek. Potřebujeme znát spolehlivé prediktivní biomarkery účinnosti a toxicity, abychom byli schopni vybírat vhodné pacienty k léčbě pomocí onkoimunoterapie. Následující řádky podávají přehled o současných moderních imunoterapeutických přístupech, které jsou již schválené nebo se dostávají do klinické praxe.
The most impactful advance in oncology in the last decade has been the introduction of immunotherapy into routine clinical practice. The combination of standard therapies and modern therapeutic modalities has enabled us to achieve increases in response rates and median overall survival. But there are still many challenges. We need reliable predictive biomarkers of efficacy and toxicity to be able to select suitable patients for the treatment with cancer immunotherapy. In this review, we report a list of therapeutic agents which are already approved or are being introduced into clinical practice.
- MeSH
- Immunotherapy, Active methods MeSH
- Cell- and Tissue-Based Therapy methods MeSH
- Dendritic Cells MeSH
- Antibodies, Monoclonal, Humanized therapeutic use MeSH
- Immunotherapy, Adoptive methods MeSH
- Immunotherapy * methods MeSH
- Medical Oncology MeSH
- Humans MeSH
- Biomarkers, Tumor therapeutic use MeSH
- Oncolytic Virotherapy methods MeSH
- Oncolytic Viruses MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
