[Tumor vaccines-therapeutic vaccination against cancer]. / Tumorvakzinierung ­ therapeutische Vakzinierung gegen Krebs.

Tumor cells always exhibit differences to normal cells. These differences can be recognized by the immune system, enabling the destruction of tumor cells by T cells, as was impressively demonstrated by the success of immune checkpoint inhibition, e.g., in malignant melanoma. Many cancers, however, do not respond to this kind of therapy. In these cases, vaccination against tumor antigens could be very helpful. Nevertheless, all of the efforts made in this respect during the past 30 years have been virtually futile. With current knowledge and technology there is new hope.

Retrospective single center analysis of outcome, risk factors and therapy in steroid refractory graft-versus-host disease after allogeneic hematopoietic cell transplantation.

Acute and chronic graft-vs.-host disease (aGvHD and cGvHD) are major complications after allogeneic hematopoietic cell transplantation (HCT) leading to substantial morbidity and mortality. This retrospective single-center study analyzes incidence, therapy, and outcome of GvHD in n = 721 patients ≥18 years having received allogeneic HCT 2004-2013 with a special focus on steroid refractory GvHD. Acute (n = 355/49.2%) and chronic (n = 269/37.3%) GvHD were mainly treated by steroids in first-line therapy. The proportion of steroid refractory aGvHD and cGvHD was 35.7% and 31.4%, respectively. As there is no standard therapy for steroid refractory GvHD, a range of different agents was used. In aGvHD, the overall response rate (ORR) of steroid refractory GvHD to second-line treatment was 27.4%. Mycophenolate mofetil (MMF) and mTOR inhibitors led to superior response rates (ORR 50.0% and 53.3%, respectively). In steroid refractory cGvHD therapy, ORR was 44.4%. Use of calcineurin inhibitors (CNI; n = 11/45.5%), MMF (n = 18/50.0%), mTOR inhibitors (n = 10/60.0%), and extracorporeal photophoresis (ECP; n = 16/56.3%) showed ORR above average. Targeted therapies lead to responses in 7.7% (n = 13). This data may help to improve the design of future prospective clinical studies in GvHD.

An Fc-optimized CD133 antibody for induction of NK cell reactivity against myeloid leukemia.

Antibody-dependent cellular cytotoxicity (ADCC) of natural killer (NK) cells largely contributes to the success of monoclonal antibody (mAb) treatment in cancer. As no antibodies are clinically available for immunotherapy of myeloid leukemias (MLs), we aimed to develop an Fc-optimized CD133 mAb for induction of NK ADCC against MLs. When comparing different available CD133 mAbs, no difference was observed with regard to binding to primary chronic myeloid leukemia cells. However, clone 293C3 recognized acute myeloid leukemia (AML) cells in a substantially higher percentage of patient cases and was thus chosen to generate chimeric mAbs with either wild-type Fc part (293C3-WT) or a variant containing amino-acid exchanges (S239D/I332E) to enhance affinity to CD16 on NK cells (293C3-SDIE). In vitro, treatment with 293C3-SDIE significantly enhanced activation, degranulation and lysis of primary CD133-positive AML cells by allogeneic and autologous NK cells as compared with its wild-type counterpart. In line with the observed lower expression levels of CD133 on healthy cells compared with malignant hematopoietic cells, 293C3-SDIE caused no relevant toxicity towards committed hematopoietic progenitor cells. In a NOD.Cg-PrkdcscidIL2rgtmWjl/Sz xenotransplantation model, 293C3-SDIE facilitated elimination of patient AML cells by human NK cells. Thus, 293C3-SDIE constitutes an attractive immunotherapeutic compound, in particular for elimination of minimal residual disease in the context of allogeneic stem cell transplantation in AML.

Generation, selection and preclinical characterization of an Fc-optimized FLT3 antibody for the treatment of myeloid leukemia.

The therapeutic efficacy of humanized or chimeric second-generation antitumor antibodies is clearly established, but often limited. In recent years, defined modifications of the glycosylation pattern or the amino-acid sequence of the human immunoglobulin G1 Fc part have resulted in the development of third-generation antibodies with improved capability to recruit Fc receptor-bearing effector cells. The first antibodies of this kind, currently evaluated in early clinical trials, are directed against lymphoma-associated antigens. Fc-engineered antibodies targeting myeloid leukemia are not yet available. We here report on the generation and preclinical characterization of an Fc-optimized antibody directed to the FMS-related tyrosine kinase 3 (FLT3), an antigen expressed on the leukemic blasts of all investigated patients with acute myeloid leukemia (AML). This antibody, termed 4G8SDIEM, mediated markedly enhanced cellular cytotoxicity against FLT3-expressing cell lines as well as blasts of AML patients. FLT3 expression levels on AML cells varied between 300 and 4600 molecules/cell and, in most cases, were substantially higher than those detected on normal hematopoietic precursor cells and dendritic cells (approximately 300 molecules/cell). Antibody-mediated cytotoxicity against these normal cells was not detectable. 4G8SDIEM has been produced in pharmaceutical quality in a university-owned production unit and is currently used for the treatment of leukemia patients.