203 research outputs found
Tumor-derived microvesicles modulate antigen cross-processing via reactive oxygen species-mediated alkalinization of phagosomal compartment in dendritic cells
Dendritic cells (DCs) are the only antigen-presenting cells able to prime naïve T cells and
cross-prime antigen-specific CD8+ T cells. Their functionality is a requirement for the
induction and maintenance of long-lasting cancer immunity. Albeit intensively investigated,
the in vivo mechanisms underlying efficient antigen cross-processing and presentation
are not fully understood. Several pieces of evidence indicate that antigen transfer to DCs
mediated by microvesicles (MVs) enhances antigen immunogenicity. This mechanism
is also relevant for cross-presentation of those tumor-associated glycoproteins such as
MUC1 that are blocked in HLA class II compartment when internalized by DCs as soluble
molecules. Here, we present pieces of evidence that the internalization of tumor-derived
MVs modulates antigen-processing machinery of DCs. Employing MVs derived from
ovarian cancer ascites fluid and established tumor cell lines, we show that MV uptake
modifies DC phagosomal microenvironment, triggering reactive oxygen species (ROS)
accumulation and early alkalinization. Indeed, tumor MVs carry radical species and the
MV uptake by DCs counteracts the chemically mediated acidification of the phagosomal
compartment. Further pieces of evidence suggest that efficacious antigen cross-priming
of the MUC1 antigen carried by the tumor MVs results from the early signaling induced by
MV internalization and the function of the antigen-processing machinery of DCs. These
results strongly support the hypothesis that tumor-derived MVs impact antigen immunogenicity
by tuning the antigen-processing machinery of DCs, besides being carrier of
tumor antigens. Furthermore, these findings have important implications for the exploitation
of MVs as antigenic cell-free immunogen for DC-based therapeutic strategies
Mammographic breast density in infertile and parous women
BACKGROUND:
Mammographic breast density is a useful marker for breast cancer risk, as breast density is considered one of the strongest breast cancer risk factors. The study objective was to evaluate and compare mammographic breast density in infertile and parous women, as infertility may be associated with high breast density and cancer occurrence.
METHODS:
This study evaluated mammographic breast density using two different systems, BIRADS and Boyd. A selected patient population of 151 women with primary infertility (case group) was compared to 154 parous women who had at least one previous pregnancy (control group). Both groups were premenopausal women aged ≥ 35.
RESULTS:
Evaluation of mammographic features showed that 66.9% of case group patients and 53.9% of control group patients were classified BIRADS-3/BIRADS-4; p < 0.05. Adjusted Odds ratio for the case group in the categories BIRADS-3/BIRADS-4 was 1.78 (95% CI: 1.10-2.89). Using the Boyd classification system, 53.6% of case group patients and 31.8% of control group patients were classified E/F; p < 0.05. Adjusted Odds ratio for case group patients in Boyd categories E/F was 2.05 (95 % CI: 1.07-3.93).
CONCLUSIONS:
Both systems yielded a higher percentage of increased breast density in the case group. Boyd and BIRADS classification systems indicate to what extend breast cancer lesions may be missed on mammography due to masking by dense tissue. Therefore, patients with a high BIRADS or Boyd score should undergo further investigation
Triple peptide vaccination as consolidation treatment in women affected by ovarian and breast cancer: clinical and immunological data of a phase I/II clinical trial
Vaccination with priming and expansion of tumour
reacting T cells is an important therapeutic option to be used
in combination with novel checkpoint inhibitors to increase
the specificity of the T cell infiltrate and the efficacy of the
treatment. In this phase I/II study, 14 high-risk disease-free
ovarian (OC) and breast cancer (BC) patients after completion
of standard therapies were vaccinated with MUC1, ErbB2
and carcinoembryonic antigen (CEA) HLA-A2+-restricted
peptides and Montanide. Patients were subjected to 6 doses
of vaccine every two weeks and a recall dose after 3 months.
ECOG grade 2 toxicity was observed at the injection site. Eight
out of 14 patients showed specific CD8+ T cells to at least one
antigen. None of 4 patients vaccinated for compassionate use
showed a CD8 activation. An OC patient who suffered from
a lymph nodal recurrence, showed specific anti-ErbB2 CD8+
T cells in the bulky aortic lymph nodes suggesting homingof the activated T cells. Results confirm that peptide vaccination
strategy is feasible, safe and well tolerated. In particular
OC patients appear to show a higher response rate compared
to BC patients. Vaccination generates a long-lasting immune
response, which is strongly enhanced by recall administrations.
The clinical outcome of patients enrolled in the trial
appears favourable, having registered no deceased patients
with a minimum follow-up of 8 years. These promising data,
in line with the results of similar studies, the high compliance
of patients observed and the favourable toxicity profile, support
future trials of peptide vaccination in clinically disease-free
patients who have completed standard treatments
Monoclonal Antibodies in Gynecological Cancer: A Critical Point of View
During the last decades, several improvements in treating gynecological malignancies have been achieved. In particular, target therapies, mostly monoclonal antibodies, have emerged as an attractive option for the treatment of these malignancies. In fact, various molecular-targeted agents have been developed for a variety of malignancies with the objective to interfere with a precise tumor associated receptor, essential for cancer cell survival or proliferation, blocking its function, of the cancer cells. Alternatively, monoclonal antibodies have been developed to block immune suppression or enhance functions of immune effector cells. So far, several monoclonal antibodies have been tested for clinical efficacy for the treatment of gynecological cancers. Antibodies against Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR) have been used in different neoplasms such as ovarian and cervical cancer. Catumazumab, a bivalent antibody against CD3 and EpCAM, is effective in the treatment of neoplastic ascites. Other antibodies are peculiar for specific cancer-associated antigen such as Oregovomab against CA125 or Farletuzumab against the folate receptor. Here we describe the preclinical and clinical experience gained up to now with monoclonal antibodies in tumors of the female genital tract and trace future therapeutic and research venues
HER2-based recombinant immunogen to target DCs through FcγRs for cancer immunotherapy
Dendritic cell (DC)-based immunotherapy is an attractive approach to induce long lasting antitumor effector cells aiming to control cancer progression. DC targeting is a critical step in the design of DC vaccines in order to optimize delivery and processing of the antigen, and several receptors have been characterized for this purpose. In this study, we employed the FcγRs to target DCs both in vitro and in vivo. We designed a recombinant molecule (HER2-Fc) composed of the immunogenic sequence of the human tumor-associated antigen HER2 (aa 364–391) and the Fc domain of a human IgG1. In a mouse model, HER2-Fc cDNA vaccination activated significant T cell-mediated immune responses towards HER2 peptide epitopes as detected by IFN-γ ELIspot and induced longer tumor latency as compared to Ctrl-Fc-vaccinated control mice. Human in vitro studies indicated that the recombinant HER2-Fc immunogen efficiently targeted human DCs through the FcγRs resulting in protein cross-processing and in the activation of autologous HER2-specific CD8+ T cells from breast cancer patients
Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort
BACKGROUND:
Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice.
METHODS:
A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively.
RESULTS:
SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced 651 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with 651 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not 655.
CONCLUSIONS:
In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin
Neoantigens from the bench to the bedside. new prospective for ovarian cancer immunotherapy
No abstract availabl
Matching might help interpretation of results of retrospective studies on neoadjuvant chemotherapy followed by surgery in patients affected by bulky cervical cancer
[No abstract available
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