The composition and quality of leukaemia-derived dendritic cells, T-cells and the cellular microenvironment is predictive for the antileukaemic T-cell cytotoxic reactions of DC-primed T-cells and the response to therapy

Conversion of leukemic cells to leukemia-derived DC (DCleu) improves antigenpresentation and generation of leukemia-specific ACTR. We studied the role of the composition/quality of DC and (DC-primed) T cells, chemokines/cytokines in the mediation of leukemia-cytotoxic reactions ex vivo or to predict the response to DC/DLI-based immunotherapy in vivo. 1) We generated DC/mature DC/DCleu from 30 AML/MDS pts (on average 23/43%/66%) and primed Tcells (in 17 cases) with DC or blasts in MLC. 2) After DCpriming on average 47% of Tcell-cases gained an ACTR, but only 23% after blast-priming. 3) The ACTR efficiency of DCpriming was superior to blast-priming (on average 44%vs34% lysed blasts). 4) About 70% of cases gained an ACTR after DCpriming with >45% proliferating/>65% CD4+/>42% memory Tcells or >40% mature DC/>65% DCleu and if >95g IFN gamma or >15g IL6/[10.sup.6] cells were in the DC-MLC. 80% of cases gained ACTR after priming with DC that produced >2000pgCXCL8 or >100pgCCL2/[10.sup.6] cells. Differences were most distinct in the group with DC primed Tcells prepared at relapse after SCT. 5) Cases with a response to therapy showed higher proportions of DCleu, proliferating, memory or CD4+ Tcells. Pts presenting with a relapse after SCT showed better ex vivo convertibility of blasts to DCleu if they had responded to a GMCSF/DLI based therapy of their relapse after SCT compared to pts with no response (72 vs 36% blasts convertible to DCleu; 44vs 29% generable DC). Moreover we found, that cases with more vs less than 60% blasts convertible to DCleu the overall survival from SCT to endpoint was 612 vs 168 days. 7) Spectratyping of the VbetaTCR region in an AML pt reveiled a more extended clonal restriction of donor Tcells after DCpriming of Tcells compared to blast-primed Tcells and the restricted pattern was also found in Tcells from the pt after SCT. Sum:DC/DCleu can be generated in any given pt independent from karyotype. DCpriming of Tcells improves the antileukaemic CTL, but can also mediate Tcell anergy. The composition of DC/ Tcells/culture supernatants is predictive for the lytic efficiency of primed Tcells and the patients' response to therapy. Tcell clones are enriched after DC- compared to blast priming and are found in vivo selected Tcells. We contribute to understand cytotoxic/ escape mechanisms and detect pts qualifying for DCbased immunotherapies. Possibly DCprimed, specific Tcells could be generated in vivo or selected from ex vivo cultures and trans