lactoferrin and Carcinoma--Non-Small-Cell-Lung

Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small-cell lung cancer (NSCLC) accounting for approximately 85% of all cases. Most patients with NSCLC are diagnosed at an advanced stage and have a poor prognosis, with a 5-year survival rate of <5%. Despite the introduction of new chemotherapeutic agents and molecularly targeted drugs, outcomes remain poor, emphasising the need for new treatment approaches. Inducing or potentiating immune responses via immunotherapeutic manipulation is a viable treatment approach for lung cancer. Antigen-specific, tumour-cell, and dendritic cell-based vaccines have all been evaluated in lung cancer, and some have shown promising clinical activity in phase II trials. These include liposomal BLP25 vaccine (L-BLP25), which targets mucin 1, and melanoma-associated antigen 3 (MAGE-A3) antigen-specific cancer immunotherapeutic (ASCI), which targets MAGE-A3, a peptide expressed almost exclusively on tumour cells. MAGE-A3 ASCI is being evaluated in the adjuvant setting in a phase III trial of patients with early-stage NSCLC, while a phase III trial of L-BLP25 is enrolling patients with unresectable stage III NSCLC. T-cell modulating agents (e.g. antibodies against programmed death 1 and cytotoxic T-lymphocyte-associated antigen-4 [CTLA-4]) are also being investigated. For example, in patients with NSCLC treated with paclitaxel and carboplatin, the phased administration of ipilimumab (an antibody against CTLA-4) resulted in substantial improvements in immune-related progression-free survival compared with chemotherapy alone (5.7 versus 4.6 months; P = 0.05). Immunotherapy in lung cancer is starting to deliver promising results in clinical trials. However, further research will be required to establish the optimal timing of therapy (i.e. in the adjuvant or metastatic settings). In addition, it will be important to determine if immunotherapies are most effective when used alone or in combination with other agents.

Topics: Antibodies, Monoclonal; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Carboplatin; Carcinoma, Non-Small-Cell Lung; CTLA-4 Antigen; Disease-Free Survival; Humans; Immunotherapy; Ipilimumab; Lactoferrin; Lung Neoplasms; Membrane Glycoproteins; Neoplasm Proteins; Nivolumab; Paclitaxel

Immunotherapeutic approaches to treating NSCLC via either adoptive transfer of immunity or stimulation of the endogenous immune system have shown increasing promise in recent years.. Talactoferrin alpha is an oral immunomodulatory agent currently in late-stage clinical trials that acts through dendritic cell recruitment and activation in the gut-associated lymphoid tissue.. Talactoferrin is a recombinant human lactoferrin that is a member of the transferrin family of iron-binding glycoproteins. Lactoferrins have multiple known biological activities including cancer protection, cellular growth and differentiation and antimicrobial and anti-inflammatory properties. This review discusses the proposed mechanism of action of talactoferrin-alpha and outlines the pre-clinical, Phase I and II data in NSCLC. The ongoing Phase III trials are discussed.. The current role of Talactoferrin alpha in the treatment of NSCLC is described and we explore potential future roles for this drug in both early stage and advanced stage disease.

Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Evaluation, Preclinical; Evidence-Based Medicine; Humans; Lactoferrin; Lung Neoplasms; Treatment Outcome

It has been quite challenging to demonstrate significant improvements in survival for patients with non-small-cell lung cancer (NSCLC) over the past decade, but targeted therapies such as epidermal growth factor receptor (EGFR) inhibitors and angiogenesis inhibitors have been associated with benefits sufficient to alter our treatment standards. In addition to variations within these classes and combinations of such agents, several novel targeted therapy strategies have been introduced and are now emerging with encouraging results in early clinical trials for patients with advanced NSCLC. Immunotherapies targeting the MUC1 protein, MAGE-A3, and EGFR have shown early evidence of clinical benefits. Belagenpumatucel-L is a nonspecific allogeneic vaccine derived from multiple lung cancer cell lines, and the agent talactoferrin alfa might improve clinical outcomes based on broad immune system activation and stimulation. Other approaches that inhibit insulin-like growth factor receptor or heat-shock protein, both involved with multiple pathways involved with cell growth and survival, have shown activity in early trials and are moving forward in trials that specifically focus on patients with advanced NSCLC. This article reviews current data and future directions for each of these approaches.

Topics: Antigens, Neoplasm; Cancer Vaccines; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Heat-Shock Proteins; Humans; Immunotherapy; Lactoferrin; Lung Neoplasms; Membrane Glycoproteins; Mucin-1; Neoplasm Proteins; Receptor, IGF Type 1; Recombinant Proteins

Talactoferrin alfa is an oral dendritic cell (DC)-mediated immunotherapy (DCMI). We tested whether talactoferrin was superior to placebo in advanced non-small-cell lung cancer (NSCLC).. An FORTIS-M trial was an international, multicenter, randomized, double-blind comparison of talactoferrin (1.5 g p.o. BID) versus placebo BID, in patients with stage IIIB/IV NSCLC whose disease had failed two or more prior regimens. Treatment was administered for a maximum of five 14-week cycles. The primary efficacy end point was overall survival (OS); secondary end points included 6- and 12-month survival, progression-free survival (PFS), and disease control rate (DCR).. Seven hundred and forty-two patients were randomly assigned (2:1) to talactoferrin (497) or placebo (245). The median OS in the intent-to-treat (ITT) population was 7.66 months in the placebo arm and 7.49 months in the talactoferrin arm [hazard ratio (HR), 1.04; 95% CI, 0.873-1.24; P = 0.6602]. The 6-month survival rates were 59.9% (95% CI, 53.4% to 65.8%) and 55.7% (95% CI, 51.1% to 59.9%), respectively. The 12-month survival rates were 32.2% (95% CI, 26.3% to 38.2%) and 30.9% (95% CI, 26.8% to 35%), respectively. The median PFS rates were 1.64 months and 1.68 months, respectively (HR, 0.99; 95% CI, 0.835-1.16; P = 0.8073). The DCRs were 38.4 and 37.6%, respectively [stratified odds ratio (OR), 0.96; 95% CI, 0.698-1.33; P = 0.8336]. The safety profiles were comparable between arms.. There was no improvement in efficacy with talactoferrin alfa in patients with advanced NSCLC whose disease had failed two or more previous regimens.

Topics: Aged; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Double-Blind Method; Drug Administration Schedule; Female; Humans; Immunotherapy; Kaplan-Meier Estimate; Lactoferrin; Male; Middle Aged; Neoplasm Staging; Placebos; Treatment Outcome

The aim of the study is to investigate the activity and safety of oral talactoferrin (TLF) plus carboplatin and paclitaxel (C/P) in patients with previously untreated stage IIIB/IV non-small cell lung cancer.. Patients (n = 110) were randomly assigned to receive C/P plus either TLF (C/P/T) or placebo (C/P/P). The primary objective of this exploratory study was assessment of confirmed response rate (RR) in the prospectively defined evaluable population with a one-tailed p = 0.05. Secondary objectives included assessment of progression-free survival (PFS), duration of response, overall survival (OS), and safety.. The trial met the primary end point of improvement in confirmed RR in the prospectively defined evaluable population. Compared with the C/P/P group, RR increased in the C/P/T group by 18% (29-47%; p = 0.05) and 15% (27-42%; p = 0.08) in the evaluable and intent-to-treat populations, respectively. Compared with the C/P/P group, the C/P/T group had a longer median PFS (4.2 versus 7.0 months), OS (8.5 versus 10.4 months), and duration of response (5.5 versus 7.6 months), although the differences were not statistically significant. Adverse events (AEs) were consistent with C/P therapy. There were fewer total AEs (472 versus 569; two-tailed p = 0.003) and grade 3/4 AEs (78 versus 105; p = 0.05) in the C/P/T group compared with the C/P/P group.. TLF, in combination with C/P, demonstrated an apparent improvement in RR, PFS, and OS in patients with previously untreated stage IIIB/IV non-small cell lung cancer and appears to enhance activity without significant additional toxicity. These results need to be confirmed in a phase III trial.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Double-Blind Method; Female; Humans; Lactoferrin; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Paclitaxel; Prospective Studies; Survival Analysis; Treatment Outcome

To investigate the activity and safety of oral talactoferrin (TLF) in patients with stages IIIB to IV non-small-cell lung cancer (NSCLC) for whom one or two prior lines of systemic anticancer therapy had failed.. Patients (n = 100) were randomly assigned to receive either oral TLF (1.5 g in 15 mL phosphate-based buffer) or placebo (15 mL phosphate-based buffer) twice per day in addition to supportive care. Oral TLF or placebo was administered for a maximum of three 14-week cycles with dosing for 12 consecutive weeks followed by 2 weeks off. The primary objective was overall survival (OS) in the intent-to-treat (ITT) patient population. Secondary objectives included progression-free survival (PFS), disease control rate (DCR), and safety.. TLF was associated with improvement in OS in the ITT patient population, meeting the protocol-specified level of significance of a one-tailed P = .05. Compared with the placebo group, median OS increased by 65% in the TLF group (3.7 to 6.1 months; hazard ratio, 0.68; 90% CI, 0.47 to 0.98; P = .04 with one-tailed log-rank test). Supportive trends were also observed for PFS and DCR. TLF was well tolerated and, generally, there were fewer adverse events (AEs) and grade ≥ 3 AEs reported in the TLF arm. AEs were consistent with those expected in late-stage NSCLC.. TLF demonstrated an apparent improvement in OS in patients with stages IIIB to IV NSCLC for whom one or two prior lines of systemic anticancer therapy had failed and was well tolerated. These results should be confirmed in a global phase III trial.

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Disease Progression; Double-Blind Method; Drug Administration Schedule; Female; Humans; Kaplan-Meier Estimate; Lactoferrin; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Odds Ratio; Platinum Compounds; Proportional Hazards Models; Treatment Failure; Treatment Outcome

We evaluated safety and activity of talactoferrin, a novel immunomodulatory protein in a phase IB trial of patients with refractory solid tumors.. Thirty-six patients with metastatic cancer who had progressed on, or were ineligible for, standard chemotherapy received single-agent oral talactoferrin. Following dose-escalation, with no DLTs , patients were randomized to 4.5 or 9 g/day talactoferrin.. Talactoferrin was well tolerated with apparent anti-cancer activity, particularly in NSCLC and RCC. One patient had a PR (RECIST) and 17 patients (47%) had stable disease (50% disease control rate). Median PFS in the twelve NSCLC and seven RCC patients was 4.2 and 7.3 months, respectively. There was no apparent difference in anti-tumor activity or adverse events between talactoferrin doses.. Oral talactoferrin was well tolerated. Although evaluated in a small number of patients, talactoferrin appeared to have anti-cancer activity, particularly in NSCLC and RCC and should be evaluated further.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell; Cell Proliferation; Demography; Female; Humans; Kidney Neoplasms; Lactoferrin; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Tomography, X-Ray Computed

Topics: AMP-Activated Protein Kinases; Autophagy; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Feedback; Humans; Lactoferrin; Lung; Lung Neoplasms; MicroRNAs

Lfcin-B, an antimicrobial peptide found in various exocrine secretions of mammals, showed antitumor effects. However, the effect and relative mechanism of Lfcin-B on non-small cell lung cancer is unclear. In this study, assay of cell viability, quantitative real-time PCR, Western blot, annexin V/propidium iodide assay, flow cytometry and tumor-xenograft model were applied to elucidate the mechanism of Lfcin-B on non-small cell lung cancer NCI-H460 (H460) cells. Lfcin-B significantly suppressed the proliferation of H460 cells in vitro. Additionally, the transcription and translation of the VEGF gene in H460 cells were restrained after exposure to Lfcin-B. Moreover, the apoptosis of H460 cells was induced by Lfcin-B through stimulating caspase-3, caspase-9 and preventing survivin expression on both the transcription and translation level. Meanwhile, Lfcin-B increased the production of reactive oxygen species and suppressed the RNA of antioxidant enzymes (GPX1, GPX2, SOD3 and catalase) in H460 cells. Finally, Lfcin-B significantly prevented the tumor growth in the H460-bearing mice model. These results indicated that Lfcin-B could be a potential candidate for the treatment of lung cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Flow Cytometry; Gene Expression; Humans; Lactoferrin; Lung Neoplasms; Mice, Nude; Reactive Oxygen Species; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Talactoferrin alfa (TLF) is a unique recombinant form of human lactoferrin. The hypothesized mechanism of action involves TLF binding to the intestinal endothelium inducing dendritic cell maturation and cytokine release leading to infiltration of tumor with monocytes and T-lymphocytes and inhibition of tumor growth.. Based on promising phase II trial results, this correlative study was undertaken to examine immune mechanism of action of TLF in metastatic non-small cell lung cancer (NSCLC) patients.. Talactoferrin was administered orally at 1.5 g bid weeks 1-12 with 2 weeks off on a 14-week cycle. Enrolled patients had a pathologic diagnosis of NSCLC previously treated with at least two lines of systemic treatment. Patients had core biopsy of tumor before initiation of talactoferrin and at week 7 on TLF. Flow cytometry and quantitative immunohistochemistry for immune correlates were performed on the biopsied specimens.. Four patients with metastatic NSCLC were enrolled. The trial was halted pre-maturely in light of negative phase III trial results. For the two patients who had repeat on-treatment tumor biopsies, a consistent increase in monocytes as a percentage of total immune cells was observed. Otherwise, no clear trend of increase or decrease was observed in any other immune cell parameters compared to matched patient pre-treatment biopsies.. Repeat biopsies for immune correlates by flow cytometry and quantitative immunohistochemistry in NSCLC patients are feasible. In the few patients sampled before trial closure, increased monocytes as a total percentage of the immune cell population within tumor was observed in response to TLF.

Topics: Aged; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lactoferrin; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local

Talactoferrin alfa (talactoferrin), an agent with immune-stimulating properties, has demonstrated safety and preliminary efficacy in clinical trials.. Ten patients (five males and five females) with stage IV non-small cell lung cancer (NSCLC) in a single-arm pilot study received orally administered talactoferrin (1.5 g, b.i.d.) for up to 24 weeks. Radiographic and immunologic studies were performed at baseline and at weeks 6 and 12. Circulating immune cells (natural killer cells [NKCs], CD4+, CD8+, and regulatory T cells) and systemic cytokine levels were measured to assess immune response.. Patients enrolled in the study had received a median of four prior chemotherapy regimens, and all patients were symptomatic. Talactoferrin was well tolerated, with no grade 3 or 4 toxicities. Median time to progression (TTP) and overall survival were 6 weeks and 14.5 weeks, respectively. The four patients with ≥9 weeks TTP had evidence of immunologic activity (three with increased NKC activity).. The median of four previous chemotherapy regimens, with elevated levels of interleukin (IL) 6 and tumor necrosis factor-alfa in most patients, suggests these patients were poor candidates for immunotherapy.

Topics: Carcinoma, Non-Small-Cell Lung; CD4-Positive T-Lymphocytes; Clinical Trials, Phase III as Topic; Disease-Free Survival; Female; Humans; Immune System; Interleukin-6; Killer Cells, Natural; Lactoferrin; Lung Neoplasms; Male; Neoplasm Staging; Pilot Projects; T-Lymphocytes, Regulatory; Tumor Necrosis Factor-alpha

Topics: Administration, Oral; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase II as Topic; Drug Approval; Humans; Lactoferrin; Lung Neoplasms; Placebos; Randomized Controlled Trials as Topic; Recombinant Proteins; Survival Rate; United States; United States Food and Drug Administration

Allelic loss on the short arm of chromosome 3 is one of the most common events in the pathogenesis of lung cancer. The lactotransferrin gene (LTF, also referred to as the lactoferrin gene, LF) is located at 3p21.3 common eliminated region 1, which is frequently deleted in lung and other cancers. The expression of the LTF gene was absent in 16 (59%) of 27 small cell lung cancer cell lines, 33 (77%) of 43 nonsmall-cell lung cancer (NSCLC) cell lines and 7 (54%) of 13 primary NSCLC, while LTF mRNA was overexpressed in 3 (7%) of 43 NSCLC cell lines. Its expression was restored by treatment with 5-aza-2'-deoxycytidine (5-aza-dC), trichostatin A (TSA) or a combination of both in a subset of lung cancer cell lines without LTF expression. In addition, we found 8 different types of nucleotide substitutions and one frameshift mutation. These results indicate that the LTF gene is inactivated by genetic and epigenetic mechanisms in lung cancer.

Topics: Base Sequence; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Epigenesis, Genetic; Frameshift Mutation; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Silencing; Humans; Lactoferrin; Lung Neoplasms; Molecular Sequence Data; Point Mutation; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Tumor Cells, Cultured