Apheresis-related enrichment of CD26++ T lymphocytes: phenotypic characterization and correlation with unfavorable outcome in autologous hematopoietic progenitor cell transplantation.

BACKGROUND: The lymphocyte surface glycoprotein CD26 anchors adenosine deaminase to the lymphocyte surface and possesses dipeptidyl peptidase IV activity. A distinct subset of CD26++ lymphocytes in autologous hematopoietic progenitor cell transplants (HPCTs) was investigated with regard to clinical outcome after autologous HPCT. The phenotype of these cells was characterized in more detail. STUDY DESIGN AND METHODS: Forty-two eligible patients (multiple myeloma, n = 31; Hodgkin's disease, n = 3; non-Hodgkin's lymphoma, n = 6; peripheral neuroectodermal tumor, n = 1; acute myeloid leukemia, n = 1) were included in a retrospective analysis. Distinct cellular subsets, including CD26+/- and CD26++ subpopulations, were analyzed for correlations with kinetics of engraftment, progression-free survival, and overall survival. RESULTS: The numbers of CD26++ T lymphocytes in the autograft correlated inversely with progression-free survival (p = 0.013). CD26++ T lymphocytes transfused per kg of body weight were predictive for the occurrence of disease progression or relapse (p = 0.006). Importantly, the numbers of CD26++ cells showed a highly variable degree of enrichment in the autograft, but no significant variations in the peripheral blood before apheresis. The characterization of CD26++ cells revealed that CD26++/CD8+ cells form a homogeneous population with a distinct T memory cell phenotype (CD45RO+, CD161++, interleukin-18Rα++, CCR7-). CONCLUSION: CD26++ lymphocytes define a discrete phenotype of T memory cells with known chemoresistance and T-cell-repopulating capacity. Their enrichment during apheresis and corresponding depletion from the circulation are associated with an adverse outcome in autologous HPCT.

Long-lasting remission of pulmonary metastases of renal cell cancer under IFN-beta therapy in a patient with multiple sclerosis.

BACKGROUND: Immunomodulary therapy based on interferon (IFN)-a has been shown to be effective in a subset of patients with advanced renal cell carcinoma (RCC). IFN-Beta has occasionally been reported to induce remissions in RCC, but is well established in the treatment of multiple sclerosis (MS). There is an ongoing debate whether hyperactivation of the immune system may convey protection against the development of cancer in MS patients. PATIENTS AND METHODS: A 54-year-old female MS patient underwent tumor nephrectomy for RCC in 1994. 1 year later, several bilateral pulmonary metastases were documented by computed tomography and were histologically confirmed thereafter. Therapy with IFN-Beta was started. RESULTS: Soon after initiation of IFN-Beta treatment, the patient achieved an almost complete remission which is still ongoing after 10 years of IFN-Beta therapy. CONCLUSION: To our knowledge, this is the longest remission under IFN-Beta treatment ever reported in an RCC patient. We conclude that IFN-Beta should be particularly considered as a therapeutic option in the rare occasion of metastatic RCC in patients with MS.

Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma.

Mutation of p53 is a rare event in multiple myeloma, but it is unknown if p53 signaling is functional in myeloma cells, and if targeted nongenotoxic activation of the p53 pathway is sufficient to kill tumor cells. Here, we demonstrate that treatment of primary tumor samples with a small-molecule inhibitor of the p53-murine double minute 2 (MDM2) interaction increases the level of p53 and induces p53 targets and apoptotic cell death. Significantly, given the importance of the bone marrow microenvironment for the support and drug resistance of myeloma cells, tumor cells undergo effective apoptosis also in the presence of stromal cells, which themselves appear to tolerate exposure to nutlin-3. The in vitro toxicity of nutlin-3 was similar to that of the genotoxic drug melphalan. Because nutlin-mediated p53 activation is not dependent on DNA damage, MDM2 antagonists may help to avoid or reduce the severe genotoxic side effects of chemotherapeutic agents currently used to treat multiple myeloma. Therefore, MDM2 antagonists may offer a new treatment option for this disease.