Prognostic impact of progression to induction chemotherapy and prior paclitaxel therapy in patients with germ cell tumors receiving salvage high-dose chemotherapy in the last 10 years: A study of the European Society for Blood and Marrow Transplantation Solid Tumors Working Party

Little is known about the prognostic impact of prior paclitaxel therapy and response to induction chemotherapy defined as the regimen preceding high-dose chemotherapy (HDCT) for the salvage therapy of advanced germ cell tumors. Twenty European Society for Blood and Marrow Transplantation centers contributed data on patients treated between 2002 and 2012. Paclitaxel used in either prior lines of therapy or in induction-mobilization regimens was considered. Multivariable Cox analyses of prespecified factors were undertaken on PFS and overall survival (OS). As of October 2013, data for 324 patients had been contributed to this study. One hundred and ninety-two patients (59.3%) had received paclitaxel. Sixty-one patients (19%) had a progression to induction chemotherapy, 234 (72%) a response (29 (9%) missing or granulocyte colony-stimulating factor without chemotherapy). Both progression to induction chemotherapy and prior paclitaxel were significantly associated with shorter OS univariably (P<0.001 and P=0.032). On multivariable analysis from the model with fully available data (N=216) progression to induction was significantly prognostic for PFS and OS (P=0.003), but prior paclitaxel was not (P=0.674 and P=0.739). These results were confirmed after multiple imputation of missing data. Progression to induction chemotherapy could be demonstrated as an independent prognostic factor, in contrast to prior paclitaxel

Radionuclide imaging of bone marrow disorders

Noninvasive imaging techniques have been used in the past for visualization the functional activity of the bone marrow compartment. Imaging with radiolabelled compounds may allow different bone marrow disorders to be distinguished. These imaging techniques, almost all of which use radionuclide-labelled tracers, such as 99mTc-nanocolloid, 99mTc-sulphur colloid, 111In-chloride, and radiolabelled white blood cells, have been used in nuclear medicine for several decades. With these techniques three separate compartments can be recognized including the reticuloendothelial system, the erythroid compartment and the myeloid compartment. Recent developments in research and the clinical use of PET tracers have made possible the analysis of additional properties such as cellular metabolism and proliferative activity, using 18F-FDG and 18F-FLT. These tracers may lead to better quantification and targeting of different cell systems in the bone marrow. In this review the imaging of different bone marrow targets with radionuclides including PET tracers in various bone marrow diseases are discussed

Interdependency of CEACAM-1, -3, -6, and -8 induced human neutrophil adhesion to endothelial cells

Members of the carcinoembryonic antigen family (CEACAMs) are widely expressed, and, depending on the tissue, capable of regulating diverse functions including tumor promotion, tumor suppression, angiogenesis, and neutrophil activation. Four members of this family, CEACAM1, CEACAM8, CEACAM6, and CEACAM3 (recognized by CD66a, CD66b, CD66c, and CD66d mAbs, respectively), are expressed on human neutrophils. CD66a, CD66b, CD66c, and CD66d antibodies each increase neutrophil adhesion to human umbilical vein endothelial cell monolayers. This increase in neutrophil adhesion caused by CD66 antibodies is blocked by CD18 mAbs and is associated with upregulation of CD11/CD18 on the neutrophil surface. To examine potential interactions of CEACAMs in neutrophil signaling, the effects on neutrophil adhesion to human umbilical vein endothelial cells of a set of CD66 mAbs was tested following desensitization to stimulation by various combinations of these mAbs. Addition of a CD66 mAb in the absence of calcium results in desensitization of neutrophils to stimulation by that CD66 mAb. The current data show that desensitization of neutrophils to any two CEACAMs results in selective desensitization to those two CEACAMs, while the cells remain responsive to the other two neutrophil CEACAMs. In addition, cells desensitized to CEACAM-3, -6, and -8 were still responsive to stimulation of CEACAM1 by CD66a mAbs. In contrast, desensitization of cells to CEACAM1 and any two of the other CEACAMs left the cells unresponsive to all CD66 mAbs. Cells desensitized to any combination of CEACAMs remained responsive to the unrelated control protein CD63. Thus, while there is significant independence of the four neutrophil CEACAMs in signaling, CEACAM1 appears to play a unique role among the neutrophil CEACAMs. A model in which CEACAMs dimerize to form signaling complexes could accommodate the observations. Similar interactions may occur in other cells expressing CEACAMs

Treatment of adult ALL patients with third-generation CD19-directed CAR T cells: results of a pivotal trial

BACKGROUND: Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL). METHODS: Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 106 and 50 × 106 CARTs/m2. Leukapheresis, manufacturing and administration of CARTs were performed in-house. RESULTS: For all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80%) achieved a complete remission (CR), including five patients (50%) with minimal residual disease (MRD)-negative CR. Response and outcome were associated with the administered CART dose. At 1-year follow-up, median overall survival was not reached and progression-free survival (PFS) was 38%. Median PFS was reached on day 120. Lack of CD39-expression on memory-like T cells was more frequent in CART products of responders when compared to CART products of non-responders. After CART administration, higher CD8 + and γδ-T cell frequencies, a physiological pattern of immune cells and lower monocyte counts in the PB were associated with response. CONCLUSION: In conclusion, third-generation CARTs were associated with promising clinical efficacy and remarkably low procedure-specific toxicity, thereby opening new therapeutic perspectives for patients with r/r ALL. Trial registration This trial was registered at www.clinicaltrials.gov as NCT03676504

RHAMM (CD168) is overexpressed on the protein level and may constitute an immunogenic antigen in advanced prostate cancer disease

5129 Introduction: Treatment options for early stage prostate cancer are well defined, and localized prostate cancer can be cured by several strategies. However therapeutic outcome in advanced tumor stages is still disappointing. One approach is to deliver targeted therapy based on identified human tumor antigens, specifically expressed in neoplastic tissue and recognised by CD4/CD8 T-cells or antibodies. Materials and Methods: We employed serological identification of antigens by recombinant expression cloning (SEREX) and data mining in SEREX related databases to identify potential immunological target structures. Consequently, candidate antigens were screened by DNA microarrays consisting of approximately 20K genes, designed to profile benign and malignant prostate tissues. Genes overexpressed on the cDNA level were evaluated on the protein level by tissue microarrays representing various disease stages including about 900 tissue cores. Protein expression was measured by the Chromavision system. Results: Ten of the targets identified by SEREX and data mining showed a significant overexpression on the 20k cDNA array in localized prostate cancer compared to benign prostatic hyperplasia and in metastases compared to localized prostate cancer. One gene which has been identified earlier as an immunogenic antigen in leukemia by our group, CD168, showed a highly significant overexpression in prostate cancer metastases compared to localized disease (p=0.007). On the protein level CD168 was highest in metastatic tissue samples and significantly higher in neoplastic localized disease compared to benign tissue (p=0.03). High CD168 expression had an association to clinical parameters known to be associated with better clinical outcome. Patients with high CD168 expression in the primaries had a significantly lower risk for biochemical failure (log rank p=0.023; RR:0.621). In cell culture experiments, the number of viable cells was reduced in blocking experiments using hormone sensitive (LNCaP) and hormone insensitive metastatic (PC3 and DU 145) prostate cancer cell lines. Conclusion: Acknowledging the proven immunogenic effects of CD168 in leukemia, this antigen is an intriguing therapeutic target in advanced prostate cancer disease. No significant financial relationships to disclose. </jats:p

Adoptive transfer and selective reconstitution of streptamer-selected cytomegalovirus-specific CD8+ T cells leads to virus clearance in patients after allogeneic peripheral blood stem cell transplantation.

Cytomegalovirus (CMV) disease constitutes a serious complication after allogeneic stem cell transplantation. For the clearance of CMV, CD8+ T cells are pivotal. STUDY DESIGN AND METHODS: Here, the novel streptamer technology was used at good manufacturing practice (GMP) level for adoptive transfer of CMV-specific T cells into acute leukemia patients with recurrent high CMV antigenemia after allogeneic stem cell transplantation. RESULTS: After a single transfusion, the frequency of CMV-specific CD8+CD45RA+CCR7- effector T cells increased dramatically from 0.0% to a maximum of 27.1% of all T cells. These T cells were clearly donor derived and did not stem from intrinsic reconstitution, as demonstrated by analysis of 1) donor chimerism through single-tandem repeats, 2) T-cell receptor excision circles, and 3) V&beta;-chain typing by polymerase chain reaction. Clinically, the specific T-cell transfer resulted in a persistent clearance of the CMV antigenemia, which allowed the patients to discontinue toxic antiviral drug therapy without further high-level reactivation of CMV, demonstrating the power of the streptamer technology. CONCLUSION: Taken together, the streptamer technology offers the advantage of selecting virus-specific CD8+ T cells at GMP level for adoptive T-cell transfer, thus inducing long-lasting specific CD8+ T-cell responses without increasing the risk for graft-versus-host disease

Prospective noninterventional study on peripheral blood stem cell mobilization in patients with relapsed lymphomas

Item does not contain fulltextHigh-dose chemotherapy followed by autologous stem cell transplantation (ASCT) to rescue hematopoiesis is considered standard care for patients with a relapsed chemosensitive lymphoma, but diagnosis of lymphoma has been a risk factor for poor mobilization in several studies. The aim of this prospective noninterventional clinical audit was to review the mobilization strategies used by EBMT centers in relapsed lymphoma and to evaluate their efficacy. Between 2010 and 2014, 275 patients with relapsed lymphoma from 30 EBMT centers were prospectively registered. Almost all patients were mobilized with chemotherapy plus G-CSF (96%), but there was a large variation in chemotherapy schedules. Thirty (11%) of them were poor mobilizers (<2 x 106 CD 34+ cells/kg body weight) at the first mobilization. Poor mobilization was not associated with gender, age, bone marrow involvement at diagnosis, primary diagnosis, number of previous chemotherapy lines, previous radiotherapy or mobilization with G-CSF alone. The use of high dose cyclophosphamide alone was associated with mobilization failure (P = 0.0006), whereas the use of a platinum-containing regimen was associated with a good mobilization outcome (P = 0.013). Because failure rate is low, we can conclude from this study that PBSC mobilization failure in relapsed lymphomas is not an important problem in the EBMT centers