Willem Lesterhuis

Dendritic Cell Vaccination in Combination with Anti-CD25 Monoclonal Antibody Treatment: A Phase I/II Study in Metastatic Melanoma Patients

Purpose: The success of cancer immunotherapy depends on the balance between effector T cells and suppressive immune regulatory mechanisms within the tumor microenvironment. In this study we investigated whether transient monoclonal antibody–mediated depletion of CD25high regulatory T cells (Treg) is capable of enhancing the immunostimulatory efficacy of dendritic cell vaccines. Experimental Design: Thirty HLA-A2.1+ metastatic melanoma patients were vaccinated with mature dendritic cells pulsed with tumor peptide and keyhole limpet hemocyanin (KLH). Half of the patients were pretreated with daclizumab, a humanized antibody against the interleukin-2 (IL-2) receptor α-chain (CD25), either four or eight days before dendritic cell vaccinations. Clinical and immunologic parameters were determined. Results: Daclizumab efficiently depleted all CD25high immune cells, including CD4+FoxP3+CD25high cells, from the peripheral blood within four days of administration. Thirty days after administration, daclizumab was cleared from the circulation and all CD25+ cells reappeared. The presence of daclizumab during dendritic cell vaccinations prevented the induction of specific antibodies in vivo but not the presence of antigen-specific T cells. Daclizumab, however, did prevent these CD25+ T cells from acquiring effector functions. Consequently, significantly less patients pretreated with daclizumab developed functional, vaccine-specific effector T cells and antibodies compared with controls. Daclizumab pretreatment had no significant effect on progression-free survival compared with the control group. Conclusions: Although daclizumab depleted the CD4+FoxP3+CD25high Tregs from the peripheral circulation, it did not enhance the efficacy of the dendritic cell vaccine. Residual daclizumab functionally suppressed de novo induced CD25+ effector cells during dendritic cell vaccinations. Our results indicate that for immunotherapeutic benefit of transient Treg depletion, timing and dosing as well as Treg specificity are extremely important. Clin Cancer Res; 16(20); 5067–78. ©2010 AACR.

Molecular pathways: the immunogenic effects of platinum-based chemotherapeutics

The platinum-based drugs cisplatin, carboplatin, and oxaliplatin belong to the most widely used chemotherapeutics in oncology, showing clinical efficacy against many solid tumors. Their main mechanism of action is believed to be the induction of cancer cell apoptosis as a response to their covalent binding to DNA. In recent years, this picture has increased in complexity, based on studies indicating that cellular molecules other than DNA may potentially act as targets, and that part of the antitumor effects of platinum drugs occurs through modulation of the immune system. These immunogenic effects include modulation of STAT signaling; induction of an immunogenic type of cancer cell death through exposure of calreticulin and release of ATP and high-mobility group protein box-1 (HMGB-1); and enhancement of the effector immune response through modulation of programmed death receptor 1-ligand and mannose-6-phosphate receptor expression. Both basic and clinical studies indicate that at least part of the antitumor efficacy of platinum chemotherapeutics may be due to immune potentiating mechanisms. Clinical studies exploiting this novel mechanism of action of these old cancer drugs have been initiated. Here, we review the literature on the immunogenic effects of platinum, summarize the clinical advances using platinum as a cytotoxic compound with immune adjuvant properties, and discuss the limitations to these studies and the gaps in our understanding of the immunologic effects of these drugs. Clin Cancer Res; 20(11); 2831–7. ©2014 AACR.

A pilot study on the immunogenicity of dendritic cell vaccination during adjuvant oxaliplatin/capecitabine chemotherapy in colon cancer patients.

Background:Dendritic cell (DC) vaccination has been shown to induce anti-tumour immune responses in cancer patients, but so far its clinical efficacy is limited. Recent evidence supports an immunogenic effect of cytotoxic chemotherapy. Pre-clinical data indicate that the combination of chemotherapy and immunotherapy may result in an enhanced anti-cancer activity. Most studies have focused on the immunogenic aspect of chemotherapy-induced cell death, but only few studies have investigated the effect of chemotherapeutic agents on the effector lymphocytes of the immune system.Methods:Here we investigated the effect of treatment with oxaliplatin and capecitabine on non-specific and specific DC vaccine-induced adaptive immune responses. Stage III colon cancer patients receiving standard adjuvant oxaliplatin/capecitabine chemotherapy were vaccinated at the same time with keyhole limpet haemocyanin (KLH) and carcinoembryonic antigen (CEA)-peptide pulsed DCs.Results:In 4 out of 7 patients, functional CEA-specific T-cell responses were found at delayed type hypersensitivity (DTH) skin testing. In addition, we observed an enhanced non-specific T-cell reactivity upon oxaliplatin administration. KLH-specific T-cell responses remained unaffected by the chemotherapy, whereas B-cell responses were diminished.Conclusion:The results strongly support further testing of the combined use of specific anti-tumour vaccination with oxaliplatin-based chemotherapy.

Early identification of antigen-specific immune responses in vivo by [18F]-labeled 3′-fluoro-3′-deoxy-thymidine ([18F]FLT) PET imaging

Current biomarkers are unable to adequately predict vaccine-induced immune protection in humans with infectious disease or cancer. However, timely and adequate assessment of antigen-specific immune responses is critical for successful vaccine development. Therefore, we have developed a method for the direct assessment of immune responses in vivo in a clinical setting. Melanoma patients with lymph node (LN) metastases received dendritic cell (DC) vaccine therapy, injected intranodally, followed by [18F]-labeled 3′-fluoro-3′-deoxy-thymidine ([18F]FLT) PET at varying time points after vaccination. Control LNs received saline or DCs without antigen. De novo immune responses were readily visualized in treated LNs early after the prime vaccination, and these signals persisted for up to 3 wk. This selective [18F]FLT uptake was markedly absent in control LNs, although tracer uptake in treated LNs increased profoundly with as little as 4.5 × 105 DCs. Immunohistochemical staining confirmed injected DC dispersion to T-cell areas and resultant activation of CD4+ and CD8+ T cells. The level of LN tracer uptake significantly correlates to the level of circulating antigen-specific IgG antibodies and antigen-specific proliferation of T cells in peripheral blood. Furthermore, this correlation was not observed with [18F]-labeled fluoro-2-deoxy-2-d-glucose. Therefore, [18F]FLT PET offers a sensitive tool to study the kinetics, localization, and involvement of lymphocyte subsets in response to vaccination. This technique allows for early discrimination of responding from nonresponding patients in anti-cancer vaccination and aid physicians in individualized decisionmaking.

Vascular Endothelial Growth Factor in Systemic Capillary Leak Syndrome

Systemic capillary leak syndrome is a rare disorder charcterized by acute attacks of severe vascular hyperpermebility causing hypotension and shock. All patients have paraproteinemia. There is a rarer variant of this syndome in which the same symptoms appear in a chronic orm. The diagnosis is made by exclusion of other causes. he cause has not been elucidated, and no treatment has een shown effective. Patient 1, a 42-year-old woman, had classic episodic ystemic capillary leak syndrome associated with monolonal gammopathy of unknown significance, immunolobulin (Ig)-G lambda. During an episode of severe apillary leak necessitating intensive care unit admission, erial samples of plasma were obtained. Vascular endohelial growth factor concentrations were elevated at the nitial presentation of symptoms and quickly decreased, orrelating with the remission of the capillary leak Figure A). Patient 2, a 66-year-old man, presented with generalized dema refractory to diuretics. A cardiac, renal, infectious, nflammatory, or malignant cause could not be identified fter extensive diagnostic procedures, including autoimune serology, echocardiography, coronary angiography, omputed tomography scanning of the thorax and abdomen, one marrow biopsy, thoracoscopic examination of the hest wall, and pleural biopsies. There was a monoclonal araproteinemia of IgA, without evidence of multiple yeloma. We concluded that the patient had the chronic orm of capillary leak syndrome. To confirm the presence of systemic hyperpermeability, e measured the transcapillary escape rate of radioactive

Skin-derived tumor specific T cells predict clinical outcome in dendritic cell vaccination studies in both stage III and IV melanoma patients

Dendritic cells (DCs) are the professional antigen-presenting cells of the immune system. Their decisive role in inducing immunity formed the rationale for DC immunotherapy: DC loaded with tumor antigens are injected into cancer patients to stimulate T cells to eradicate tumors.