Immunologic responses to xenogeneic tyrosinase DNA vaccine administered by electroporation in patients with malignant melanoma

BACKGROUND: Prior studies show that intramuscular injection and particle-mediated epidermal delivery of xenogeneic melanosomal antigens (tyrosinase or Tyr, gp100) induce CD8(+) T cell responses to the syngeneic protein. To further define the optimal vaccination strategy, we conducted a phase I study of in vivo electroporation (EP) of a murine Tyr DNA vaccine (pINGmuTyr) in malignant melanoma patients. METHODS: Human leukocyte antigen (HLA)-A1, A2, A24 or B35 stage IIb-IV melanoma patients received up to five doses of the mouse tyrosinase DNA vaccine by EP every three weeks at dose levels of 0.2 mg, 0.5 mg, or 1.5 mg per injection. Peripheral blood mononuclear cells (PBMC) were collected, cultured with a peptide pool containing eight HLA class I-restricted Tyr-specific T-cell epitopes, and analyzed by HLA-A*0101-restricted tetramers and intracellular cytokine staining (ICS). RESULTS: Twenty-four patients received ≥1 dose of the pINGmuTyr vaccine; PBMCs from 21 patients who completed all five doses were available for Tyr immune assays. The only common toxicity was grade 1 injection site reaction. Six of 15 patients (40%) in the 1.5 mg dose cohort developed Tyr-reactive CD8(+) T cell responses following stimulation, defined as a ≥3 standard deviation increase in baseline reactivity by tetramer or ICS assays. No Tyr-reactive CD8(+) T cell response was detected in the 0.2 mg and 0.5 mg dose cohort patients. Epitope spreading of CD8(+) T cell response to NY-ESO-1 was observed in one patient with vitiligo. One patient subsequently received ipilimumab and developed an enhanced Tyr-reactive response with polyfunctional cytokine profile. After a median follow-up of 40.9 months, median survival has not been reached. CONCLUSIONS: A regimen of five immunizations with pINGmuTyr administered by EP was found to be safe and resulted in Tyr-reactive immune responses in six of 15 patients at 1.5 mg dose cohort. TRIAL REGISTRATION: ClinicalTrials.gov NCT0047113

Bevacizumab in combination with oxaliplatin and doxorubicin or liposomal doxorubicin for hepatocellular cancer: A case series

Aims: Despite the emergence of sorafenib as the standard treatment for patients with advanced hepatocellular cancer (HCC), therapy remains sub-optimal and toxic. Methods: We report on five patients with advanced HCC treated with bevacizumab, oxaliplatin and doxorubicin or liposomal doxorubicin. Results: Of the five patients, four had cirrhosis; two patients had Child-Pugh A cirrhosis, while one each had Child-Pugh B and C cirrhosis. Grade 3/4 toxicity was uncommon. Four patients had a decrease of >= 50% in alpha-fetoprotein levels following therapy and one patient each had a radiographic complete response and stable disease. Conclusion: These data add to the growing phase II data that bevacizumab-containing regimens are active in advanced HCC patients. Further evaluation of regimens containing bevacizumab with oxaliplatin and/or doxorubicin may be warranted

Gefitinib vs. chemotherapy as first-line therapy in advanced non-small cell lung cancer: Meta-analysis of phase III trials

Gefitinib is an oral tyrosine kinase inhibitor against the epidermal growth factor receptor (EGFR). It has been shown to be active in patients with advanced non-small cell lung cancer (NSCLC) whose tumors contain EGFR mutations. We performed a meta-analysis of four randomized studies that compared gefitinib with chemotherapy in the first-line treatment of patients with advanced NSCLC: IPASS, North-East Japan, West Japan and first-SIGNAL studies. Patients were selected either on the basis of known EGFR mutations or based on clinicopathologic criteria – non-smokers with adenocarcinomas – associated with increased likelihood of EGFR mutations. Nearly 2000 patients were enrolled on these four trials. Median ages ranged from 57 to 64years. Seventy-six percent were women and 86% were non-smokers. Overall, gefitinib was associated with significantly less toxicity than chemotherapy and improved quality-of-life. Gefitinib also produced higher response rates in the EGFR mutation-positive patients (72% vs. 38%, odds ratio 4.04, p<10−15), as well as improved progression-free survival (PFS; hazard ratio 0.45, p<10−16). Overall survival (OS) was not significantly different between treatment groups (p=0.35). This meta-analysis confirms the results of each individual study and narrows the confidence intervals of these results. In patients with known EGFR mutations or whose tumors are likely to harbor a mutation, upfront gefitinib or chemotherapy are associated with similar OS. Gefitinib is associated with less fatigue, myelosuppression and nausea than chemotherapy (but produces more skin rash, diarrhea and pneumonitis). Patients receiving gefitinib have improved quality-of-life compared to those receiving chemotherapy, making it an appropriate first-line choice

Successful treatment of two lung cancer patients with erlotinib following gefitinib-induced hepatotoxicity

Introduction: Hepatotoxicity secondary to gefitinib, an oral tyrosine kinase inhibitor (TKI) against the epidermal growth factor receptor (EGFR), is under-appreciated, even though it has a reported incidence of 10-20% in phase II trials. Methods/results: We present two patients with non-small cell lung cancer (NSCLC) who developed grade 2/3 hepatotoxicity starting between 4 and 6 weeks after initiation of gefitinib, with toxicity peaking between 10 and 20 weeks. Both patients were switched to treatment with erlotinib, another EGFR TKI, without further development of hepatotoxicity. One patient with measurable metastatic disease achieved a durable near complete response while on erlotinib. The other patient experienced recurrence of hepatotoxicity when gefitinib was briefly reintroduced. Conclusions: Patients with NSCLC receiving gefitinib should undergo routine monitoring of liver enzymes. For those who develop gefitinib-induced hepatotoxicity but are otherwise deriving clinical benefit, consideration can be given to switching to erlotinib. (C) 2010 Elsevier Ireland Ltd. All rights reserved

Cetuximab in the first-line treatment of K-ras wild-type metastatic colorectal cancer: the choice and schedule of fluoropyrimidine matters

Cetuximab, a monoclonal antibody against the epidermal growth factor receptor, inconsistently improves response rates (RR), progression-free survival (PFS) and overall survival (OS) in the first-line treatment of advanced colorectal cancer patients with K-ras wild-type (WT) tumors. We performed a meta-analysis of four trials where K-ras WT Pts received a fluoropyrimidine (infusional vs. bolus 5-fluorouracil (5-FU) vs. capecitabine) and oxaliplatin or irinotecan with and without cetuximab (CRYSTAL, OPUS, COIN and NORDIC VII trials) and two trials, where K-ras WT and mutant patients received cetuximab and a fluoropyrimidine (capecitabine in a German AIO study and infusional 5-FU in the CECOG study) with oxaliplatin versus irinotecan. We sought to determine whether the choice of fluoropyrimidine or of oxaliplatin versus irinotecan affects the response to cetuximab. Meta-analysis was performed in the context of a mixed effects model with a random effect for each study. Only patients treated with infusional 5-FU-based chemotherapy derived benefit from cetuximab. Relative to infusional 5-FU, patients treated with capecitabine/bolus 5-FU-based doublet chemotherapy had a 42 % (95 % CI 21-58 %; p < 0.001) decrease in response probability and a 52 % (95 % CI 20-93 %; p < 0.001) and 33 % (95 % CI 7-65 %; p = 0.012) increase, respectively, in risk of progression and death. The choice of oxaliplatin or irinotecan did not affect benefit from cetuximab. The lack of benefit for cetuximab with capecitabine/bolus 5-FU regimens is unexpected. Cetuximab should only be used with infusional 5-FU regimens in the first-line treatment of K-ras WT colorectal cancer patients. Further study is urgently needed to elucidate the basis of this observation

Can ¹⁸F-FDG PET/CT Radiomics Features Predict Clinical Outcomes in Patients with Locally Advanced Esophageal Squamous Cell Carcinoma?

This study aimed to assess the usefulness of radiomics features of 18F-FDG PET/CT in patients with locally advanced esophageal cancers (ESCC) in predicting outcomes such as clinical tumor (cT) and nodal (cN) categories, PET response to induction chemotherapy (PET response), progression-free survival (PFS), and overall survival (OS). Pretreatment PET/CT images from patients who underwent concurrent chemoradiotherapy from July 2002 to February 2017 were segmented, and data were split into training and test sets. Model development was performed on the training datasets and a maximum of five features were selected. Final diagnostic accuracies were determined using the test dataset. A total of 86 PET/CTs (58 men and 28 women, mean age 65 years) were segmented. Due to small lesion size, 12 patients were excluded. The diagnostic accuracies as derived from the CT, PET, and combined PET/CT test datasets were as follows: cT category—70.4%, 70.4%, and 81.5%, respectively; cN category—69.0%, 86.2%, and 86.2%, respectively; PET response—60.0%, 66.7%, and 70.0%, respectively; PFS—60.7%, 75.0%, and 75.0%, respectively; and OS—51.7%, 55.2%, and 62.1%, respectively. A radiomics assessment of locally advanced ESCC has the potential to predict various clinical outcomes. External validation of these models would be further helpful