Jacek Mackiewicz

Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25

Dalil Hannani, Marie Vétizou, David Enot, Sylvie Rusakiewicz, Nathalie Chaput, David Klatzmann, Melanie Desbois, Nicolas Jacquelot, Nadège Vimond, Salem Chouaib, Christine Mateus, James P Allison, Antoni Ribas, Jedd D Wolchok, Jianda Yuan, Philip Wong, Michael Postow, Andrzej Mackiewicz, Jacek Mackiewicz, Dirk Schadendorff, Dirk Jaeger, Alan J Korman, Keith Bahjat, Michele Maio, Luana Calabro, Michele WL Teng, Mark J Smyth, Alexander Eggermont, Caroline Robert, Guido Kroemer, Laurence Zitvogel

Design of clinical trials for therapeutic cancer vaccines development

Advances in molecular and cellular biology as well as biotechnology led to definition of a group of drugs referred to as medicinal products of advanced technologies. It includes gene therapy products, somatic cell therapeutics and tissue engineering. Therapeutic cancer vaccines including whole cell tumor cells vaccines or gene modified whole cells belong to somatic therapeutics and/or gene therapy products category. The drug development is a multistep complex process. It comprises of two phases: preclinical and clinical. Guidelines on preclinical testing of cell based immunotherapy medicinal products have been defined by regulatory agencies and are available. However, clinical testing of therapeutic cancer vaccines is still under debate. It presents a serious problem since recently clinical efficacy of the number of cancer vaccines has been demonstrated that focused a lot of public attention. In general clinical testing in the current form is very expensive, time consuming and poorly designed what may lead to overlooking of products clinically beneficial for patients. Accordingly regulatory authorities and researches including Cancer Vaccine Clinical Trial Working Group proposed three regulatory solutions to facilitate clinical development of cancer vaccines: cost-recovery program, conditional marketing authorization, and a new development paradigm. Paradigm includes a model in which cancer vaccines are investigated in two types of clinical trials: proof-of-principle and efficacy. The proof-of-principle trial objectives are: safety; dose selection and schedule of vaccination; and demonstration of proof-of-principle. Efficacy trials are randomized clinical trials with objectives of demonstrating clinical benefit either directly or through a surrogate. The clinical end points are still under debate.

Long-term survival of high-risk melanoma patients immunized with a Hyper-IL-6-modified allogeneic whole-cell vaccine after complete resection

Objective: Two single arm, Phase II trials (3 and 5) were undertaken to determine the efficacy and toxicity of an adjuvant treatment using Hyper-IL-6 gene-modified whole-cell allogeneic melanoma vaccine in patients with stage IIIB–IV resected disease. Research design and methods: Ninety-seven and 99 patients were enrolled into Trials 3 and 5, respectively. The primary endpoint was disease-free survival (DFS), and the secondary was overall survival (OS). Vaccine was administered eight times every 2 weeks (induction), every month (maintenance) until patients death. At progression, maintenance was continued or induction was repeated followed by maintenance. Results: Median follow-up was 10.5 and 6.2 years for Trials 3 and 5, respectively. No grade 3 or 4 toxicities were observed. An extension of DFS and OS was observed, when compared with historical non-treated controls. DFS probability at 5 years for Trials 3 and 5 was, respectively, 54.8% and 40.6% for stage IIIB, 25.0% and 24.0% for IIIC, and 8.5% and 17.7% for IV. OS probability at 5 years was, respectively, 66.7% and 56.3% for IIIB, 43.8% and 39.8% for IIIC, and 26.1% and 41.2% for IV. Conclusions: Continuous vaccination, regardless of the disease progression, re-induction, and immunization of patients until death resulted in patients a long-term survival.

Efficacy and safety of ipilimumab therapy in patients with metastatic melanoma: a retrospective multicenter analysis

Aim of the study The Patient Assistance Program, a type of expanded access program, was initiated for compassionate purposes to provide ipilimumab to patients with unresectable stage III or IV melanoma with failed previous treatment. The aim of this analysis is to evaluate efficacy, safety, and tolerability of ipilimumab therapy in daily clinical practice. Material and methods We analyzed 50 patients (29 males, 21 females) aged 21 to 76 years (median: 49 years). An ipilimumab dose of 3 mg/kg was administered intravenously every 3 weeks for a total of 4 doses. Patients were assessed for response rate, progression-free survival and overall survival, and monitored for adverse events. Results The objective response (complete or partial response) rate was 12%. Median overall survival was 8 months and median progression-free survival was 3 months. In patients with ECOG-PS 0, the median overall survival was 16 months. Immune-related adverse events (irAEs) occurred in 48% of the patients, grade 3 or 4 irAEs were reported in 8% of the patients, and there were no toxic deaths. Conclusions Ipilimumab demonstrated clinical benefit in previously treated advanced melanoma patients. Although clinical benefit is limited to a minority of the patients, there is a benefit in terms of overall survival in this group of patients.

What is new in the treatment of advanced melanoma? State of the art.

The incidence of melanoma is increasing steadily both in Poland and worldwide. Until 2010 three drugs were approved for the treatment of metastatic melanoma – dacarbazine (DTIC) in Europe and USA, fotemustine in Europe and interleukin-2 (IL-2) in USA. Approval of ipilimumab and vemurafenib in Europe and USA has changed the standard of care, while the next candidates such as dabrafenib and trametinib have improved survival in phase III studies in metastatic melanoma patients. An encouraging treatment strategy is the combination of dabrafenib and trametinib, evaluated in a phase I/II study with an ongoing phase III trial. Another promising new immune modulating monoclonal antibody (mAb) is anti-PD1 (BMS-936558), tested in an early phase trial in monotherapy or in combination with a multipeptide vaccine in metastatic melanoma patients. Ipilimumab or BRAF inhibitors (vemurafenib, dabrafenib) seem to be active in patients with brain metastases. Intensive research of melanoma vaccines is currently being carried out in a number of countries worldwide. However, no vaccine in the treatment of melanoma has been approved by regulatory authorities so far. Lack of effective therapy in patients with high-risk resected melanoma led to a number of clinical studies of adjuvant treatment. Interferon-α (INF-α) therapy in this setting is still controversial. A dendritic cell-based vaccine in a randomized phase II trial showed a survival benefit over the control group in patients with high-risk resected melanoma. Promising results of long-term survival of advanced resected melanoma patients in a phase II study evaluating the genetically modified tumour vaccine (GMTV) AGI-101 were reported. This review provides an update on clinical strategies used or tested in patients with metastatic melanoma.

Resistance to vemurafenib can be reversible after treatment interruption: a case report of a metastatic melanoma patient.

AbstractAbout 40% to 60% of melanomas present BRAF mutation. Selective BRAF inhibitors such as vemurafenib and dabrafenib are currently approved for the treatment of advanced melanoma patients with BRAF mutation. The treatment-induced tumor regression occurs in the majority of patients; however, acquired resistance to BRAF inhibitors is observed in most of the patients after 6 to 7 months. After progression of the disease, the patient might be offered treatment with ipilimumab followed by chemotherapy. Subsequent lines of systemic treatment of metastatic melanoma patients do not exist.Here we report a case of a 59-year-old woman with a diagnosis of BRAF-mutant metastatic melanoma that responded to initial treatment with vemurafenib. Subsequently, after disease progression, the patient received chemotherapy. Since no clinical response to dacarbazine was observed, carboplatin with paclitaxel were applied. Transient partial response was obtained, which was followed by further disease progression. Then retreatment with vemurafenib was applied. The patient developed very short-term tumor regression and significant biochemical response (serum lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase) to the treatment. However, following 5 weeks of retreatment, the patient developed progression of the disease. Our clinical observation indicates that in melanoma patients who developed resistance to selective BRAF inhibitors, rechallenge after treatment interruption might be beneficial.

Febrile Neutropenia in a Metastatic Melanoma Patient Treated with Ipilimumab - Case Report

Background: Ipilimumab is a fully human monoclonal antibody (mAb) targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab is currently approved in the U.S. and Europe for the treatment of metastatic melanoma in the first- and second-line treatment. Treatment with ipilimumab is linked to immune-related adverse events (irAEs) occurring in the majority of patients. These specific AEs include dermatitis, gastrointestinal disorders (diarrhea, colitis), hepatitis, hypophysitis, hypothyroidism, neuropathy, and iritis/inflammation of the ciliary body. Case Report: We report a case of febrile neutropenia with agranulocytosis in the blood smear of a 35-year-old metastatic melanoma patient treated with ipilimumab 3 mg/kg. Conclusion: This AE was probably caused by antineutrophil antibodies associated with ipilimumab treatment. To our knowledge this is the first case report of febrile neutropenia in a metastatic melanoma patient treated with ipilimumab 3 mg/kg.

Recent advances in melanoma treatment – American Society of Clinical Oncology (ASCO) 2012 perspective

The 2012 ASCO (American Society of Clinical Oncology) annual meeting has been held once again at the McCormick Conference Center in Chicago, Illinois, where ASCO has booked a 10-year run for the meeting. The meeting was attended by more than 30,000 oncology professionals from around the world. Of more than 4500 abstracts published at the meeting, 310 were related to melanoma. Here we report the results of the most interesting clinical trials presented at the meeting. Apart from updated overall survival (OS) results of a phase 3 study evaluating the efficacy of vemurafenib and some new data on ipilimumab (expanded access program [EAP] and treatment of patients with brain metastases) we report on practice changing trials: a phase 3 (BREAK) trial evaluating efficacy of dabrafenib and a phase 3 study (METRIC) assessing trametinib in the treatment of metastatic melanoma patients. Another encouraging treatment strategy is combination of dabrafenib and trametinib evaluated in a phase I/II study. Results of new immune checkpoint targeting by monoclonal antibody anti-PD1 (BMS-936558) in an early phase trial in monotherapy or in combination with a multipeptide vaccine in metastatic melanoma patients are presented. Also, results of dendritic cell-based vaccine (randomized phase II trial) immunization in patients with high risk resected melanoma are shown. Furthermore, results of other melanoma immunotherapy strategies evaluated in early phase studies are reported.

Programmed cell death 1 checkpoint inhibitors in the treatment of patients with advanced melanoma

The treatment landscape of advanced melanoma has changed significantly following the discovery and marketing authorisation of immune checkpoints inhibitors. Ipilimumab (anti-CTLA-4) was the first one to be approved, and it. demonstrated long-term survival in about 20% of patients. Subsequently, anti-programmed cell death-1 (a-PD-1) antibodies (pembrolizuamb, nivolumab), inhibitors of PD-1/programmed cell death-1 ligand (PD1-L) synapse, showed higher clinical efficacy with lower toxicity comparing to ipilimumab. The highest clinical benefit in patients was observed when nivolumab and ipiliumumab were combined. However, the above strategy, due to very high toxicity, has limitations for use in all patients with advanced melanoma. Notwithstanding, patients treated with anti-PD1 beyond disease progression benefit from treatment continuation; further studies are warranted in this indication. Furthermore, patients responding to treatment with anti-PD1 will benefit from the therapy after its discontinuation. Immune checkpoint inhibitors are clinically effective regardless of BRAF mutation. Currently there is no recommendation regarding which treatment option should be selected for the treatment of the population – immunotherapy or targeted therapy with BRAF and MEK inhibitors. Randomised trials are ongoing comparing these two treatment strategies in patients with BRAF mutation. Encouraging results were observed in early phase trials in patients receiving the combination of immune and targeted therapy. Phase 3 studies are underway. Patients with elevated serum lactate dehydrogenase present poor prognosis regardless of the systemic treatment used. novel treatment strategies should probably be developed for these patients.

lncRNA in HNSCC: challenges and potential

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cause of cancer mortality in the world. Some progress has been made in the therapy of HNSCC, however treatment remains unsatisfactory. Recent studies have shown that different types of long non-coding RNAs (lncRNAs) are dysregulated in HNSCC and correlate with tumor progression, lymph node metastasis, clinical stage and poor prognosis. lncRNAs are a class of functional RNA molecules that can not be translated into proteins but can modulate the activity of transcription factors or regulate changes in chromatin structure. The lncRNAs might have potential of biomarker in HNSCC diagnosis, prognosis, prediction and targeted treatment. In this review we describe the potential role of lncRNAs as new biomarkers and discuss their features including source of origin, extraction methods, stability, detection methods and data normalization and potential function as biomarkers in HNSCC.