Autoantibodies against the signal peptide domain of MUC1 in patients with multiple myeloma: Implications for disease diagnosis and prognosis.

Naturally generated autoantibodies to tumor-associated antigens such as MUC1 can assist in cancer diagnosis and prognosis. While previous studies have concentrated on the tandem repeat array domain of MUC1, here we focused on MUC1's signal peptide domain. We used ELISA assays with MUC1-specific epitopes and antibodies to quantify soluble MUC1 antigen and anti-MUC1 autoantibodies against the tandem repeat array and signal peptide domains in 15 naïve donors and 27 multiple myeloma cancer patients. We showed a significant increase in up to 24-fold (P<0.004) only in the levels of anti-MUC1 signal peptide autoantibodies in the sera of multiple myeloma patients vs. naïve donors. This increase stemmed chiefly from the preferred immunogenicity of the signal peptide. Moreover, a significant positive correlation (R(2)=0.5361, P<0.048, Pearson correlation) was shown between the levels of soluble MUC1 and anti-MUC1 signal peptide autoantibodies in multiple myeloma patients with progressive disease while under therapy. This is an initial report on the existence of autoantibodies to a signal peptide domain in general and to the MUC1 signal peptide domain in particular in cancer patients. The autoantibodies had MUC1 rather than signal peptide specificity. The specific nature of the antigen leading to generation of these autoantibodies is still unclear because it is unlikely that the target antigen is a major histo-compatibility complex-peptide complex and we could not trace soluble MUC1 signal peptide fragments in naïve donors and multiple myeloma patients. Further validation of these findings may improve diagnostic and prognostic capabilities for MUC1-positive multiple myeloma patients and potentially, patients with other MUC1-positive cancers, as well.

Immunotherapeutic approaches to improve graft-versus-tumor effect and reduce graft-versus-host disease.

The therapeutic efficacy of allogeneic stem cell transplantation is mainly based on the alloreactive immune response of the graft against the host. However, the graft-versus-host process can be viewed as a double-edged sword since it is responsible for both the beneficial graft-versus-tumor effect and the deleterious graft-versus-host disease. During the last two decades, intensive research has been focused on the development of novel immunotherapeutic methods aimed to dissociate graft-versus-host disease from graft-versus-tumor effect. A brief description of these efforts is discussed in this review.

Multidonor bone marrow transplantation improves donor engraftment and increases the graft versus tumor effect while decreasing graft-versus-host disease.

In partially matched donor transplantation, mandatory T-cell depletion (TCD) increases the risks of rejection/graft failure, relapse, and post-transplant infections. A multi-donor approach was offered to resolve some of these drawbacks. This hypothesis was previously tested in a TCD fully mismatched murine model. However, the effect of multi-donor transplantation (MDT) on graft-versus-host disease (GVHD) and graft versus tumor (GVT) effect were never tested. To assess the safety and efficacy of MDT, we used it in non-TCD transplantation and murine breast carcinoma model. We found that when transplanting non-TCD MDT composed by C57Bl/6 and C3H cells into BALB/c, a consistent trichimerism is established, dominated by C57Bl/6 cells. Following MDT the study animals experienced reduced GVHD compare with those transplanted from C57Bl/6 alone, while the GVT effect was superior. We conclude that MDT may serve as a technique that suppresses GVHD while maintaining the GVT effect.

Post-autologous stem cell transplantation administration of rituximab improves the outcome of patients with aggressive B cell non-Hodgkin's lymphoma.

The major cause of treatment failure following high-dose therapy with autologous stem cell transplantation (ASCT) for aggressive B cell non-Hodgkin's lymphoma (NHL) is persistent disease or recurrence. We describe our experience with the administration of rituximab post-ASCT, either as maintenance therapy or for the treatment of relapsed disease in patients with aggressive B cell NHL. Fifty-six patients achieved complete remission post-transplant, and 19 of them received maintenance with rituximab. Maintenance with rituximab resulted in statistically significant superior outcome in terms of progression free (PFS; p = 0.002) and overall survival (OS; p = 0.011). The median PFS and OS of patients in the maintenance arm has not been reached yet, while the median PFS and OS of patients in the control arm were 29 and 42 months, respectively. Fifty-four patients had disease progression or relapsed post-ASCT, and 15 of them received rituximab in combination with chemo- and/or radiotherapy in order to achieve disease remission. Therapeutic administration of rituximab resulted in statistically significant prolongation of OS (p = 0.021). The median OS of patients treated with rituximab was 17 months, while median OS of patients in the control group was 10 months. We consider that the results of our study are promising but need to be verified within large randomized trials.

Post-hematopoietic stem cell transplantion immune-mediated cytopenias.

Immune-mediated cytopenias after allogeneic stem cell transplantation can be categorized as either alloimmune when host or donor immunity reacts against donor or host elements, respectively, or autoimmune when donor immunity reacts against donor hematopoietic tissue, owing to poorly understood mechanisms that result in severe impairment of central and peripheral tolerance. Immune cytopenias are manifested as monolineage or more rarely as bilineage cytopenias, and are usually mediated through humoral immune mechanisms. On the contrary, immune-mediated pancytopenia is a rare event with only few cases reported in the literature. The exact pathogenesis of immune pancytopenia is not well known although it is possible that cellular immunity may play a significant role. The importance of these syndromes lies in the fact that they can cause severe morbidity and mortality. Differential diagnosis from other causes of post-transplant pancytopenia is of extreme value because these disorders can respond to various treatment modalities.

Allogeneic stem cell transplantation for the treatment of diseases associated with a deficiency in bone marrow products.

Our understanding of the pathophysiology of hematopoietic failure associated syndromes led to the developmental of potentially curative procedures for the treatment of many diseases including Severe aplastic anemia, Fanconi's anemia, Primary immunodeficiency, Osteopetrosis, and Metabolic diseases. Although the number of patients that were transplanted for bone marrow deficiency diseases is relatively low as compared to patients with hematological malignancies, the impact on the knowledge of hematopoiesis and transplantation biology is tremendous. Moreover, the patient's average young age suffering from these diseases further encourage searching for curative approaches. Lucking a fully MHC matched donor, remained a significant obstacle in stem cell transplantation for non-malignant hematological disorders. Lessons from attempts to cure aplasic anemia with bone marrow transplantation guided us to the improvement of pretransplant conditioning regimens and prevention of graft versus host reactions after transplantation. Furthermore, in recent years optimization of disease specific protocol have been successfully designed and clinically applied.