This open label clinical study provides updated evaluation of the strategy of single unit cord blood transplants (CBTs) with co-infusion of third-party donor (TPD) mobilized hematopoietic stem cells (MHSC). Fifty-five adults with high-risk hematological malignancies, median age 34 years (16-60 years) and weight 70 kg (43-95 kg), received CBTs (median 2.39 Â 10 7 total nucleated cell (TNC) per kg and 0.11 Â 10 6 CD34 þ per kg) and TPD-MHSC (median 2.4 Â 106 CD34 þ per kg and 3.2 Â 10 3 CD3 þ per kg). Median time to ANC and to CB-ANC 40.5 Â 10 9 /l as well as to full CB-chimerism was 10, 21 and 44 days, with maximum cumulative incidences (MCI) of 0.96, 0.95 and 0.91. Median time to unsupported platelets 420 Â 10 9 /l was 32 days (MCI 0.78). MCI for grades I-IV and III-IV acute GVHD (aGVHD) were 0.62 and 0.11; 12 of 41 patients (29%) who are at risk developed chronic GVHD, becoming severely extensive in three patients. Relapses occurred in seven patients (MCI ¼ 0.17). The main causes of morbi-mortality were post-engraftment infections. CMV reactivations were the most frequent, their incidence declining after the fourth month. Five-year overall survival and disease-free survival (Kaplan-Meier) were 56 % and 47% (63% and 54% for patients p40 years). In conclusion, CBT with single units of relatively low cell content and 0-3 HLA mismatches is feasible as a first choice option for adult patients who lack a readily available adequate adult donor.
Purpose: This report describes the development and preclinical qualification tests of secondgeneration anti-carcinoembryonic (CEA) designerTcells for use in human trials. Experimental Design: The progenitor first-generation immunoglobulin-T-cell receptor (IgTCR) that transmits Signal 1-only effectively mediated chimeric immune receptor (CIR)^directed cytotoxicity, but expressor T cells succumbed to activation-induced cell death (AICD). The second-generation CIR (termed ''Tandem'' for two signals) was designed to transmit TCR Signal 1 and CD28 Signal 2 to render T cells resistant to AICD and provide prolonged antitumor effect in vivo. Results: A CIR was created that combines portions of CD28,TCR~, and a single chain antibody domain (sFv) specific for CEA into a single molecule (IgCD28TCR). As designed, the genemodified Tandem T cells exhibit the new property of being resistant to AICD, showing instead an accelerated proliferation on tumor contact. Tandem T cells are more potent than first generation in targeting and lysing CEA + tumor. Tandem T cells secrete high levels of interleukin-2 and IFNg on tumor contact that first-generationTcells lacked, but secretion was exhaustible, suggesting a need for interleukin-2 supplementation in therapy even for these second-generation agents. Finally, second-generationTcells were more effective in suppressing tumor in animal models. Conclusion: An advanced generation of anti-CEA designer T cells is described with features that promise a more potent and enduring antitumor immune response in vivo. These preclinical data qualify the human use of this agent that is currently undergoing trial in patients with CEA + cancers.
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