A CD4(+) T-cell immune response to a conserved epitope in the circumsporozoite protein correlates with protection from natural Plasmodium falciparum infection and disease.

Many human T-cell responses specific for epitopes in Plasmodium falciparum have been described, but none has yet been shown to be predictive of protection against natural malaria infection. Here we report a peptide-specific T-cell assay that is strongly associated with protection of humans in The Gambia, West Africa, from both malaria infection and disease. The assay detects interferon-gamma-secreting CD4(+) T cells specific for a conserved sequence from the circumsporozoite protein, which binds to many human leukocyte antigen (HLA)-DR types. The correlation was observed using a cultured, rather than an ex vivo, ELISPOT assay that measures central memory-'type T cells rather than activated effector T cells. These findings provide direct evidence for a protective role for CD4(+) T cells in humans, and a precise target for the design of improved vaccines against P. falciparum.

Enhanced T-cell immunogenicity of plasmid DNA vaccines boosted by recombinant modified vaccinia virus Ankara in humans.

In animals, effective immune responses against malignancies and against several infectious pathogens, including malaria, are mediated by T cells. Here we show that a heterologous prime-boost vaccination regime of DNA either intramuscularly or epidermally, followed by intradermal recombinant modified vaccinia virus Ankara (MVA), induces high frequencies of interferon (IFN)-gamma-secreting, antigen-specific T-cell responses in humans to a pre-erythrocytic malaria antigen, thrombospondin-related adhesion protein (TRAP). These responses are five- to tenfold higher than the T-cell responses induced by the DNA vaccine or recombinant MVA vaccine alone, and produce partial protection manifest as delayed parasitemia after sporozoite challenge with a different strain of Plasmodium falciparum. Such heterologous prime-boost immunization approaches may provide a basis for preventative and therapeutic vaccination in humans.

The prognostic role of inflammatory markers in patients with metastatic colorectal cancer treated with bevacizumab: A translational study [ASCENT].

BACKGROUND: In spite of demonstrating prognostic and possibly predictive benefit in retrospective cohorts and meta-analyses of cancer populations, including colorectal cancer (CRC), prospective evaluation of the relationship between neutrophil to lymphocyte ratio (NLR) and treatment outcomes in previously untreated mCRC patients receiving bevacizumab-based therapy has not yet been performed. METHODS: An open-label, single arm, multi-centre study. Patients received first-line bevacizumab plus XELOX or mFOLFOX6 (Phase-A) and continued bevacizumab plus FOLFIRI beyond first progression (Phase-B). Analyses included the association of NLR with phase A progression free survival (PFS) and overall survival (OS). A sub-study investigated the safety in patients with the primary in situ tumor. An exploratory sub-study examined relationships of circulating proteomic markers with PFS. RESULTS: Phase-A enrolled 128 patients; median age was 64 years (range: 26-84), 70 (55%) were female, 71 (56%) were PS-0 and 51 (40%) had primary in situ tumor. Fifty-three (41%) patients entered Phase-B. The median baseline (b) NLR was 3.2 (range: 1.5-20.4) with 32 (25%) patients having bNLR > 5. The PFS hazard ratio (HR) by bNLR > 5 versus ≤ 5 was 1.4 (95% CI: 0.9-2.2; p = 0.101). The median PFS was 9.2 months (95% CI: 7.9-10.8) for Phase-A and 6.7 months (95% CI: 3.0-8.2) for Phase-B. The HR for OS based on bNLR > 5 versus ≤ 5 was 1.6 (95% CI: 1.0-2.7; p = 0.052). The median OS was 25 months (95% CI: 19.2-29.7) for the full analysis set and 14.9 months for Phase-B. Baseline levels of nine proteomic markers showed a relationship with PFS. Treatment related toxicities were consistent with what has previously been published. There were 4 (3%) instances of GI perforation, of which, 3 (6%) occurred in the primary in situ tumor group. CONCLUSIONS: Results from this study are aligned with the previously reported trend towards worse PFS and OS in patients with higher bNLR. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01588990; posted May 1, 2012.

3D radiotherapy can be safely combined with sandwich systemic gemcitabine chemotherapy in the management of pancreatic cancer: factors influencing outcome.

PURPOSE: The aim of this Phase II study was to examine whether concurrent continuous infusion 5-fluorouracil (CI 5FU) plus three-dimensional conformal planning radiotherapy sandwiched between gemcitabine chemotherapy is effective, tolerable, and safe in the management of pancreatic cancer. METHODS AND MATERIALS: Patients were enrolled in two strata: (1) resected pancreatic cancer at high risk of local relapse (postsurgery arm, n = 22) or (2) inoperable pancreatic cancer in head or body without metastases (locally advanced arm, n = 41). Gemcitabine was given at 1,000 mg/m(2) weekly for 3 weeks followed by 1 week rest then 5-6 weeks of radiotherapy and concurrent CI 5FU (200 mg/m(2)/day). After 4 weeks' rest, gemcitabine treatment was reinitiated for 12 weeks. RESULTS: For the two arms combined, treatment-related Grade 3 and 4 toxicities were reported by 25 (39.7%) and 7 (11.1%) patients, respectively. No significant late renal or hepatic toxicity was observed. In the postsurgery arm (R1 54.5%), median time to progressive disease from surgery was 11.0 months, median time to failure of local control was 32.9 months, and median survival time was 15.6 months. The 1- and 2-year survival rates were 63.6% and 31.8%. No significant associations between outcome and mutations in K-ras or TP53 or microsatellite instability were identified. Post hoc investigation of cancer antigen 19-9 levels found baseline levels and increases postbaseline were associated with shorter survival (p = 0.0061 and p < 0.0001, respectively). CONCLUSIONS: This three-dimensional chemoradiotherapy regimen is safe and promising, with encouraging local control for a substantial proportion of patients, and merits testing in a randomized trial.

Patient attitudes towards chemotherapy as assessed by patient versus physician: a prospective observational study in advanced non-small cell lung cancer.

BACKGROUND: In the treatment of advanced cancer, a physician's ability to accurately identify a patient's attitude towards treatment is critical. This paper describes the extent of any differences observed between patient attitudes towards chemotherapy for advanced non-small cell lung cancer (NSCLC) as assessed by patients themselves versus their physicians. PATIENTS AND METHODS: Patients with stage IIIB or IV NSCLC who received gemcitabine plus cisplatin or carboplatin were enrolled into this prospective observational study. Patients and their physicians completed questionnaires containing descriptions of seven patient-specific attitudes. A pre-defined algorithm was used to categorize patients into one of the three 'need' categories based on the questionnaire responses: (A) "maximum extension of survival with acceptance of high toxicity", (B) "maximum extension of survival only if coupled with normal life style", and (C) "relief of symptoms". Each patient was categorized based on his own response, as well as his physician's response. RESULTS: A total of 1895 patients were enrolled from 19 countries across 3 continents. Data from 1884 patients were analysed. Based on patient versus physician responses, respectively, the distribution of patients was 60% versus 39% in need category A, 26% versus 33% in B, and 14% versus 29% in C. Patient self-assessed versus physician-assessed need category identification was aligned for 891 patients (47.3%): 541 (29%) in A, 218 (12%) in B, 132 (7%) in C. While there was slight agreement between the identification of 'need' categories by physicians and patients (kappa=0.18, 95% CI: 0.15-0.21), physicians also tended to place patients further down the scale (towards C) than patients placed themselves (P<0.001). CONCLUSIONS: Patients have varying needs from cancer chemotherapy and it may not always be correctly identified by the treating physician. Physicians may underestimate patient's desire for extended survival compared with symptom relief.

Gemcitabine and split-dose paclitaxel or docetaxel in metastatic breast cancer: a randomised phase II study.

PURPOSE: The purpose was to evaluate the activity and toxicity of split-dose paclitaxel or docetaxel in combination with gemcitabine in patients with metastatic breast cancer (MBC) who had previously received anthracyclines. PATIENTS AND METHODS: A total of 210 patients were randomly assigned to one of three treatment arms: gemcitabine 1,250 mg/m(2) Days 1 and 8 and paclitaxel 175 mg/m(2) as a 3-h infusion on Day 1 (GP1); gemcitabine 1,000 mg/m(2) Days 1 and 8 and paclitaxel 100 mg/m(2) as a 1-h infusion on Days 1 and 8 (GP2); gemcitabine 1,000 mg/m(2) Days 1 and 8 and docetaxel 40 mg/m(2) as a 1-h infusion on Days 1 and 8 (GD). Cycles were repeated every 3 weeks. RESULTS: For the 204 patients evaluable for response assessment, the response rates were 48.6% for GP1, 52.2% for GP2, and 52.3% for GD. Median response duration, time to treatment failure, and time to progression (TTP) were similar in each arm. Median TTP for GP1, GP2 and GD was 7.5, 7.0 and 7.4 months, respectively. For the 208 patients evaluable for safety, the most common grade 3/4 toxicity for each regimen was neutropaenia, with 64%, 57%, and 68% for GP1, GP2, and GD, respectively. Grade 4 neutropaenia, grade 3/4 anaemia, febrile neutropaenia, and diarrhoea were more common in the docetaxel arm, as was the use of intravenous antibiotics and blood transfusions. CONCLUSION: The study confirmed the high activity of gemcitabine-taxane combinations in MBC. Split-dose paclitaxel had similar activity and toxicity to the 3-weekly administration. The split-dose docetaxel regimen had similar activity to the paclitaxel combinations though associated with higher toxicity.

Dimorphic Plasmodium falciparum merozoite surface protein-1 epitopes turn off memory T cells and interfere with T cell priming.

The leading blood-stage malaria vaccine candidate antigen, Plasmodium falciparum merozoite surface protein-1 (MSP-1) occurs in two major allelic types worldwide. The molecular basis promoting this stable dimorphism is unknown. In this study, we have shown that allelic altered peptide ligand (APL) T cell epitopes of MSP-1 mutually inhibited IFN-gamma secretion as well as proliferation of CD4+ T cells in 27/34 malaria exposed Gambian volunteers. Besides this inhibition of malaria-specific immunity, the same variant epitopes were also able to impair the priming of human T cells in malaria naive individuals. Epitope variants capable of interfering with T cell priming as well as inhibiting memory T cell effector functions offer a uniquely potent combination for immune evasion. Indeed, enhanced co-habitation of parasites bearing such antagonistic allelic epitope regions was observed in a study of 321 West African children, indicating a survival advantage for parasites able to engage this inhibitory immune interference mechanism.

Phase II trial of gemcitabine-carboplatin-paclitaxel as neoadjuvant chemotherapy for operable non-small cell lung cancer.

BACKGROUND: The aim of this single-arm phase II study was to evaluate the efficacy, feasibility, and safety of the gemcitabine-carboplatin-paclitaxel combination as neoadjuvant chemotherapy in patients with operable non-small cell lung cancer (NSCLC). METHODS: Patients with stage IB, II, or IIIA NSCLC were given three cycles of chemotherapy followed by tumor resection. Each 21-day cycle consisted of gemcitabine 1000 mg/m on days 1 and 8, carboplatin AUC 5 on day 1, and paclitaxel 175 mg/m on day 1. RESULTS: Forty-four patients were enrolled: 18.2% of patients had stage IB, 15.9% had stage II, and 65.9% had stage IIIA NSCLC. All patients received three cycles of treatment. The clinical tumor response rate was 76.2% (32 of 42 patients; 95% CI, 60.5-87.9%). Thirty-six patients had a complete tumor resection, five of whom had a complete pathological response with no viable tumor cells in the resected tumor on histological examination. Median time to progression was 13.6 months (95% CI, 8.9, >16 months), and 26 of 44 patients (59.1%) had progressed. The 1-year disease-free survival rate was 53.6% (95% CI, 38.7-68.5%), and the 1-year survival rate was 86.0% (95% CI, 75.7-96.4%). Grade 3 and 4 neutropenia each occurred in 38.6% of patients, and grade 3 infection occurred in 2.3% of patients; grade 3 and 4 thrombocytopenia occurred in 25.0% and 0% of patients, respectively. CONCLUSION: The gemcitabine-carboplatin-paclitaxel combination showed promising efficacy and seemed to be safe and feasible as neoadjuvant chemotherapy in patients with operable-stage NSCLC.

Safety and immunogenicity of DNA/modified vaccinia virus ankara malaria vaccination in African adults.

The present study is an investigation of the safety and immunogenicity of DNA and modified vaccinia virus Ankara (MVA) candidate vaccines, each encoding the malaria DNA sequence multiple epitope-thrombospondin related adhesion protein (ME-TRAP), against Plasmodium falciparum. DNA ME-TRAP and MVA ME-TRAP are safe and immunogenic for effector and memory T cell induction. MVA ME-TRAP, with or without prior DNA ME-TRAP immunization, was more immunogenic and more cross-reactive in malaria-exposed individuals than in malaria-naive individuals, a finding suggesting that recombinant MVA vaccines are particularly promising for the development of a malaria vaccine for exposed populations. Both CD4(+) and CD8(+) T cells were induced by these vaccines.

Induction of T helper type 1 and 2 responses to 19-kilodalton merozoite surface protein 1 in vaccinated healthy volunteers and adults naturally exposed to malaria.

Plasmodium falciparum malaria is a major cause of death in the tropics. The 19-kDa subunit of P. falciparum merozoite surface protein 1 (MSP-1(19)), a major blood stage vaccine candidate, is the target of cellular and humoral immune responses in animals and humans. In this phase I trial of MSP-1(19), immunization of nonexposed human volunteers with either of the two allelic forms of recombinant MSP-1(19) induced high levels of antigen-specific Th1 (gamma interferon) and Th2 (interleukin 4 [IL-4] and IL-10) type lymphokines. The adjustment of the antigen dose and number of immunizations regulated the level of specificity of immune responses and Th1/Th2 bias of responses induced by vaccination. Novel conserved and allelic T-cell epitopes which induced cross-strain immune responses were identified. Importantly, responses to many of these novel epitopes were also present in adults exposed to malaria, both in east (Kenya) and west Africa (The Gambia). These data suggest that epitope-specific naturally acquired MSP-1(19) immune responses in endemic populations can be boosted by vaccination.