BackgroundAnti-programmed cell death protein 1 (PD-1) antibodies are now routinely administered for metastatic melanoma and for increasing numbers of other cancers, but still only a fraction of ...patients respond. Better understanding of the modes of action and predictive biomarkers for clinical outcome is urgently required. Cancer rejection is mostly T cell-mediated. We previously showed that the presence of NY-ESO-1-reactive and/or Melan-A-reactive T cells in the blood correlated with prolonged overall survival (OS) of patients with melanoma with a heterogeneous treatment background. Here, we investigated whether such reactive T cells can also be informative for clinical outcomes in metastatic melanoma under PD-1 immune-checkpoint blockade (ICB).MethodsPeripheral blood T cell stimulation by NY-ESO-1 and Melan-A overlapping peptide libraries was assessed before and during ICB in two independent cohorts of a total of 111 patients with stage IV melanoma. In certain cases, tumor-infiltrating lymphocytes could also be assessed for such responses. These were characterized using intracellular cytokine staining for interferon gamma (IFN-γ), tumor negrosis factor (TNF) and CD107a. Digital pathology analysis was performed to quantify NY-ESO-1 and Melan-A expression by tumors. Endpoints were OS and progression-free survival (PFS).ResultsThe initial presence in the circulation of NY-ESO-1- or Melan-A-reactive T cells which became no longer detectable during ICB correlated with validated, prolonged PFS (HR:0.1; p>0.0001) and OS (HR:0.2; p=0.021). An evaluation of melanoma tissue from selected cases suggested a correlation between tumor-resident NY-ESO-1- and Melan-A-reactive T cells and disease control, supporting the notion of a therapy-associated sequestration of cells from the periphery to the tumor predominantly in those patients benefitting from ICB.ConclusionsOur findings suggest a PD-1 blockade-dependent infiltration of melanoma-reactive T cells from the periphery into the tumor and imply that this seminally contributes to effective treatment.
Objective To evaluate the association between female cystic fibrosis (CF) carrier status and in vitro fertilization (IVF) response and outcomes. The presence of cystic fibrosis transmembrane ...conductance regulator (CFTR) gene mutations in male carriers has been associated with infertility, yet possible adverse effects on the ovarian function and reproductive outcomes of female carriers have not been studied to date. Design Retrospective cohort study. Setting Private academic, clinical reproductive center. Patient(s) Females <40 years of age who were screened for CFTR mutations and received IVF treatment between July 2002 and March 2013. Intervention(s) Patients initiated controlled ovarian hyperstimulation with frequent monitoring, vaginal oocyte retrieval, fertilization, embryo transfer, and a pregnancy test. Various measures of IVF stimulation response and cycle outcome were evaluated for both carriers and noncarriers. Main Outcome Measure(s) Analysis was performed by logistic regression and Poisson regression. Result(s) IVF cycles (n = 199) from CFTR mutation carrier patients (n = 112) were analyzed. No significant differences in outcome were noted when carriers of different mutation loci were compared in aggregate with the noncarrier group (n = 6,420 cycles from 3,555 patients). Significant differences were noted for some metrics when the carriers were grouped by mutation loci. Conclusion(s) Overall, no significant differences in stimulation response and cycle outcome were noted between female CFTR mutation carriers and noncarriers. Further research is needed to investigate whether the differences noted between specific CFTR mutation loci are clinically relevant and whether CFTR mutations may impact reproductive outcomes outside the context of assisted reproductive technologies.
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