Иммунотерапия злокачественных глиом: современное состояние проблемы и перспективные направления

Despite aggressive multimodal treatment prognosis for malignant gliomas remains poor. The low efficiency of conventional cytostatic therapy forced to look for alternative approaches to treatment. This review deals with active immunotherapy using tumor vaccines and adoptive cell therapy. Vaccinotherapy may be carried out using tumor lysates or individual peptides, or mRNA. To improve the immunogenicity of vaccines dendritic cells and various immunoadjuvants are widely used. When using lysate vaccine in patients with newly diagnosed glioblastoma multiforme median progression-free survival is 9,5–18 months, and median overall survival is 16,25–35,9 months, significantly more than the historical control. Peptide vaccines to WT-1, survivin, mutated isocitrate dehydrogenase (IDHR132H), mutated epidermal growth factor receptor (EGFRvIII) are under investigation. Promising are the methods of vaccinotherapy against glioma stem cells antigens, cytomegalovirus antigens. The possibility of integration of immunotherapy in the existing treatment standards, as well as a combination of several immunotherapeutic strategies, has been studied extensively.Несмотря на агрессивное мультимодальное лечение прогноз при злокачественных глиомах остается плохим. Низкая эффективность традиционной цитостатической терапии вынуждает искать альтернативные подходы к лечению. В данном обзоре рассматриваются вопросы активной иммунотерапии с помощью противоопухолевых вакцин и адоптивной клеточной терапии. Вакцинотерапия может осуществляться с использованием опухолевых лизатов или отдельных пептидов или мРНК. Для улучшения иммуногенности вакцины используются дендритные клетки и различные иммуноадъюванты. При использовании лизатной вакцины при вновь выявленной мультиформной глиобластоме медиана выживаемости без прогрессирования составляет 9,5–18 месяцев, а медиана общей выживаемости 16,25–35,9 месяца, что значительно выше, чем в историческом контроле. Среди пептидных вакцин изучаются вакцины к WT-1, сурвивину, мутированному варианту изоцитратдегидрогеназы (IDHR132H), мутированному варианту рецептора эпидермального фактора роста (EGFRvIII). Перспективными представляются методы вакцинотерапии против антигенов стволовых клеток глиом, цитомегаловирусных антигенов. Активно изучается возможность интеграции иммунотерапии в существующие стандарты лечения, а также комбинация нескольких иммунотерапевтических стратегий

Опухолевое микроокружение как мишень терапии злокачественных глиом

Microglial cells in malignant gliomas closely interact with tumor cells. Microenvironment provides local immunosuppression, which promotes escape of tumors from immune system control. Numerous cytokines secreted by microenvironment support survival, nutrition, growth, proliferation and invasion of tumor cells. Microenvironment-targeted therapy is no less important than the traditional cytostatic therapy. Seem promising therapies aimed at reducing the recruitment of immune cells and their amounts in the tumor tissue, at neutralizationof the immunosuppressive properties of microglia and / or inversion of its suppressive phenotype, as well as disinhibition and stimulation of antineoplastic functions of microenvironment.Клетки микроглии в злокачественных глиомах тесным образом взаимодействуют с опухолевыми клетками. Микроокружение обеспечивает локальную иммуносупрессию, которая способствует ускользанию опухоли от иммунного контроля со стороны организма. Многочисленные цитокины, секретируемые микроокружением обеспечивают выживание, питание, рост, пролиферацию и инвазию опухолевых клеток. Лечебное воздействие на микроокружение является не менее значимым, чем традиционная цитостатическая терапия. Перспективными представляются методы терапии, направленные на снижение рекрутинга иммунных клеток и их количества в ткани опухоли, на нейтрализацию иммуносупрессивных свойств микроглии и/или инверсию ее супрессивного фенотипа, а также на растормаживание и стимуляцию тумороцидных функций микроокружения

A Phase II Biomarker-Embedded Study of Lapatinib plus Capecitabine as First-line Therapy in Patients with Advanced or Metastatic Gastric Cancer

Abstract An exploratory phase II biomarker-embedded trial (LPT109747; NCT00526669) designed to determine the association of lapatinib-induced fluoropyrimidine gene changes with efficacy of lapatinib plus capecitabine as first-line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinoma independent of tumor HER2 status. Tumor biopsies obtained before and after 7-day lapatinib (1,250 mg) to analyze changes in gene expression, followed by a 14-day course of capecitabine (1,000 mg/m2 twice daily, 14/21 days) plus lapatinib 1,250 mg daily. Blood samples were acquired for pharmacokinetic analysis. Primary clinical objectives were response rate (RR) and 5-month progression-free survival (PFS). Secondary objectives were overall survival (OS), PFS, time to response, duration of response, toxicity, and identification of associations between lapatinib pharmacokinetics and biomarker endpoints. Primary biomarker objectives were modulation of 5-FU-pathway genes by lapatinib, effects of germline SNPs on treatment outcome, and trough steady-state plasma lapatinib concentrations. Sixty-eight patients were enrolled; (75% gastric cancer, 25% gastroesophageal junction). Twelve patients (17.9%) had confirmed partial response, 31 (46.3%) had stable disease, and 16 (23.9%) had progressive disease. Median PFS and OS were 3.3 and 6.3 months, respectively. Frequent adverse events included diarrhea (45%), decreased appetite (39%), nausea (36%), and fatigue (36%). Lapatinib induced no changes in gene expression from baseline and no significant associations were found for SNPs analyzed. Elevated baseline HER3 mRNA expression was associated with a higher RR (33% vs. 0%; P = 0.008). Lapatinib plus capecitabine was well tolerated, demonstrating modest antitumor activity in patients with advanced gastric cancer. The association of elevated HER3 and RR warrants further investigation as an important player for HER-targeted regimens in combination with capecitabine. Mol Cancer Ther; 15(9); 2251–8. ©2016 AACR.</jats:p

Efficacy and Safety of Trastuzumab Emtansine Plus Capecitabine vs Trastuzumab Emtansine Alone in Patients With Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer A Phase 1 and Randomized Phase 2 Trial

Importance: ERBB2 (HER2)-targeted therapy provides benefits in metastatic breast cancer (mBC) and gastric cancer, but additional treatments are needed to maximize efficacy and quality of life. Objective: To determine maximum tolerated doses (MTDs) of trastuzumab emtansine (T-DM1) plus capecitabine in patients with previously treated ERBB2-positive mBC and locally advanced/metastatic gastric cancer (LA/mGC) (phase 1) and the efficacy and safety of this combination vs T-DM1 alone in patients with mBC (phase 2). Design, setting, and participants: The MTD in phase 1 was assessed using a 3 + 3 design with capecitabine dose modification. Phase 2 was an open-label, randomized, international multicenter study of patients with mBC treated with T-DM1 plus capecitabine or T-DM1 alone. Eligible patients had previously treated ERBB2-positive mBC or LA/mGC with no prior chemotherapy treatment for advanced disease. Interventions: Patients in the phase 1 mBC cohort received capecitabine (750 mg/m2, 700 mg/m2, or 650 mg/m2 twice daily, days 1-14 of a 3-week cycle) plus T-DM1 3.6 mg/kg every 3 weeks. Patients with LA/mGC received capecitabine at the mBC phase 1 MTD, de-escalating as needed, plus T-DM1 2.4 mg/kg weekly. In phase 2, patients with mBC were randomized (1:1) to receive capecitabine (at the phase 1 MTD) plus T-DM1 or T-DM1 alone. Main outcomes and measures: The phase 1 primary objective was to identify the MTD of capecitabine plus T-DM1. The phase 2 primary outcome was investigator-assessed overall response rate (ORR). Results: In phase 1, the median (range) age was 54.0 (37-71) and 57.5 (53-70) years for patients with mBC and patients with LA/mGC, respectively. The capecitabine MTD was identified as 700 mg/m2 in 11 patients with mBC and 6 patients with LA/mGC evaluable for dose-limiting toxic effects. In phase 2, between October 2014 and April 2016, patients with mBC (median [range] age, 52.0 [28-80] years) were randomized to receive combination therapy (n = 81) or T-DM1 (n = 80). The ORR was 44% (36 of 81 patients) and 36% (29 of 80 patients) in the combination and T-DM1 groups, respectively (difference, 8.2%; 90% CI, -4.5 to 20.9; P = .34; clinical cutoff, May 31, 2017). Adverse events (AEs) were reported in 78 of 82 patients (95%) in the combination group, with 36 (44%) experiencing grade 3-4 AEs, and 69 of 78 patients (88%) in the T-DM1 group, with 32 (41%) experiencing grade 3-4 AEs. No grade 5 AEs were reported. Conclusions and relevance: Adding capecitabine to T-DM1 did not statistically increase ORR associated with T-DM1 in patients with previously treated ERBB2-positive mBC. The combination group reported more AEs, but with no unexpected toxic effects

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

Whole Exome Sequencing Study Suggests an Impact of FANCA, CDH1 and VEGFA Genes on Diffuse Gastric Cancer Development

Gastric cancer (GC) is one of the most common cancer types in the world with a high mortality rate. Hereditary predisposition for GC is not fully elucidated so far. The aim of this study was identification of possible new candidate genes, associated with the increased risk of gastric cancer development. Whole exome sequencing (WES) was performed on 18 DNA samples from adenocarcinoma specimens and non-tumor-bearing healthy stomach tissue from the same patient. Three pathogenic variants were identified: c.1320+1G&gt;A in the CDH1 gene and c.27_28insCCCAGCCCCAGCTACCA (p.Ala9fs) of the VEGFA gene were found only in the tumor tissue, whereas c.G1874C (p.Cys625Ser) in the FANCA gene was found in both the tumor and normal tissue. These changes were found only in patients with diffuse gastric cancer and were absent in the DNA of healthy donors

Whole Exome Sequencing Study Suggests an Impact of <i>FANCA</i>, <i>CDH1</i> and <i>VEGFA</i> Genes on Diffuse Gastric Cancer Development

Gastric cancer (GC) is one of the most common cancer types in the world with a high mortality rate. Hereditary predisposition for GC is not fully elucidated so far. The aim of this study was identification of possible new candidate genes, associated with the increased risk of gastric cancer development. Whole exome sequencing (WES) was performed on 18 DNA samples from adenocarcinoma specimens and non-tumor-bearing healthy stomach tissue from the same patient. Three pathogenic variants were identified: c.1320+1G>A in the CDH1 gene and c.27_28insCCCAGCCCCAGCTACCA (p.Ala9fs) of the VEGFA gene were found only in the tumor tissue, whereas c.G1874C (p.Cys625Ser) in the FANCA gene was found in both the tumor and normal tissue. These changes were found only in patients with diffuse gastric cancer and were absent in the DNA of healthy donors