Autologous cell immunotherapy (IGV-001) with IGF-1R antisense oligonucleotide in newly diagnosed glioblastoma patients.

Standard-of-care first-line therapy for patients with newly diagnosed glioblastoma (ndGBM) is maximal safe surgical resection, then concurrent radiotherapy and temozolomide, followed by maintenance temozolomide. IGV-001, the first product of the Goldspire™ platform, is a first-in-class autologous immunotherapeutic product that combines personalized whole tumor-derived cells with an antisense oligonucleotide (IMV-001) in implantable biodiffusion chambers, with the intent to induce a tumor-specific immune response in patients with ndGBM. Here, we describe the design and rationale of a randomized, double-blind, phase IIb trial evaluating IGV-001 compared with placebo, both followed by standard-of-care treatment in patients with ndGBM. The primary end point is progression-free survival, and key secondary end points include overall survival and safety.

Glioblastoma (GBM) is a fast-growing brain tumor that happens in about half of all gliomas. Surgery is the first treatment for patients with newly diagnosed GBM, followed by the usual radiation and chemotherapy pills named temozolomide. Temozolomide pills are then given as a long-term treatment. The outcome for the patient with newly diagnosed GBM remains poor. IGV-001 is specially made for each patient. The tumor cells are removed during surgery and mixed in the laboratory with a small DNA, IMV-001. This mix is the IGV-001 therapy that is designed to give antitumor immunity against GBM. IGV-001 is put into small biodiffusion chambers that are irradiated to stop the growth of any tumor cells in the chambers. In the phase IIb study, patients with newly diagnosed GBM are chosen and assigned to either the IGV-001 or the placebo group. A placebo does not contain any active ingredients. The small biodiffusion chambers containing either IGV-001 or placebo are surgically placed into the belly for 48 to 52 h and then removed. Patients then receive the usual radiation and chemotherapy treatment. Patients must be adults aged between 18 and 70 years. Patients also should be able to care for themselves overall, but may be unable to work or have lower ability to function. Patients with tumors on both sides of the brain are not eligible. The main point of this study is to see if IGV-001 helps patients live longer without making the illness worse compared with placebo. Clinical Trial Registration: NCT04485949 (ClinicalTrials.gov).

Targeted immunotherapy for glioblastoma involving whole tumor-derived autologous cells in the upfront setting after craniotomy.

PURPOSE: To date, immunotherapeutic approaches in glioblastoma (GBM) have had limited clinical efficacy as compared to other solid tumors. Here we explore autologous cell treatments that have the potential to circumvent treatment resistance to immunotherapy for GBM. METHODS: We performed literature review and assessed clinical outcomes in phase 1 safety trials as well as phase 2 and 3 autologously-derived vaccines for the treatment of newly-diagnosed GBM. In one recent review of over 3,000 neuro-oncology phase 2 and phase 3 clinical trials, most trials were nonblinded (92%), single group (65%), nonrandomized (51%) and almost half were GBM trials. Only 10% involved a biologic and only 2.2% involved a double-blind randomized trial design. RESULTS: With this comparative literature review we conclude that our autologous cell product is uniquely antigen-inclusive and antigen-agnostic with a promising safety profile as well as unexpected clinical efficacy in our published phase 1b trial. We have since designed a rigorous double-blinded add-on placebo-controlled trial involving our implantable biologic drug device. We conclude that IGV-001 provides a novel immunotherapy platform for historically intransigent ndGBM in this ongoing phase 2b trial (NCT04485949).

Margetuximab Versus Trastuzumab in Patients With Previously Treated HER2-Positive Advanced Breast Cancer (SOPHIA): Final Overall Survival Results From a Randomized Phase 3 Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Final overall survival (OS) in SOPHIA (ClinicalTrials.gov identifier: NCT02492711), a study of margetuximab versus trastuzumab, both with chemotherapy, in patients with previously treated human epidermal growth factor receptor 2-positive advanced breast cancer, is reported with updated safety. Overall, 536 patients in the intention-to-treat population were randomly assigned to margetuximab (15 mg/kg intravenously once every 3 weeks; n = 266) plus chemotherapy or trastuzumab (6 mg/kg intravenously once every 3 weeks after a loading dose of 8 mg/kg; n = 270) plus chemotherapy. Primary end points were progression-free survival, previously reported, and OS. Final OS analysis was triggered by 385 prespecified events. The median OS was 21.6 months (95% CI, 18.89 to 25.07) with margetuximab versus 21.9 months (95% CI, 18.69 to 24.18) with trastuzumab (hazard ratio [HR], 0.95; 95% CI, 0.77 to 1.17; P = .620). Preplanned, exploratory analysis of CD16A genotyping suggested a possible improvement in OS for margetuximab in CD16A-158FF patients versus trastuzumab (median OS, 23.6 v 19.2 months; HR, 0.72; 95% CI, 0.52 to 1.00) and a possible improvement in OS for trastuzumab in CD16A-158VV patients versus margetuximab (median OS, 31.1 v 22.0 months; HR, 1.77; 95% CI, 1.01 to 3.12). Margetuximab safety was comparable with trastuzumab. Final overall OS analysis did not demonstrate margetuximab advantage over trastuzumab. Margetuximab studies in patients with human epidermal growth factor receptor 2-positive breast cancer with different CD16A allelic variants are warranted.

Work productivity burden and indirect costs associated with carcinoid syndrome diarrhea.

Objectives: We estimated the indirect costs of work productivity burden from carcinoid syndrome diarrhea (CSD) among employed, insured adults in the United States. Methods: Retrospective cohort study of patients ≥18 years old with CS who did and did not have CSD (2014-2016). Eligible patients had continuous health plan enrollment for ≥12 months prior to their first CS claim and for ≥30 days after. Univariate analyses of clinical and work productivity outcomes and indirect costs were conducted. Multivariate analyses examined associations of CSD with work productivity measures, controlling for baseline characteristics. Results: A total of 1,880 patients with CS were eligible, including 577 with CSD and 1,303 with CS only. Baseline characteristics were generally similar. Patients with CSD missed half of eligible workdays (median 56%, 146/260); those with CS-only missed one-third (38%, 100/260). Work productivity was lower and the associated costs were higher in the presence of CSD. Patients with CSD had more absenteeism, short-term disability, and lost workdays which translated into incremental mean costs of $16,679 greater than those with CS only. Conclusion: Indirect costs related to work productivity losses among adults with CSD are significant, which further add to the burden of CSD to society.

Direct costs of carcinoid syndrome diarrhea among adults in the United States.

BACKGROUND: The burden of carcinoid syndrome (CS) among patients with neuroendocrine tumors is substantial and has been shown to result in increased healthcare resource use and costs. The incremental burden of CS diarrhea (CSD) is less well understood, particularly among working age adults who make up a large proportion of the population of patients with CS. AIM: To estimate the direct medical costs of CSD to a self-insured employer in the United States. METHODS: CS patients with and without CSD were identified in the IBM® MarketScan® Database, including the Medicare Supplemental Coordination of Benefits database. Eligible patients had ≥ 1 medical claim for CS with continuous health plan enrollment for ≥ 12 mo prior to their first CS diagnosis and for ≥ 30 d after, no claims for acromegaly, and no clinical trial participation during the study period (2014-2016). Baseline demographic and clinical characteristics, including comorbidities and treatment, were analyzed using descriptive statistics. Measures of healthcare resource use and costs were compared between patients with and without CSD, including Emergency Department (ED) visits, hospital admissions and length of stay, physician office visits, outpatient services, and prescription claims, using univariate and multivariate analyses to evaluate associations of CSD with healthcare resource use and costs, controlling for baseline characteristics. RESULTS: Overall, 6855 patients with CS were identified of which 4,043 were eligible for the analysis (1352 with CSD, 2691 with CS only). Baseline demographic and clinical characteristics were similar between groups with the exception of age, underlying tumor type, and health insurance plan. Patients with CSD were older, had more comorbidities, and received more somatostatin analog therapy at baseline. Patients with CSD required greater use of healthcare resources and incurred higher costs than their peers without CSD, including hospitalizations (44% vs 25%) and ED visits (55% vs 31%). The total adjusted annual healthcare costs per patient were 50% higher (+ $23865) among those with CSD, driven by outpatient services (+ 56%), prescriptions (+ 48%), ED visits (+ 26%), physician office visits (+ 21%), and hospital admissions (+ 11%). CONCLUSION: The economic burden of CSD is greater than that of CS alone among insured working age adults in the United States, which may benefit from timely diagnosis and management.

Burden of Carcinoid Heart Disease in Patients With Carcinoid Syndrome Initiating Somatostatin Analogues.

PURPOSE: As a result of overproduction of serotonin, patients with uncontrolled carcinoid syndrome (CS) may develop carcinoid heart disease (CaHD). However, the prevalence and health care resources to manage CaHD are not well understood. This study investigated the prevalence and economic burden of CaHD among adults with CS in the United States. METHODS: This retrospective study analyzed insurance claims of patients with CS initiating somatostatin analogue (SSA) therapy. Eligible patients had ≥1 medical claim for CS with continuous insurance coverage for 1 year before and at least 30 days after initiating SSA therapy. Markers for CaHD were identified using a predetermined list of medical and/or procedural claims based on the clinical experience of a practicing cardiologist. Case subjects had a documented medical/procedural claim for a marker of CaHD during the study period; control subjects had no markers for CaHD. Baseline characteristics were assessed during the pre-SSA treatment initiation period. Economic outcomes (health care resources and expenditures) were assessed in the follow-up period after SSA treatment initiation and compared between incident case subjects and control subjects. Descriptive statistics were used to assess demographic and clinical characteristics. Univariate and multivariate models were used to assess differences in health care resource use and costs between case subjects and control subjects. FINDINGS: A total of 654 patients met the eligibility criteria; 248 (38%) had a prevalent marker of CaHD and were excluded from the economic analysis. The analytic sample included 406 patients with CS, 185 (46%) of whom had an incident CaHD marker (case subjects) and 221 were controls. Baseline characteristics between the case subjects and control subjects were similar with the exception that case subjects tended to be older. Average health care resource use and costs were higher among case subjects (total costs, $51,825 vs $29,068; P < 0.01), driven by average hospital admissions (1.4 vs 0.7) with increased length of stay (4.3 vs 2.0 days), office visits (22.8 vs 19.8), and outpatient services (22.3 vs 15.4; all, P < 0.05). IMPLICATIONS: CaHD may be common among patients with CS before initiating SSA therapy and within 2 years of starting SSA therapy, suggesting suboptimal control of serotonin production. Patients with CaHD incur substantial economic costs in addition to the clinical morbidity compared with patients with CS and no CaHD.

TELEPRO: Patient-Reported Carcinoid Syndrome Symptom Improvement Following Initiation of Telotristat Ethyl in the Real World.

BACKGROUND: When carcinoid syndrome (CS) diarrhea (CSD) is inadequately controlled with long-acting somatostatin analogs (SSAs), clinical practice guidelines recommend addition of the tryptophan hydroxylase inhibitor telotristat ethyl (TE). In a 12-week multinational, randomized controlled trial, TE added to SSA reduced peripheral serotonin and the frequency of CSD. We evaluated real-world effectiveness of TE using patient-reported data from a nurse support program over 3 months. MATERIALS AND METHODS: This study used a deidentified data set of patients initiating TE who opted into a nurse support program between March and November 2017 and reported CS symptom burden at baseline and at least one follow-up time point at months 1, 2, and 3. Patients reported demographic and medical history information as well as frequency of bowel movements (BMs) and flushing episodes, severity of nausea, urgency and abdominal pain (0 "no/not at all" to 100 "worst imaginable/very urgent"), and stool form (1 "very hard" to 10 "watery"). Mean changes from baseline in CS symptom burden were reported using paired-sample t tests and Wilcoxon signed-rank tests. RESULTS: Most patients initiating TE enrolled in the nurse program (791/898, 88%), of whom 369 (47%) were included in the analysis. Patients treated with TE reported significant reductions in CSD and other CS symptoms (all p < .001). At least half of patients treated with TE experienced ≥30% improvement from baseline in BM frequency and an average reduction of at least two BMs per day within 3 months. CONCLUSION: Patients taking SSA therapy showed substantial burden of disease before initiating TE and significant improvements with the addition of TE treatment in this real-world effectiveness study. IMPLICATIONS FOR PRACTICE: Patients with carcinoid syndrome diarrhea uncontrolled by high doses of long-acting somatostatin analogs may be candidates for additional therapy with the tryptophan hydroxylase inhibitor telotristat ethyl. Understanding the real-world prevalence of uncontrolled symptoms and the effectiveness of telotristat ethyl in clinical practice may further support clinical and policy decisions for these patients. This study investigated self-reported carcinoid syndrome symptom burden and improvements among patients initiating telotristat ethyl and participating in a voluntary nurse support program. Disease burden and off-label somatostatin analog treatment before initiating telotristat ethyl were high, and symptoms improved markedly over 1, 2, and 3 months of treatment.

Development of inhibitors of the IGF-IR/PI3K/Akt/mTOR pathway.

Progress has been made towards the development of agents targeting tyrosine kinase receptors and other molecules involved in signalling pathways important for cell proliferation, motility, and apoptosis. Inhibitor molecules designed to be highly specific with the aim of decreasing toxicity have proven to be generally well tolerated. However, the efficacy of targeted agents may be impacted by cross-talk between pathways and downregulation of negative feed-back loops. That is the case of the IGF-IR/PI3K/Akt/mTOR pathway. This issue raises the question of how these targeted agents could be combined to prevent or delay resistance without significantly increasing toxicity. Several mTOR inhibitors have been approved for cancer therapy, and late-stage clinical trials of IGF-IR inhibitors are underway. The outcome of ongoing clinical studies of IGF-IR, PI3K, Akt and mTOR inhibitors as well as further testing of the combination of these agents will be key for the development of therapeutic options in a wide range of oncology indications.

Is a novel I214M substitution in the NEFL gene a cause of Charcot-Marie-Tooth disease? Functional analysis using cell culture models.

Recent studies have shown that mutations in neurofilament light subunit gene (NEFL) cause Charcot-Marie-Tooth (CMT) disease. Since the first description of the Gln333Pro mutation in the NEFL gene, 10 pathogenic mutations in the NEFL gene have been reported in patients affected with CMT disease. We report a novel I214M amino acid substitution in the NEFL gene in two unrelated patients affected with CMT. Because the I214M amino acid substitution in the NEFL protein was not detected in a CMT affected brother of the proband, its pathogenic effect became unclear. In order to determine whether this amino acid substitution is a benign polymorphism or causative of the disease, we performed a functional analysis of the mutant I214M neurofilament protein (NFL). Transfections of the mutant protein in cultured cells revealed an increased tendency to form highly compacted filamentous structures but no other alterations of neurofilament assembly or transport were observed. Furthermore, the sibling of one of the patients was also affected with CMT but did not have the I214M substitution. These data suggest that this I214M substitution in the NEFL gene was not a direct cause of the disease but could be a polymorphism or possibly a modifier of the CMT phenotype.

The role of microtubule actin cross-linking factor 1 (MACF1) in the Wnt signaling pathway.

MACF1 (microtubule actin cross-linking factor 1) is a multidomain protein that can associate with microfilaments and microtubules. We found that MACF1 was highly expressed in neuronal tissues and the foregut of embryonic day 8.5 (E8.5) embryos and the head fold and primitive streak of E7.5 embryos. MACF1(-/-) mice died at the gastrulation stage and displayed developmental retardation at E7.5 with defects in the formation of the primitive streak, node, and mesoderm. This phenotype was similar to Wnt-3(-/-) and LRP5/6 double-knockout embryos. In the absence of Wnt, MACF1 associated with a complex that contained Axin, beta-catenin, GSK3beta, and APC. Upon Wnt stimulation, MACF1 appeared to be involved in the translocation and subsequent binding of the Axin complex to LRP6 at the cell membrane. Reduction of MACF1 with small interfering RNA decreased the amount of beta-catenin in the nucleus, and led to an inhibition of Wnt-induced TCF/beta-catenin-dependent transcriptional activation. Similar results were obtained with a dominant-negative MACF1 construct that contained the Axin-binding region. Reduction of MACF1 in Wnt-1-expressing P19 cells resulted in decreased T (Brachyury) gene expression, a DNA-binding transcription factor that is a direct target of Wnt/beta-catenin signaling and required for mesoderm formation. These results suggest a new role of MACF1 in the Wnt signaling pathway.

Mutations in the neurofilament light gene linked to Charcot-Marie-Tooth disease cause defects in transport.

Neurofilament light gene mutations have been linked to a subset of patients with Charcot-Marie-Tooth disease, the most common inherited motor and sensory neuropathy. We have previously shown that Charcot-Marie-Tooth-linked mutant neurofilament light assembles abnormally in non-neuronal cells. In this study, we have characterized the effects of expression of mutant neurofilament light proteins on axonal transport in a neuronal cell culture model. We demonstrated that the Charcot-Marie-Tooth-linked neurofilament light mutations: (i) affect the axonal transport of mutant neurofilaments; (ii) have a dominant-negative effect on the transport of wild-type neurofilaments; (iii) affect the transport of mitochondria and the anterograde axonal transport marker human amyloid precursor protein; (iv) result in alterations of retrograde axonal transport and (v) cause fragmentation of the Golgi apparatus. Increased neuritic degeneration was observed in neuronal cells overexpressing neurofilament light mutants. Our results suggest that these generalized axonal transport defects could be responsible for the neuropathy in Charcot-Marie-Tooth disease.

The G336S variant in the human neurofilament-M gene does not affect its assembly or distribution: importance of the functional analysis of neurofilament variants.

The human neurofilament medium (hNFM) subunit is one of the 3 neurofilament (NF) polypeptides, which are the most abundant intermediate filament (IF) proteins in post-mitotic neurons. The formation of neurofilamentous aggregates is a pathological hallmark of many neurodegenerative diseases, including the Lewy bodies found in Parkinson disease (PD). A Gly336Ser (G336S) variant in the rod domain of hNFM has recently been described in a patient with early-onset autosomal-dominant PD. In this study, we have generated a mammalian expression vector encoding the variant hNFM cDNA and characterized its effects on the formation of heteropolymeric IFs in heterologous cell lines. We have also investigated the distribution of the (G336S) hNFM variant protein in neuronal CAD cells, as well as the effects of the variant on the distribution of other cellular organelles and proteins. Our results demonstrate that the G336S variant does not affect the formation of IF networks nor the distribution of the variant hNFM protein. Our data suggest that if the G336S variant is involved in the development of PD, it does not appear to be due to defects in the assembly and distribution of NFs.

Phenotypic analysis of neurofilament light gene mutations linked to Charcot-Marie-Tooth disease in cell culture models.

Mutations in the neurofilament light (NFL) gene cause Charcot-Marie-Tooth (CMT) disease. There is a wide range of clinical presentations in CMT patients harboring NFL mutations, with patients classified as CMT2E or CMT1F. In this study, we analyzed the effects of five NFL mutations on the assembly and intracellular distribution of intermediate filaments (IFs), and compared the results with those obtained previously for other NFL mutations. Although all NFL mutants affected the formation of IF networks, our data show differential effects on the assembly of IFs depending on the exact nature of the mutation. Defective transport of the mutant NFL subunits was observed for all the CMT-linked NFL mutations, but the characteristics of this defect also depended on the specific mutation. These results show that defects in the assembly and transport of NFs are common to all NFL mutants studied thus far, but the exact nature of the defect appears to be correlated with each mutant genotype.

Effects of Charcot-Marie-Tooth-linked mutations of the neurofilament light subunit on intermediate filament formation.

Neurofilaments (NFs) are the major intermediate filaments (IFs) of mature neurons. They play important roles in the structure and function of axons. Recently, two mutations in the neurofilament light (NFL) subunit have been identified in families affected by Charcot-Marie-Tooth (CMT) neuropathy type 2. We have characterized the effects of these NFL mutations on the formation of IF networks using a transient transfection system. Both mutations disrupted the self-assembly of human NFL. The Q333P mutant in the rod domain of NFL also disrupted the formation of rat and human NFL/NFM heteropolymers. The phenotypes produced by the P8R mutation in the head domain of NFL were less severe. The P8R mutant NFL co-polymerized with NFM to form bundled filaments and, less often, aggregates. Our results suggest that alterations in the formation of a normal IF network in neurons elicited by these NFL mutations may contribute to the development of Charcot-Marie-Tooth neuropathy.