Among patients with newly diagnosed myeloma, survival in recipients of a hematopoietic stem-cell autograft followed by a stem-cell allograft from an HLA-identical sibling is superior to that in recipients of tandem stem-cell autografts. (ClinicalTrials.gov number, NCT00415987 [ClinicalTrials.gov].).

Before the introduction of new drugs, we designed a trial where treatment of newly diagnosed myeloma patients was based on the presence or absence of HLAidentical siblings. First-line treatments included a cytoreductive autograft followed by a nonmyeloablative allograft or a second melphalan-based autograft. Here, we report long-term clinical outcomes and discuss them in the light of the recent remarkable advancements in the treatment of myeloma. After a median follow-up of 7 years, median overall survival (OS) was not reached (P ‫؍‬ .001) and event-free survival (EFS) was 2.8 years (P ‫؍‬ .005) for 80 patients with HLAidentical siblings and 4.25 and 2.4 years for 82 without, respectively. Median OS was not reached (P ‫؍‬ .02) and EFS was 39 months (P ‫؍‬ .02) in the 58 patients who received a nonmyeloablative allograft whereas OS was 5.3 years and EFS 33 months in the 46 who received 2 highdose melphalan autografts. Among patients who reached complete remission in these 2 cohorts, 53% and 19% are in continuous complete remission. Among relapsed patients rescued with "new drugs," median OS from the start of salvage therapy was not reached and was 1.7 (P ‫؍‬ .01) years, respectively. Allografting conferred a long-term survival and disease-free advantage over standard autografting in this comparative study. IntroductionAutologous transplantation has been regarded as the standard of care for young myeloma patients. 1 Recently, "new drugs" such as lenalidomide and bortezomib have prolonged survival. 2,3 Allografting has been considered the only potential cure. 4 However, the high transplant-related mortality (TRM) has limited its use. 5,6 After the observation that donor engraftment could be obtained after reduced-intensity purine analogbased or nonmyeloablative low-dose total body irradiation (TBI)-based conditionings, allografting has become more feasible with acceptable toxicity. [7][8][9] Combining an autograft with a nonmyeloablative conditioning and an allograft has lowered TRM to approximately 15% in myeloma. 10,11 However, role and timing of allografting remain to be determined and convincing evidence that an allograft should routinely be performed is lacking.We report the long-term results of a trial, designed before the introduction of "new drugs," where the treatment assignment of newly diagnosed patients under the age of 66 was based on the presence or absence of an HLA-identical sibling (ClinicalTrials. gov number, NCT00415987). 12 Methods Patients and treatmentsA total of 245 patients were consecutively diagnosed with stage IIA-IIIB myeloma from September 1998 to July 2004 at 5 Italian centers: San Giovanni Battista Hospital, Tosine; University of Udine, Udine; Santa Croce e Carle Hospital, Cuneo; Sant Antonio e Biagio Hospital, Alessandrio; IRCC, Candiole. Of 199 patients, 166 with at least 1 sibling were HLA-typed to search for a potential sibling donor. Written informed consent was obtained from all patients. The study was approved by the 5 Institutional Review Boards according to the Declaration o...

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Donor-derived cytokine-induced killer (CIK) can be infused as adoptive immunotherapy after hematopoietic cell transplant (HCT). Promising results were recently reported in HLA-identical HCT, where mild grafts versus host (GVH) events were observed. To extend this strategy across major HLA barriers (e.g. HLA-haploidentical HCT), further studies on CIK cells' alloreactivity are needed. We hypothesized that alloreactivity and anti-tumor activity of CIK cells segregate within two different cell subsets and could consequently be separated according to CD56 and CD3 expression. We tested CIK cells expanded from seven patients who underwent HCT as treatment of metastatic colorectal cancer. We found that CIK cells maintained their alloreactivity across major HLA barriers when tested as bulk population; after CD56-positive selection, anti-tumor activity was restricted to the CD3+/CD56+ cell fraction and alloreactivity versus HLA-mismatched PBMC was restricted to the CD3+/CD56- cell fraction. Bulk CIK cells from engrafted patients did not exhibit alloreactivity in response to host- or donor-derived PBMC, confirming their low potential for GVH across minor HLA barriers. Moreover, we tested if CIK cells expanded from engrafted patients after HCT were as effective as donor-derived ones and could be considered as an alternative option. The expansion rate and tumor cell killing was comparable to that observed in sibling donors. In conclusion, depletion of CD3+/CD56- cells might reduce the risk of GVH without affecting the tumor-killing capacity and could help extending CIK infusions across major HLA barriers. Engrafted patients after HCT could also be considered as an effective alternative option to donor-derived CIK cells.

Unresectable metastatic bone sarcoma and soft-tissue sarcomas (STS) are incurable due to the inability to eradicate chemoresistant cancer stem-like cells (sCSC) that are likely responsible for relapses and drug resistance. In this study, we investigated the preclinical activity of patient-derived cytokine-induced killer (CIK) cells against autologous bone sarcoma and STS, including against putative sCSCs. Tumor killing was evaluated both in vitro and within an immunodeficient mouse model of autologous sarcoma. To identify putative sCSCs, autologous bone sarcoma and STS cells were engineered with a CSC detector vector encoding eGFP under the control of the human promoter for OCT4, a stem cell gene activated in putative sCSCs. Using CIK cells expanded from 21 patients, we found that CIK cells efficiently killed allogeneic and autologous sarcoma cells in vitro. Intravenous infusion of CIK cells delayed autologous tumor growth in immunodeficient mice. Further in vivo analyses established that CIK cells could infiltrate tumors and that tumor growth inhibition occurred without an enrichment of sCSCs relative to control-treated animals. These results provide preclinical proof-of-concept for an effective strategy to attack autologous sarcomas, including putative sCSCs, supporting the clinical development of CIK cells as a novel class of immunotherapy for use in settings of untreatable metastatic disease. Cancer Res; 74(1); 119-29. Ó2013 AACR.