Abstract only
e20040
Background: Advanced stage cutaneous T-cell lymphomas (CTCLs) remain an unmet medical need. Immunomodulatory agents such as mogamulizumab, anti-KIR3DL2 and brentuximab vedotin ...(BV), an anti-CD30 antibody–drug conjugate (ADC) coupled to monomethyl-auristatin-E (MMAE), provided encouraging results but new targeted therapies are needed. Inducible Co-Stimulator (ICOS), a T-cell costimulatory receptor involved in the development of CTCLs, arouses interest. Methods: We used immunohistochemistry to study ICOS expression in skin biopsies of 23 patients with early-stage mycosis fungoides (MF), 12 with transformed MF (TMF) and 17 with Sézary Syndrome (SS), at diagnosis or in relapse. ICOS expression by circulating Sézary cells and regulatory T cells (Tregs) in patients with SS was evaluated using flow cytometry, and compared to healthy donors (HD) lymphocytes. In 5 patients with SS, we also analyzed concomitant biopsies from involved nodes. Then, we investigated the efficacy of anti-ICOS ADCs generated by coupling murine anti-ICOS monoclonal antibodies with MMAE, in comparison to BV. We used ICOS
+
CTCL cell lines (MyLa and MJ), murine xenograft models with MyLa and ICOS
+
Patient Derived Xenografts (PDXs) from patients with SS and angioimmunoblastic T-cell lymphoma (AITL). Results: ICOS was highly expressed by the cutaneous atypical lymphocytic infiltrates in respectively 61%, 75% and 88% of patients with early-stage MF, TMF and SS, such as in the 5 patients with node involvement. ICOS expression by circulating Sézary cells was strong: 69±7.3% versus 38.8±7.1% of non-tumoral CD4
+
cells ( p< 0.009; CI95%: 8.7-51.6); and 31±3.2% of CD4+ cells in HD ( p< 0.0001; CI95%:20.3-46.3). Percentages of ICOS
+
Tregs were significantly higher in patients with SS than in HD. In CTCL cell lines, we observed a significant dose-dependent decrease in cell viability in the presence of anti-ICOS ADCs. In a mouse xenograft model (MyLa), anti-ICOS ADCs provided a longer overall survival (OS) than BV (HR = 15.2;CI95%:3.2-71.1; p< 0.0006). Finally, in ICOS
+
PDXs anti-ICOS ADCs significantly improved OS, and reduced the number of tumor cells in the blood, bone marrow and spleen. No evidence of ADC toxicity was observed in treated mice. Conclusions: All together our results show that ICOS is a therapeutic target of interest in CTCLs and provide the preliminary basis for a therapeutic trial
Rare individuals, termed HIV controllers, spontaneously control HIV infection by mounting efficient T cell responses against the virus. Protective CD4
T cell responses from HIV controllers involve ...high-affinity public T cell receptors (TCRs) recognizing an immunodominant capsid epitope (Gag293) presented by a remarkably broad array of human leukocyte antigen (HLA) class II molecules. Here, we determine the structures of a prototypical public TCR bound to HLA-DR1, HLA-DR11, and HLA-DR15 molecules presenting the Gag293 epitope. TCR recognition was driven by contacts with the Gag293 epitope, a feature that underpinned the extensive HLA cross-restriction. These high-affinity TCRs promoted mature immunological synapse formation and cytotoxic capacity in both CD4
and CD8
T cells. The public TCRs suppressed HIV replication in multiple genetic backgrounds ex vivo, emphasizing the functional advantage conferred by broad HLA class II cross-restriction.
The use of new Direct Acting Antivirals, specific of HCV, has greatly improved the HCV treatment. Most of the DAA are specific of HCV genotypes. Genotyping methods may target different regions of the ...HCV genome, though only the whole genome sequencing could confirm the correct genotype. The present study describes the virological investigation of a treatment failure due to the false identification of an unusual 2k/1b recombinant HCV form. It describes the sequencing methods, and the similarity analysis of the sequences to different genotype query sequences, to identify the recombination breakpoint.
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