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ABSTRACT: Ipilimumab, a CTLA-4-blocking monoclonal antibody, improved the overall survival (OS) of advanced melanoma patients treated in prospective clinical trials. We here report a study on the outcome of patients with pretreated advanced melanoma offered ipilimumab (at its licensed dose of 3 mg/kg, every 3 wk for a total of 4 doses) in an expanded access program at a single-center university hospital. Of the 50 patients initiating ipilimumab, 31 patients completed induction therapy and 9 patients were offered reinduction therapy. Most immune-related adverse events were mild and reversible. The best objective response rate by mWHO-criteria included 1 complete response and 4 partial responses (best objective response rate of 10%). Two additional patients obtained a partial response by immune-related response criteria. Median OS was 7 months, with a 1- and 2-year survival rate of 45.2% and 28.8%, respectively. Long-term disease control with ipilimumab was observed in 7 patients of which 4 received reinduction. Baseline serum C-reactive protein (CRP) and the absolute lymphocyte count (ALC) measured on week 6 significantly correlated with OS. In conclusion, in this single-center experience with ipilimumab for advanced pretreated melanoma patients, clinical outcome was comparable with the results of published prospective studies. Reinduction therapy was of importance for maintaining long-term disease control in the majority of responding patients. Baseline CRP and ALC at week 6 deserve further prospective evaluation as prognostic and/or predictive (surrogate) markers.
Journal of immunotherapy (Hagerstown, Md.: 1997) 04/2013; 36(3):215-22. · 3.20 Impact Factor
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ABSTRACT: Treatment of melanoma patients with mRNA electroporated dendritic cells (TriMixDC-MEL) stimulates T-cell responses against the presented tumor-associated antigens (TAAs). In the current clinical trials, melanoma patients with systemic metastases are treated, requiring priming and/or expansion of preexisting TAA-specific T cells that are able to migrate to both the skin and internal organs. We monitored the presence of TAA-specific CD8(+) T cells infiltrating the skin at sites of intradermal TriMixDC-MEL injection (SKILs) and within the circulation of melanoma patients treated in two clinical trials. In 10 out of fourteen (71%) patients screened, CD8(+) T cells recognizing any of the four TAA presented by TriMixDC-MEL cellular vaccine were found in both compartments. In total, 30 TAA-specific T-cell responses were detected among the SKILs and 29 among peripheral blood T cells, of which 24 in common. A detailed characterization of the antigen specificity of CD8(+) T-cell populations in four patients indicates that the majority of the epitopes detected were only recognized by CD8(+) T cells derived from either skin biopsies or peripheral blood, indicating that some compartmentalization occurs after TriMix-DC therapy. To conclude, functional TAA-specific CD8(+) T cells distribute both to the skin and peripheral blood of patients after TriMixDC-MEL therapy.
BioMed research international. 01/2013; 2013:976383.
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ABSTRACT: A decade of collective work by tumor immunologists has led to improved large scale generation, maturation, antigen loading and administration of dendritic cells (DCs) to cancer patients, promoting enhanced antitumor activity. We alleviated the HLA-restriction in DC therapy and demonstrated that it is meaningful to treat patients with DCs irrespective of their HLA type.
Oncoimmunology. 11/2012; 1(8):1392-1394.
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ABSTRACT: Ipilimumab 3 mg/kg was the first agent to improve survival of pretreated advanced melanoma patients. Nonconventional response patterns to ipilimumab have been reported widely, but most of these data were from studies with ipilimumab 10 mg/kg. Here, case reports from five patients treated within an expanded access program (EAP) with ipilimumab at its licensed dose of 3 mg/kg illustrate the efficacy of ipilimumab in an expanded access setting and the range of different tumor response patterns encountered. The durable clinical benefit seen in these patients despite the observed atypical response patterns highlights the necessity for comprehensive clinical decision making.
Cancer Investigation 10/2012; · 1.85 Impact Factor
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ABSTRACT: Metastasis to the brain is a frequent event in patients with advanced melanoma. Despite treatment with neurosurgery, pancranial irradiation and high-precision conformal radiotherapy, the prognosis of patients suffering from melanoma brain metastasis has remained very poor. Ipilimumab is a new effective immunotherapy for the treatment of advanced melanoma and has demonstrated activity against brain metastases. We report three patients successfully treated with ipilimumab who subsequently developed focal necrosis of the brain following prior radiotherapy of their melanoma brain metastases. As new active systemic treatment options become available that improve the survival of patients with melanoma brain metastases, adequate diagnosis and management of the late sequela from radiation to the brain is likely to gain importance in the management of these patients.
European journal of cancer (Oxford, England: 1990) 06/2012; 48(16):3045-51. · 4.12 Impact Factor
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ABSTRACT: The v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene is mutated at position 600 in about 50% of melanoma. Mutant BRAF activates the downstream effectors of the RAS-RAF-MEK-MAPK pathways and is a driver oncogene in these melanoma cells. Selective BRAF-V600 inhibitors (vemurafenib, dabrafenib) have high antitumor activity against BRAF-V600-mutant melanoma with objective tumor response rates. Resistance, however, develops within less than a year in the majority of patients. Several different mechanisms have been found to mediate acquired resistance, but these do not involve the occurrence of secondary mutations in the BRAF gene. Two patients with BRAF-V600E mutant melanoma who had documented progression during treatment with dabrafenib/GSK1120212 and dabrafenib, respectively, were rechallenged with dabrafenib and vemurafenib after a treatment-free interval of 8 and 4 months during which further progression was documented. Both patients showed a marked clinical response and, in both, objective tumor regression (qualifying as a mixed and a partial response according to RECIST) was documented. These two case observations indicate that resistance to BRAF-selective inhibitors can be reversible following treatment interruption.
Melanoma research 05/2012; · 2.06 Impact Factor
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ABSTRACT: A female patient with stage IV-M1c (distant lymph node and breast metastases), chemotherapy-refractory melanoma was treated with the cytotoxic T-lymphocyte antigen 4 (CTLA-4)-inhibitory monoclonal antibody ipilimumab. At first evaluation following induction treatment, there was marked increase in the volume of the lymphadenopathies (including new adenopathies) and strong uptake of (18)Fluorodeoxy-D-glucose ((18)FDG); marked enlargement of the spleen and interstitial lung infiltrates were also observed. Non-necrotising granulomas were discovered on transbronchial mucosal biopsy and cytology on bronchoalveolar lavage established the diagnosis of sarcoidosis. There was a marked clinical and (18)FDG-positron emission tomography/computed tomography ((18)FDG-PET/CT) documented response following six weeks of corticotherapy. At follow-up, progression of subdiaphragmatic melanoma lymph node metastases was documented. Regression of these metastatic sites was observed during treatment with the selective v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor vemurafenib. The patient died due to progressive disease after three months of vemurafenib treatment. Our case report illustrates the need to take into consideration exacerbation of sarcoidosis as a potential confounder in the assessment of tumor response in a melanoma patient treated with the anti-CTLA-4 mononclonal antibody ipilimumab.
Anticancer research 04/2012; 32(4):1355-9. · 1.73 Impact Factor
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ABSTRACT: The efficacy of cancer immunotherapy can be improved by treatment with full-length tumor antigen and by combining several antigens. This approach allows the induction of a broad immune response irrespective of the patient's HLA type which at the same time challenges immune monitoring. Also, the number of available lymphocytes is most often limited and minimal in vitro restimulations of the lymphocytes should maintain information about the actual in vivo situation. To overcome these hurdles, we developed a method to measure the CD8(+) and CD4(+) T-cell responses directly ex vivo. Skin biopsies taken from dendritic cell (DC)-induced DTH reactions from melanoma patients participating in a DC-clinical trial served as lymphocyte source. Antigen-specificity of skin infiltrating lymphocytes was investigated by coculture with antigen-presenting autologous B cells and assessed for CD137 upregulation and enhanced cytokine secretion. Using this approach we could detect treatment-specific CD8(+) T-cells without restimulation in vitro. Upregulation of the activation marker CD137 correlated with the upregulation of the lytic marker CD107a. CD137 upregulation by treatment-specific CD4(+) lymphocytes however was more pronounced after antigen-specific in vitro restimulation. Both CD8(+) and CD4(+) lymphocytes could be further expanded using the same B cells as for screening allowing characterization of the recognized antigenic region. In addition, this technique can be extended to detect a broader array of T-cell functions and to monitor a large cohort of patients. We believe that this approach of direct ex vivo monitoring, irrespective of the patient's HLA-type or the recognized peptide, and using a limited number of lymphocytes is a valuable tool in the immune monitoring of current cellular immunotherapies.
Journal of immunological methods 03/2012; 377(1-2):23-36. · 2.35 Impact Factor
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An M T Van Nuffel,
Daphné Benteyn, Sofie Wilgenhof,
Lauranne Pierret,
Jurgen Corthals,
Carlo Heirman,
Pierre van der Bruggen,
Pierre G Coulie,
Bart Neyns,
Kris Thielemans,
Aude Bonehill
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ABSTRACT: It is generally thought that dendritic cells (DCs) loaded with full-length tumor antigen could improve immunotherapy by stimulating broad T-cell responses and by allowing treatment irrespective of the patient's human leukocyte antigen (HLA) type. To investigate this, we determined the specificity of T cells from melanoma patients treated with DCs loaded with mRNA encoding a full-length tumor antigen fused to a signal peptide and an HLA class II sorting signal, allowing presentation in HLA class I and II. In delayed-type hypersensitive (DTH)-biopsies and blood, we found functional CD8(+) and CD4(+) T cells recognizing novel treatment-antigen-derived epitopes, presented by several HLA types. Additionally, we identified a CD8(+) response specific for the signal peptide incorporated to elicit presentation by HLA class II and a CD4(+) response specific for the fusion region of the signal peptide and one of the antigens. This demonstrates that the fusion proteins contain newly created immunogenic sequences and provides evidence that ex vivo-generated mRNA-modified DCs can induce effector CD8(+) and CD4(+) T cells from the naive T-cell repertoire of melanoma patients. Thus, this work provides definitive proof that DCs presenting the full antigenic spectrum of tumor antigens can induce T cells specific for novel epitopes and can be administered to patients irrespective of their HLA type.
Molecular Therapy 02/2012; 20(5):1063-74. · 6.87 Impact Factor
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An M.T. Van Nuffel,
Daphné Benteyn, Sofie Wilgenhof,
Lauranne Pierret,
Jurgen Corthals,
Carlo Heirman,
Pierre van der Bruggen,
Pierre G. Coulie,
Bart Neyns,
Kris Thielemans,
Aude Bonehill
Molecular Therapy. 01/2012;
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ABSTRACT: Dendritic cells (DCs) electroporated with mRNA encoding CD70, CD40L and a constitutively active toll-like receptor 4 (TriMix-DC) have an increased T-cell stimulatory capacity. In a prospective phase IB clinical trial, we treated melanoma patients with intradermal and intravenous injections of autologous TriMix-DC co-electroporated with mRNA encoding full-length MAGE-A3, MAGE-C2, tyrosinase and gp100. We report here the immunological and clinical results obtained in one patient with a particularly favorable outcome. This patient had stage IV-M1c melanoma with documented progression during dacarbazine chemotherapy and received 5 TriMix-DC injections. Following DC therapy, a broad CD8(+) T-cell response against multiple epitopes derived from all four treatment antigens was found in the blood and among T cells derived from DTH biopsy. In addition, CD4(+) T cells recognizing different MAGE-A3-derived epitopes were detected in DTH-derived cells. A spontaneous anti-MAGE-C2 CD8(+) T-cell response was present prior to TriMix-DC therapy and increased during treatment. The tumor response was assessed with 18-fluorodeoxyglucose-positron emission/computed tomography. We documented a partial tumor response according to RECIST criteria with a marked reduction in (18)F-FDG-uptake by lung, lymph node and bone metastases. The patient remains free from progression after 12 months of follow-up. This case report indicates that administration of autologous TriMix-DC by the combined intradermal and intravenous route can mediate a durable objective tumor response accompanied by a broad T-cell response in a chemorefractory stage IV-M1c melanoma patient.
Cancer Immunology and Immunotherapy 12/2011; 61(7):1033-43. · 3.70 Impact Factor
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ABSTRACT: Although the resection of solitary visceral melanoma metastases is indicated when possible, further progression of metastatic disease is seen in the vast majority of patients. New modalities of immunotherapy can offer durable disease control in a significant proportion of melanoma patients.
A 28-year-old man was diagnosed with stage III melanoma in 2003 and was treated with autologous dendritic cells in the adjuvant setting. Five years later melanoma metastases causing small bowel obstruction were surgically removed and he was retreated with dendritic cells. Following 5 months without disease manifestations, the patient presented with intermittent abdominal discomfort. Following the visualization of a hot spot at the level of the jejunum on 18F-fluorodeoxyglucose position-emission tomography, the patient underwent a laparotomy, during which a solitary melanoma metastasis of the small bowel causing intussusception was resected. The patient has so far remained disease-free, more than one year after the latest surgical intervention.
Combined modality treatment with surgery and immunotherapy may result in an improved long-term outcome for patients with metastatic melanoma.
Anticancer research 10/2011; 31(10):3579-83. · 1.73 Impact Factor
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Sofie Wilgenhof,
An M T Van Nuffel,
Jurgen Corthals,
Carlo Heirman,
Sandra Tuyaerts,
Daphné Benteyn,
Arlette De Coninck,
Ivan Van Riet,
Guy Verfaillie,
Judith Vandeloo,
Aude Bonehill,
Kris Thielemans,
Bart Neyns
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ABSTRACT: The immunostimulatory capacity of dendritic cells is improved by co-electroporation with mRNA encoding CD40 ligand, constitutively active toll-like receptor 4, and CD70 (TriMix-DC). This pilot clinical trial evaluated the feasibility, safety, and immunogenicity of a therapeutic vaccination containing autologous TriMix-DC co-electroporated with mRNA encoding a human leukocyte antigen class II-targeting signal linked to 1 of 4 melanoma-associated antigens (MAGE-A3, MAGE-C2, tyrosinase, and gp100) in patients with advanced melanoma. Thirty-five American Joint Committee on Cancer stage III/IV melanoma patients received autologous TriMix-DC (4 administrations 2 weeks apart). Immune monitoring was performed by evaluating skin biopsies of delayed type IV hypersensitivity (DTH) reactions for presence of vaccinal antigen-specific DTH-infiltrating lymphocytes (DIL). Thereafter, patients could receive interferon-alpha-2b (IFN-α-2b) 5 MU subcutaneously 3 times weekly and additional TriMix-DC every 8 weeks. TriMix-DC-related adverse events comprised grade 2 local injection site reactions (all patients), and grade 2 fever and lethargy (2 patients). Vaccinal antigen-specific DIL were found in 0/6 patients tested at vaccine initiation and in 12/21 (57.1%) assessed after the fourth vaccine. A positive postvaccination DTH test correlated with IL-12p70 secretion capacity of TriMix-DC. No objective responses to TriMix-DC alone were seen according to RECIST. Twenty-nine patients received IFN-α-2b after the fourth vaccine without unexpected adverse events. During TriMix-DC/IFN-α-2b combination therapy, 1 partial response and 5 stable disease (disease control of >6 months with regression of metastases) were observed in 17 patients with evaluable disease at baseline. In conclusion, this study demonstrated that therapeutic vaccination with autologous TriMix-DC is feasible, safe, and immunogenic and can be combined with sequential IFN-α-2b.
Journal of immunotherapy (Hagerstown, Md.: 1997) 06/2011; 34(5):448-56. · 3.20 Impact Factor
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European Journal of Nuclear Medicine 03/2011; 38(7):1390-1. · 4.53 Impact Factor
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Sofie Wilgenhof,
Lauranne Pierret,
Jurgen Corthals,
An M T Van Nuffel,
Carlo Heirman,
Truus Roelandt,
Arlette De Coninck,
Guy Verfaillie,
Frederik Vandenbroucke,
Ivan Van Riet,
Aude Bonehill,
Kris Thielemans,
Bart Neyns
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ABSTRACT: Metastatic melanoma runs a predictable detrimental course in the vast majority of patients. New modalities of immunotherapy, such as melanoma antigen-specific therapeutic vaccination and cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor blockade by monoclonal antibodies (mAbs), have been associated with atypical kinetics of tumor response that differ from those observed during cytotoxic treatment. Recently, new tumor response criteria have been proposed based on the tumor response characteristics observed in clinical studies with ipilimumab (the so-called 'immune-related response criteria'). We report three illustrative cases of the American Joint Committee on Cancer stage IV-M1c melanoma patients who experienced atypical kinetics of tumor response to the treatment with the CTLA-4-blocking mAb, ipilimumab (case 1), or an autologous dendritic cell vaccine in combination with interferon α-2b (cases 2 and 3). These cases show that atypical response patterns not only relate to the outcome of CTLA-4-blocking mAb therapy but also to the treatment with therapeutic vaccines and interferon α-2b.
Melanoma research 02/2011; 21(2):152-9. · 2.06 Impact Factor
