Julie Charles

Nivolumab in Previously Untreated Melanoma without BRAF Mutation

BACKGROUNDnNivolumab was associated with higher rates of objective response than chemotherapy in a phase 3 study involving patients with ipilimumab-refractory metastatic melanoma. The use of nivolumab in previously untreated patients with advanced melanoma has not been tested in a phase 3 controlled study.nnnMETHODSnWe randomly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks and dacarbazine-matched placebo every 3 weeks) or dacarbazine (at a dose of 1000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks). The primary end point was overall survival.nnnRESULTSnAt 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P<0.001). The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P<0.001). The objective response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P<0.001). The survival benefit with nivolumab versus dacarbazine was observed across prespecified subgroups, including subgroups defined by status regarding the programmed death ligand 1 (PD-L1). Common adverse events associated with nivolumab included fatigue, pruritus, and nausea. Drug-related adverse events of grade 3 or 4 occurred in 11.7% of the patients treated with nivolumab and 17.6% of those treated with dacarbazine.nnnCONCLUSIONSnNivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation. (Funded by Bristol-Myers Squibb; CheckMate 066 ClinicalTrials.gov number, NCT01721772.).

Characterization of Circulating Dendritic Cells in Melanoma: Role of CCR6 in Plasmacytoid Dendritic Cell Recruitment to the Tumor

Dendritic cells (DCs) are central cells in the development of antitumor immune responses, but the number and function of these cells can be altered in various cancers. Whether these cells are affected during the development of melanoma is not known. We investigated the presence, phenotype, and functionality of circulating myeloid DCs (MDCs) and plasmacytoid DCs (PDCs) in newly diagnosed melanoma patients, compared to controls. The frequencies of PDCs and MDCs were equivalent in melanoma patients as compared with normal subjects. Both circulating DC subsets were immature, but on ex vivo stimulation with R848 they efficiently upregulated their expression of costimulatory molecules. We found that circulating DCs from melanoma patients and controls displayed similar pattern of expression of the chemokine receptors CXCR3, CXCR4, CCR7, and CCR10. Strikingly, PDCs from melanoma patients expressed higher levels of CCR6 than control PDCs, and were able to migrate toward CCL20. Further data showed that CCR6-expressing PDCs were present in melanoma primary lesions, and that CCL20 was produced in melanoma tumors. These results suggest that PDCs and MDCs are functional in melanoma patients at the time of diagnosis, and that CCL20 may participate to their recruitment from the blood to the tumor.

Efficacy and Safety of Nivolumab Alone or in Combination With Ipilimumab in Patients With Mucosal Melanoma: A Pooled Analysis.

Purpose Mucosal melanoma is an aggressive malignancy with a poor response to conventional therapies. The efficacy and safety of nivolumab (a programmed death-1 checkpoint inhibitor), alone or combined with ipilimumab (a cytotoxic T-lymphocyte antigen-4 checkpoint inhibitor), have not been reported in this rare melanoma subtype. Patients and Methods Data were pooled from 889 patients who received nivolumab monotherapy in clinical studies, including phase III trials; 86 (10%) had mucosal melanoma and 665 (75%) had cutaneous melanoma. Data were also pooled for patients who received nivolumab combined with ipilimumab (n = 35, mucosal melanoma; n = 326, cutaneous melanoma). Results Among patients who received nivolumab monotherapy, median progression-free survival was 3.0 months (95% CI, 2.2 to 5.4 months) and 6.2 months (95% CI, 5.1 to 7.5 months) for mucosal and cutaneous melanoma, with objective response rates of 23.3% (95% CI, 14.8% to 33.6%) and 40.9% (95% CI, 37.1% to 44.7%), respectively. Median progression-free survival in patients treated with nivolumab combined with ipilimumab was 5.9 months (95% CI, 2.8 months to not reached) and 11.7 months (95% CI, 8.9 to 16.7 months) for mucosal and cutaneous melanoma, with objective response rates of 37.1% (95% CI, 21.5% to 55.1%) and 60.4% (95% CI, 54.9% to 65.8%), respectively. For mucosal and cutaneous melanoma, respectively, the incidence of grade 3 or 4 treatment-related adverse events was 8.1% and 12.5% for nivolumab monotherapy and 40.0% and 54.9% for combination therapy. Conclusion To our knowledge, this is the largest analysis of data for anti-programmed death-1 therapy in mucosal melanoma to date. Nivolumab combined with ipilimumab seemed to have greater efficacy than either agent alone, and although the activity was lower in mucosal melanoma, the safety profile was similar between subtypes.

A Novel Cancer Vaccine Strategy Based on HLA-A*0201 Matched Allogeneic Plasmacytoid Dendritic Cells

Background The development of effective cancer vaccines still remains a challenge. Despite the crucial role of plasmacytoid dendritic cells (pDCs) in anti-tumor responses, their therapeutic potential has not yet been worked out. We explored the relevance of HLA-A*0201 matched allogeneic pDCs as vectors for immunotherapy. Methods and Findings Stimulation of PBMC from HLA-A*0201+ donors by HLA-A*0201 matched allogeneic pDCs pulsed with tumor-derived peptides triggered high levels of antigen-specific and functional cytotoxic T cell responses (up to 98% tetramer+ CD8 T cells). The pDC vaccine demonstrated strong anti-tumor therapeutic in vivo efficacy as shown by the inhibition of tumor growth in a humanized mouse model. It also elicited highly functional tumor-specific T cells ex-vivo from PBMC and TIL of stage I-IV melanoma patients. Responses against MelA, GP100, tyrosinase and MAGE-3 antigens reached tetramer levels up to 62%, 24%, 85% and 4.3% respectively. pDC vaccine-primed T cells specifically killed patients own autologous melanoma tumor cells. This semi-allogeneic pDC vaccine was more effective than conventional myeloid DC-based vaccines. Furthermore, the pDC vaccine design endows it with a strong potential for clinical application in cancer treatment. Conclusions These findings highlight HLA-A*0201 matched allogeneic pDCs as potent inducers of tumor immunity and provide a promising immunotherapeutic strategy to fight cancer.

Nivolumab improved survival vs dacarbazine in patients with untreated advanced melanoma

The hazard ratio (HR) for death was 0.42 (99.79% CI 0.25–0.73; P < 0.0001) in favor of nivolumab, with 1year OS rate 73% (95% CI, 66%–79%) for nivolumab vs 42% (95% CI, 33%–51%) for dacarbazine. Median OS was not reached for nivolumab and was 10.8 months for dacarbazine. Median progression-free survival (PFS) was 5.1 months for nivolumab and 2.2 months for dacarbazine (HR for death or progression 0.43, 95% CI 0.34–0.56; P < 0.0001). Objective response rate was 40% (84/210) vs 14% (29/208) for nivolumab and dacarbazine, respectively (P < 0.0001). Median duration of response was not reached for nivolumab and 6 months for dacarbazine. At the time of data cutoff, responses were ongoing in 86% (72/84) of nivolumab and 52% (15/29) of dacarbazine responders. PD-L1 positivity (using a 5% tumor cell surface staining cutoff) appeared to be associated with improved OS in the nivolumab arm (85% of PD-L1+ and 71% of PD-L1-/ indeterminate patients alive at the time of last followup). Both PD-L1+ and PD-L1-/indeterminate patients receiving nivolumab had improved OS vs dacarbazine (un-stratified HR 0.30, 95% CI, 0.15–0.60 in PD-L1+ patients; 0.48, 95% CI, 0.32–0.71 in PD-L1-/indeterminate patient, both in favor of the nivolumab arm). The most common nivolumab-related adverse events (AEs) were fatigue, pruritus, and nausea. Drug-related grade 3–4 AEs were reported in 12% vs 18% of patients receiving nivolumab vs dacarbazine, respectively. AEs led to discontinuation in 7% and 12% of dacarbazinevs nivolumab-treatment patients, respectively. Conclusions Compared to dacarbazine, nivolumab significantly improved OS and PFS in previously untreated patients with BRAF wild-type metastatic melanoma with an acceptable safety profile.

Plasmacytoid Dendritic Cells Support Melanoma Progression by Promoting Th2 and Regulatory Immunity through OX40L and ICOSL

Combining the analyses of samples from melanoma patients and from melanoma-bearing humanized mice, the authors delineated the mechanism by which plasmacytoid dendritic cells mediate tumor progression and early relapse and identified potential therapeutic options for patients with metastatic melanoma. Even though melanoma is considered to be one of the most immunogenic solid tumors, handling its development remains a challenge. The basis for such escape from antitumor immune control has not yet been documented. Plasmacytoid dendritic cells (pDC) are emerging as crucial but still enigmatic cells in cancer. In melanoma, the function of tumor-infiltrating pDCs remains poorly explored. We investigated the pathophysiologic role of pDCs in melanoma, both ex vivo from a large cohort of melanoma patients and in vivo in melanoma-bearing humanized mice. pDCs were found in high proportions in cutaneous melanoma and tumor-draining lymph nodes, yet associated with poor clinical outcome. We showed that pDCs migrating to the tumor microenvironment displayed particular features, subsequently promoting proinflammatory Th2 and regulatory immune profiles through OX40L and ICOSL expression. Elevated frequencies of interleukin (IL)-5-, IL-13- and IL-10–producing T cells in patients with melanoma correlated with high proportions of OX40L- and ICOSL-expressing pDCs. Strikingly TARC/CCL17, MDC/CCL22, and MMP-2 found in the melanoma microenvironment were associated with pDC accumulation, OX40L and ICOSL modulation, and/or early relapse. Thus, melanoma actively exploits pDC plasticity to promote its progression. By identifying novel insights into the mechanism of hijacking of immunity by melanoma, our study exposes potential for new therapeutic opportunities. Cancer Immunol Res; 1(6); 402–15. ©2013 AACR.

Haploinsufficiency for NR3C1 , the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive leukemia for which knowledge on disease mechanisms and effective therapies are currently lacking. Only a handful of recurring genetic mutations have been identified and none is specific to BPDCN. In this study, through molecular cloning in an index case that presented a balanced t(3;5)(q21;q31) and molecular cytogenetic analyses in a further 46 cases, we identify monoallelic deletion of NR3C1 (5q31), encoding the glucocorticoid receptor (GCR), in 13 of 47 (28%) BPDCN patients. Targeted deep sequencing in 36 BPDCN cases, including 10 with NR3C1 deletion, did not reveal NR3C1 point mutations or indels. Haploinsufficiency for NR3C1 defined a subset of BPDCN with lowered GCR expression and extremely poor overall survival (P = .0006). Consistent with a role for GCR in tumor suppression, functional analyses coupled with gene expression profiling identified corticoresistance and loss-of-EZH2 function as major downstream consequences of NR3C1 deletion in BPDCN. Subsequently, more detailed analyses of the t(3;5)(q21;q31) revealed fusion of NR3C1 to a long noncoding RNA (lncRNA) gene (lincRNA-3q) that encodes a novel, nuclear, noncoding RNA involved in the regulation of leukemia stem cell programs and G1/S transition, via E2F. Overexpression of lincRNA-3q was a consistent feature of malignant cells and could be abrogated by bromodomain and extraterminal domain (BET) protein inhibition. Taken together, this work points to NR3C1 as a haploinsufficient tumor suppressor in a subset of BPDCN and identifies BET inhibition, acting at least partially via lncRNA blockade, as a novel treatment option in BPDCN.

An "anaplastic" Kaposi's sarcoma mimicking a Stewart-Treves syndrome. A case report and a review of literature.

Cutaneous angiosarcoma (AGS) developing in a lymphedematous arm, after lymphadenectomy in the context of breast cancer, is the definition of the classical Stewart-Treves syndrome. Like AGS, many tumors such as Kaposis sarcoma (KS) could develop in chronic lymphedema. We describe the case of a 50-year-old woman who presented with several nodules on the left lymphedematous arm evocative of a Stewart-Treves syndrome, 2 years after a left mastectomy and a homolateral lymphadenectomy. The histological examination revealed an atypical vascular proliferation suggesting AGS, but endothelial atypical cells nuclei were strongly stained by herpes human virus 8 antibody. The final diagnosis was an “anaplastic” KS mimicking a Stewart-Treves syndrome. The total regression of the lesion was obtained by elastic contention and intradermic liposomal doxorubicin. “Anaplastic” KS is a rare histological form of nodular KS, which mimics a cutaneous AGS but classically expresses herpes human virus 8. It is essential to know about this entity, particularly in a lymphedematous arm, to avoid aggressive treatment such as amputation.

Plasma Circulating Tumor DNA Levels for the Monitoring of Melanoma Patients: Landscape of Available Technologies and Clinical Applications

Melanoma is a cutaneous cancer with an increasing worldwide prevalence and high mortality due to unresectable or metastatic stages. Mutations in BRAF, NRAS, or KIT are present in more than 60% of melanoma cases, but a useful blood-based biomarker for the clinical monitoring of melanoma patients is still lacking. Thus, the analysis of circulating tumor cells (CTCs) and/or cell-free circulating tumor DNA (ctDNA) analysis from blood (liquid biopsies) appears to be a promising noninvasive, repeatable, and systemic sampling tool for detecting and monitoring melanoma. Here, we review the molecular biology-based strategies used for ctDNA quantification in melanoma patients, as well as their main clinical applications. Droplet digital PCR (ddPCR) and next generation sequencing (NGS) technologies appear to be two versatile and complementary strategies to study rare variant mutations for the detection and monitoring of melanoma progression. Among the different clinical uses of ctDNA, we highlight the assessment of molecular heterogeneity and the identification of genetic determinants for targeted therapy as well as the analysis of acquired resistance. Importantly, ctDNA quantification might also be a novel biomarker with a prognostic value for melanoma patients.

Access to molecular guided therapy for Langerhans cell histiocytosis patients

To the Editor: The patient described in our case report presented with intolerable skin discomfort related to a BRAF V600E positive, multi-refractory Langerhans cell histiocytosis (LCH), resulting in suicidal ideation. In our institution, the patient was eligible for an off-label vemurafenib treatment after multidisciplinary consultation and signed informed consent. At that time, no French trials were ongoing or available for BRAF V600E LCH. A rapid clinical response allowed us to quickly lower treatment to a quarter of the initial dose. Currently, the patient remains under treatment with minimal adverse events and has been in complete remission for 18 months. Haroche and colleagues raised an important question in their comments: Should clinicians prescribe targeted therapies for histiocytic disorders in the absence of life-threatening complications? In their experience, 1 of 8 patients treated with vemurafenib for Erdheim-Chester disease developed a cutaneous squamous cell carcinoma. This is 1 of the most frequent adverse events of anti-RAF treatments. These are skin tumors that are less aggressive and easily resectable even when infiltrating. To our knowledge, no cases of locally advanced nonresectable or metastatic cutaneous squamous cell carcinomas have ever been reported with vemurafenib. Moreover, Haroche and colleagues mentioned that secondary neoplasms were reported after vemurafenib therapy in a small number of patients with advanced melanomas. However, no citation is provided, and we are not aware of any such cases in the literature. The current reference treatments for LCH include thalidomide, methotrexate, etoposide, vinblastine, or cytarabine, which are all associated with numerous and frequent adverse events, including secondary tumors. To date, these are the only drugs that are routinely administered topatientswith LCH. It isworth noting that these cytotoxic drugs are not exclusively reserved for patients with life-threatening complications, but are also administered for advanced disease. Molecular profiling has emerged as an appropriate and robust tool to guide the clinician’s choice of treatment in oncology. In LCH diseases, a routine screening for BRAF status would lead to the