We have investigated the cytotoxic response to allogeneic I-E and I-A antigens in bulk culture and limiting dilution experiments. A high degree of specific killing could be generated from unprimed T cells of I-E-negative strains upon stimulation with cells expressing I-E. In such conditions, cytotoxic T lymphocytes (CTL) were generated in the absence of a specific proliferative response. The frequency determinations by means of limiting dilution experiments showed that I-E-specific CTL precursors were much less frequent than the K and D specific precursors. The results suggest the existence of a population of I-E-specific CTL that failed to grow under conditions that allowed the growth of class I-specific CTL.
F1 hybrid mice injected with parental T lymphocytes undergo a graft-versus-host (GvH) reaction, one of the consequences being a highly depressed cytotoxic T-lymphocyte (CTL) potential against alloantigens and modified self antigens. In the present study we demonstrate that concanavalin A (Con A) can be used for analysing such GvH-mediated immune suppression. Thus, both alloantigen- and Con A-induced responses were reduced by approximately 80% in F1 suppressed (F1s) animals as compared to F1 control (F1c) mice. Although interleukin 2 (IL-2) production was found to be reduced by approximately 50% it did not account for the reduced CTL response in F1s mice. The addition of IL-2 to Con A-stimulated F1s spleen cell cultures did not reconstitute the response. The results suggest that the suppressive mechanism operates by preventing a large fraction of Lyt-2+ CTL precursors from acquiring IL-2 reactivity. However, a small fraction of CTL precursors, escaped the suppression and differentiated into effector CTL.
2642 Background: INVAC-1 is an optimized DNA plasmid encoding an inactive form of human Telomerase Reverse Transcriptase (hTERT), a universal tumor antigen expressed in most of human tumors with little or no expression in somatic cells. We report here the final results of a First-In-Human Phase I study evaluating INVAC-1 as a single agent in patients (pts) with advanced solid tumors, ended in June 2018. Methods: A two center Phase I trial evaluated INVAC-1 given monthly for a minimum of 3 cycles and up to 9 cycles by intradermal injection followed by electroporation (n = 20) or using a needle-free injection system (n = 6). Primary objectives included safety, tolerability and dose limiting toxicities to identify the maximum tolerated dose and recommended phase 2 dose. Secondary objectives included immune response (assessed by IFN-γ Elispot) and anti-tumor activity. Immuno-monitoring included detection of autoantibodies, lymphocyte phenotyping and inflammatory cytokine levels in blood. Anti-tumor activity was evaluated through RECIST 1.1 adapted to immune response, and plasma circulating tumor DNA (ctDNA). Results: 26 pts with refractory/progressive tumors were enrolled and treated with 3 escalating doses of 100, 400 and 800 µg. 15 pts experienced stable disease according to RECIST. For 11 of them, the treatment was extended, up to 9 months. INVAC-1 was well tolerated with no dose-limiting toxicities. No significant biological signs of autoimmunity were observed. No significant modification in inflammatory plasma cytokines levels was observed after INVAC-1 administration. INVAC-1 triggered de novo or enhanced pre-existing CD4/CD8 specific anti-hTERT response in 63% of pts. This specific anti-hTERT immune response was enhanced ex vivo by adding the immune checkpoint inhibitor nivolumab. ctDNA was evaluated in 17 pts. We observed a ctDNA decrease in 6 cases, a stable level in 5 cases and an increase in 6 cases. Conclusions: Results indicate that INVAC-1 was well tolerated and immunogenic at the doses and schedule tested. Disease stabilization was obtained for the majority of pts (58%) according to RECIST criteria or ctDNA levels. Clinical trial information: NCT02301754.
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