Purpose: CT-011 is a humanized IgG1 monoclonal antibody that modulates the immune response through interaction with PD-1, a protein belonging to the B7 receptor family present on lymphocytes. The objectives of this phase I study were to assess the dose-limiting toxicities, to determine the maximum tolerated dose, and to study the pharmacokinetics of CT-011 administered once to patients with advanced hematologic malignancies. Experimental Design: Seventeen patients were treated with escalating doses of CT-011 ranging from 0.2 to 6 mg/kg. For pharmacokinetic analysis, blood samples were withdrawn from the patients before and immediately after treatment and at 24 hours, 48 hours, and on days 7, 14, and 21. CT-011blood levels were assessed with a specific ELISA and derived concentrations were used to calculate pharmacokinetic parameters. Activation of the immune system was assessed by measuring peripheral blood CD4 + , CD8 + , and CD69 + lymphocytes. Results: The study showed the antibody to be safe and well tolerated in this patient population. No single maximum tolerated dose was defined in this study. Clinical benefit was observed in 33% of the patients with one complete remission. Pharmacokinetic analyses show that serum C max and the AUC of CT-011 increased proportionally with dose. The median t 1/2 of CT-011 ranged from 217 to 410 hours. Sustained elevation in the percentage of peripheral blood CD4 + lymphocytes was observed up to 21days following CT-011treatment. Conclusions: A single administration of 0.2 to 6.0 mg/kg of CT-011is safe and well tolerated in patients with advanced hematologic malignancies.

Purpose: Adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL) has shown promising results in metastatic melanoma patients. Although objective response rates of over 50% have been reported, disadvantages of this approach are the labor-intensive TIL production and a very high drop-out rate of enrolled patients, limiting its widespread applicability.Previous studies showed a clear correlation between short TIL culture periods and clinical response. Therefore, we used a new TIL production technique using unselected, minimally cultured, bulk TIL (Young-TIL). The use of Young-TIL is not restricted to human leukocyte antigen (HLA)-A2 patients.The purpose of this study is to explore the efficacy and toxicity of adoptively transferred Young-TIL following lympho-depleting chemotherapy in metastatic melanoma patients, refractory to interleukin-2 and chemotherapy.Experimental Design: Young-TIL cultures for 90% of the patients were successfully generated, enabling the treatment of most enrolled patients. We report here the results of 20 evaluated patients.Results: Fifty percent of the patients achieved an objective clinical response according to the Response Evaluation Criteria in Solid Tumors, including two ongoing complete remissions (20+, 4+ months) and eight partial responses (progression-free survival: 18+, 13+, 10+, 9, 6+, 4, 3+, and 3 months). All responders are currently alive. Four additional patients showed disease stabilization. Side effects were transient and manageable.Conclusion: We showed that lympho-depleting chemotherapy followed by transfer of short-term cultured TIL can mediate tumor regression in 50% of metastatic melanoma with manageable toxicity. The convincing clinical results combined with the simplification of the process may thus have a major effect on cell therapy of cancer. Clin Cancer Res; 16(9); 2646-55. ©2010 AACR.

Results of reduced intensity conditioning regimen (RIC) in the HLA identical haematopoietic stem cell transplantation (HSCT) setting have not been compared to those after myeloablative (MA) regimen HSCT in patients with acute myeloblastic leukaemia (AML) over 50 years of age. With this aim, outcomes of 315 RIC were compared with 407 MA HSCT recipients. The majority of RIC was fludarabine-based regimen associated to busulphan (BU) (53%) or low-dose total body irradiation (24%). Multivariate analyses of outcomes were used adjusting for differences between both groups. The median follow-up was 13 months. Cytogenetics, FAB classification, WBC count at diagnosis and status of the disease at transplant were not statistically different between the two groups. However, RIC patients were older, transplanted more recently, and more frequently with peripheral blood allogeneic stem cells as compared to MA recipients. In multivariate analysis, acute GVHD (II-IV) and transplant-related mortality were significantly decreased (P ¼ 0.01 and Po10 À4 , respectively) and relapse incidence was significantly higher (P ¼ 0.003) after RIC transplantation. Leukaemia-free survival was not statistically different between the two groups. These results may set the grounds for prospective trials comparing RIC with other strategies of treatment in elderly AML.