Stephanie Du Four

Single-center experience with ipilimumab in an expanded access program for patients with pretreated advanced melanoma.

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.

Correlation of EGFR, IDH1 and PTEN status with the outcome of patients with recurrent glioblastoma treated in a phase II clinical trial with the EGFR-blocking monoclonal antibody cetuximab

Mutation and gene amplification of the epithelial growth factor receptor (EGFR) is one of the most common genetic alterations in glioblastoma (GB). EGFR is, therefore, an attractive molecular target for the treatment of GB. EGFR-targeted therapies however have been largely ineffective in clinical trials. In this study, we investigated the correlation between the EGFR gene amplification status, expression of the EGFR variant III (EGFRvIII) and EGFR variant IV (EGFRvIV) mutations, expression of the phosphatase and tensin homologue gene on chromosome 10 (PTEN) and mutation of the isocitrate dehydrogenase 1 (IDH1) gene and the survival of patients suffering from recurrent glioblastoma who were treated with the EGFR-targeted monoclonal antibody cetuximab in a prospective phase II clinical trial. EGFR amplification was detected in 19 out of 35 GB (54%), EGFRvIII expression in 11 (31.4%) and EGFRvIV expression in 7 (20%). The EGFRvIII and EGFRvIV mutations were exclusively found in GB with EGFR amplification and were almost mutually exclusive with IDH1 mutation (EGFRvIII mutation was found in 1 out of 11 GB with an IDH1 mutation). Patients with an EGFR amplification lacking EGFRvIII expression had a significantly superior progression free survival (PFS) and a numerical better overall survival (OS) following treatment with cetuximab [median PFS 3.03 vs. 1.63 months (p=0.006); median OS 5.57 vs. 3.97 months (p=0.12)]. Within the subgroup of patients with EGFR amplification, patients with EGFRvIII positive glioblastoma had a worse survival [median PFS 1.63 vs. 3.03 months (p=0.01); median OS 3.27 vs. 5.57 months (p=0.08)]. Our observations indicate that the type of EGFR mutation may determine the outcome of GB patients treated with cetuximab. Prospective investigation of both the EGFR amplification and mutation status in clinical trials with EGFR-targeted therapies for GB is indicated.

Radiation necrosis of the brain in melanoma patients successfully treated with ipilimumab, three case studies.

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.

Axitinib increases the infiltration of immune cells and reduces the suppressive capacity of monocytic MDSCs in an intracranial mouse melanoma model

Melanoma patients are at a high risk of developing brain metastases, which are strongly vascularized and therefore have a significant risk of spontaneous bleeding. VEGF not only plays a role in neo-angiogenesis but also in the antitumor immune response. VEGFR-targeted therapy might not only have an impact on the tumor vascularization but also on tumor-infiltrating immune cells. In this study, we investigated the effect of axitinib, a small molecule TKI of VEGFR-1, -2, and -3, on tumor growth and on the composition of tumor-infiltrating immune cells in subcutaneous and intracranial mouse melanoma models. In vivo treatment with axitinib induced a strong inhibition of tumor growth and significantly improved survival in both tumor models. Characterization of the immune cells within the spleen and tumor of tumor-bearing mice respectively showed a significant increase in the number of CD3+CD8+ T cells and CD11b+ cells of axitinib-treated mice. More specifically, we observed a significant increase of intratumoral monocytic myeloid-derived suppressor cells (moMDSCs; CD11b+Ly6ChighLy6G-). Interestingly, in vitro proliferation assays showed that moMDSCs isolated from spleen or tumor of axitinib-treated mice had a reduced suppressive capacity on a per cell basis as compared to those isolated from vehicle-treated mice. Moreover, MDSCs from axitinib-treated animals displayed the capacity to stimulate allogeneic T cells. Thus, treatment with axitinib induces differentiation of moMDSC toward an antigen-presenting phenotype. Based on these observations, we conclude that the impact of axitinib on tumor growth and survival is most likely not restricted to direct anti-angiogenic effects but also involves important effects on tumor immunity.

Intratumoral delivery of TriMix mRNA results in T-cell activation by cross-presenting dendritic cells

Intratumoral injection of CTL-stimulatory agents could provide another avenue for immunotherapy. TriMix mRNA, comprising three DC-oriented stimulatory mRNAs, was examined in mouse models and provides a rationale for clinical testing in solid and accessible tumors. Modulating the activity of tumor-infiltrating dendritic cells (TiDC) provides opportunities for novel cancer interventions. In this article, we report on our study of the uptake of mRNA by CD8α+ cross-presenting TiDCs upon its intratumoral (i.t.) delivery. We exploited this property to deliver mRNA encoding the costimulatory molecule CD70, the activation stimuli CD40 ligand, and constitutively active Toll-like receptor 4, referred to as TriMix mRNA. We show that TiDCs are reprogrammed to mature antigen-presenting cells that migrate to tumor-draining lymph nodes (TDLN). TriMix stimulated antitumor T-cell responses to spontaneously engulfed cancer antigens, including a neoepitope. We show in various mouse cancer models that i.t. delivery of TriMix mRNA results in systemic therapeutic antitumor immunity. Finally, we show that the induction of antitumor responses critically depends on TiDCs, whereas it only partially depends on TDLNs. As such, we provide a platform and a mechanistic rationale for the clinical testing of i.t. administration of TriMix mRNA. Cancer Immunol Res; 4(2); 146–56. ©2015 AACR.

Symptomatic Histologically Proven Necrosis of Brain following Stereotactic Radiation and Ipilimumab in Six Lesions in Four Melanoma Patients

Four cases previously treated with ipilimumab with a total of six histologically confirmed symptomatic lesions of RNB without any sign of active tumour following stereotactic irradiation of MBM are reported. These lesions were all originally thought to be disease recurrence. In two cases, ipilimumab was given prior to SRT; in the other two ipilimumab was given after SRT. The average time from first ipilimumab to RNB was 15 months. The average time from SRT to RNB was 11 months. The average time from first diagnosis of MBM to last follow-up was 20 months at which time three patients were still alive, one with no evidence of disease. These cases represent approximately three percent of the total cases of melanoma and ten percent of those cases treated with ipilimumab irradiated in our respective centres collectively. We report this to highlight this new problem so that others may have a high index of suspicion, allowing, if clinically warranted, aggressive surgical salvage, possibly resulting in increased survival. Further studies prospectively collecting data to understand the denominator of this problem are needed to determine whether this problem is just the result of longer survival or whether there is some synergy between these two modalities that are increasingly being used together.

Patterns of Response in Patients with Pretreated Metastatic Melanoma who Received Ipilimumab 3 mg/kg in a European Expanded Access Program: Five Illustrative Case Reports

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.

Early-Onset Creutzfeldt-Jakob Disease Mimicking Immune-Mediated Encephalitis

Objectives The objective of this study is to explore the clinical, radiological, and pathological manifestations of a rare subtype of prion disease and their implication for differential diagnosis in case of an early onset neuropsychiatric deterioration. Methods We discuss a patients’ clinical history, as well as the string of investigations and symptomatological evolution that finally led to a pathological diagnosis. Results Our patient had the extremely rare VV1 type sporadic Creutzfeldt-Jakob disease (sCJD). We explain the differential diagnosis of progressive encephalomyelitis with rigidity and myoclonus and its implications for treatment. Conclusion sCJD, especially the VV1 subtype, can present at an early age with an insidious psychiatric onset. Classical findings of prion disease—14-3-3 protein, PSWC on electroencephalography, and magnetic resonance imaging patterns—are not always present. The presence of neural autoantibodies does not always implicate pathogenicity in the presence of other neurological/neurodegenerative conditions.

Focal radiation necrosis of the brain in patients with melanoma brain metastases treated with pembrolizumab

Up to 60% of patients with metastatic melanoma develop melanoma brain metastasis (MBM) during the course of their disease. Surgery, radiosurgery (SRS), stereotactic radiotherapy (SRT), and whole‐brain radiation therapy (WBRT) or combinations of these are commonly used local treatment modalities. Inhibitory monoclonal antibodies against the CTLA‐4 and PD‐1 immune checkpoint receptors significantly improved the survival of metastatic melanoma patients, including patients with MBM. This prolonged survival, and potentially also the immunostimulatory mechanisms, may expose patients to a higher risk for long‐term complications such as focal postradiation necrosis of the brain (RNB).

Meningoencephaloradiculitis following infection with tick borne encephalitis virus: case report and review of the literature

Tick borne encephalitis (TBE) is an infectious zoonotic disease caused by an RNA virus that is endemic to Central and Eastern Europe, Russia, and large parts of Asia. The tick borne encephalitis virus (TBEV) is transmitted through the saliva of infected ticks and infected goat milk. In the vast majority of cases, an infection with TBEV has a subclinical course. However, in some cases, it leads to neurological symptoms due to meningitis, meningoencephalitis, meningoencephalomyelitis, or meningoencephaloradiculitis. Here, we present the first case of meningoencephaloradiculitis in Belgium.