Purpose: Immunotherapy for hepatocellular carcinoma (HCC) shows considerable promise in improving clinical outcomes. HepaVac-101 represents a single-arm, first-in-man Phase I/II multicenter cancer vaccine trial for HCC (NCT03203005). It combines multi-peptide antigens (IMA970A) with the TLR7/8/RIG I agonist CV8102. IMA970A includes 5 HLA-A*24 and 7 HLA-A*02 as well as 4 HLA-DR restricted peptides selected after mass spectrometric identification in human HCC tissues or cell lines. CV8102 is an RNA-based immunostimulator inducing a balanced Th1/Th2 immune response. Experimental Design: 82 patients with very early to intermediate stage HCCs were enrolled and screened for suitable HLA haplotypes and 22 put on study treatment. This consisted in a single infusion of low-dose cyclophosphamide followed by 9 intradermal coadministrations of IMA970A and CV8102. Only patients with no disease relapse after standard of care treatments were vaccinated. Primary endpoints of HepaVac-101 clinical trial were safety, tolerability and antigen-specific T-cell responses. Secondary or exploratory endpoints included additional immunological parameters and survival endpoints. Results: The vaccination showed a good safety profile. Transient mild-to-moderate injection-site reactions were the most frequent IMA970A/CV8102-related side effects. Immune responses against {greater than or equal to}1 vaccinated HLA class I tumor-associated peptide (TAA) and {greater than or equal to}1 vaccinated HLA class II TAA were respectively induced in 37% and 53% of the vaccinees. Conclusion: Immunotherapy may provide a great improvement in treatment options for HCC. HepaVac-101 is a first-in-man clinical vaccine trial with multiple novel HLA class I- and class II-restricted TAAs against HCC. The results are initial evidence for safety and immunogenicity of the vaccine. Further clinical evaluations are warranted.
BackgroundFragile-X-Mental-Retardation-1- (FMR1)-gene is supposed to be a key gene for ovarian reserve and folliculogenesis. It contains in its 5’-UTR a triplet-base-repeat (CGG), that varies between 26 and 34 in general population. CGG-repeat-lengths with 55–200 repeats (pre-mutation = PM) show instable heredity with a tendency to increase and are associated with premature-ovarian-insufficiency or failure (POI/POF) in about 20%. FMR1-mRNA-expression in leucocytes and granulosa cells (GCs) increases with CGG-repeat-length in PM-carriers, but variable FMR1-expression profiles were also described in women with POI without PM-FMR1 repeat-length. Additionally, associations between low numbers of retrieved oocytes and elevated FMR1-expression levels have been shown in GCs of females with mid-range PM-CGG-repeats without POI. Effects of FMR1-repeat-lengths-deviations (n < 26 or n > 34) below the PM range (n < 55) on ovarian reserve and response to ovarian stimulation remain controversial.MethodsWe enrolled 229 women undergoing controlled ovarian hyperstimulation for IVF/ICSI-treatment and devided them in three ovarian-response-subgroups: Poor responder (POR) after Bologna Criteria, polycystic ovary syndrome (PCO) after Rotterdam Criteria, or normal responder (NOR, control group). Subjects were subdivided into six genotypes according to their be-allelic CGG-repeat length. FMR1-CGG-repeat-length was determined using ALF-express-DNA-sequencer or ABI 3100/3130 × 1-sequencer. mRNA was extracted from GCs after follicular aspiration and quantitative FMR1-expression was determined using specific TaqMan-Assay and applying the ΔΔCT method. Kruskall-Wallis-Test or ANOVA were used for simple comparison between ovarian reserve (NOR, POR or PCO) and CGG-subgroups or cohort demographic data. All statistical analysis were performed with SPSS and statistical significance was set at p ≤ 0.05.ResultsA statistically significant increase in FMR1-mRNA-expression-levels was detected in GCs of PORs with heterozygous normal/low-CGG-repeat-length compared with other genotypes (p = 0.044).ConclusionFemale ovarian response may be negatively affected by low CGG-alleles during stimulation. In addition, due to a low-allele-effect, folliculogenesis may be impaired already prior to stimulation leading to diminished ovarian reserve and poor ovarian response. A better understanding of FMR1 expression-regulation in GCs may help to elucidate pathomechanisms of folliculogenesis disorders and to develop risk-adjusted treatments for IVF/ICSI-therapy. Herewith FMR1-genotyping potentially provides a better estimatation of treatment outcome and allows the optimal adaptation of stimulation protocols in future.
This study compared the embryological features of mature and immature oocytes (different stages) collected from stimulated cycles of in vitro fertilization (IVF). Immature oocytes were identified, classified as PI (prophase I - germinal vesicle, GV) or MI (metaphase I), were matured in vitro and fertilized using the intra-cytoplasmic sperm injection (ICSI) technique. Fertilization potential, cleavage, and subsequent transfer/cryopreservation of the embryos derived from these in vitro matured oocytes were compared with those of in vivo matured oocytes (collected at the MII stage). The characteristics of embryos derived from gametes recovered in the MI and MII stages were similar. The fertilization rate of immature oocytes recovered in PI was significantly lower than that of MII oocytes (P = 0.031), and the cleavage rate of the PI group was also lower than that of the MI (P = 0.004) and MII (P < 0.001) groups. In vitro maturation of MI oocytes is a suitable alternative when immature oocytes are recovered, as their characteristics and development are similar to those of in vivo matured oocytes. Optimization of outcomes for PI oocytes will require development of techniques that can distinguish which of these gametes will mature and fertilize.
Granulosa cells (GCs) play a major role in folliculogenesis and are crucial for oocyte maturation and growth. In these cells, the mTOR/AKT signalling pathway regulates early folliculogenesis by maintaining the dormancy of primordial follicles, while FSH induces their further differentiation and maturation. Because changes in number of CGG triplets in FMR1 exon 1 (below or beyond normal values of 26-34 triplets) affect ovarian reserve and pre-mutations containing >54 CGG triplets represent a known risk factor for premature ovarian insufficiency/failure, we investigated in the human GC model (COV434) how FMR1/FMRP and mTOR/AKT are expressed and potentially interact during GC proliferation. As FMR protein (FMRP) is expressed mainly in human ovarian GCs, we used these after inducing their proliferation using recombinant FSH (rFSH) and the repression of the mTOR/AKT signalling pathway. We showed that AKT and mTOR expression levels significantly increase after stimulation with rFSH, while S6K and FMR1 expression decrease. After inhibiting mTOR and AKT, FMR1 and S6K expression significantly increased. Only AKT inhibition led to decreased FMRP levels, as expected due to the known FMR1/FMRP negative feedback loop. But rFSH and the mTOR inhibition increased them, indicating a decoupling of this FMR1/FMRP negative feedback loop in our model system.
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