Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial

OLIVIA, a multinational phase II study, suggests that bevacizumab plus FOLFOXIRI improves outcomes, including response rates, resection rates, and progression-free survival, compared with bevacizumab plus mFOLFOX-6 in patients with initially unresectable liver metastases from colorectal cance

Successful Expansion but Not Complete Restriction of Tropism of Adeno-Associated Virus by In Vivo Biopanning of Random Virus Display Peptide Libraries

Targeting viral vectors to certain tissues in vivo has been a major challenge in gene therapy. Cell type-directed vector capsids can be selected from random peptide libraries displayed on viral capsids in vitro but so far this system could not easily be translated to in vivo applications. Using a novel, PCR-based amplification protocol for peptide libraries displayed on adeno-associated virus (AAV), we selected vectors for optimized transduction of primary tumor cells in vitro. However, these vectors were not suitable for transduction of the same target cells under in vivo conditions. We therefore performed selections of AAV peptide libraries in vivo in living animals after intravenous administration using tumor and lung tissue as prototype targets. Analysis of peptide sequences of AAV clones after several rounds of selection yielded distinct sequence motifs for both tissues. The selected clones indeed conferred gene expression in the target tissue while gene expression was undetectable in animals injected with control vectors. However, all of the vectors selected for tumor transduction also transduced heart tissue and the vectors selected for lung transduction also transduced a number of other tissues, particularly and invariably the heart. This suggests that modification of the heparin binding motif by target-binding peptide insertion is necessary but not sufficient to achieve tissue-specific transgene expression. While the approach presented here does not yield vectors whose expression is confined to one target tissue, it is a useful tool for in vivo tissue transduction when expression in tissues other than the primary target is uncritical

Peptide Ligands Incorporated into the Threefold Spike Capsid Domain to Re-Direct Gene Transduction of AAV8 and AAV9 In Vivo

Efficiency and specificity of viral vectors are vital issues in gene therapy. Insertion of peptide ligands into the adeno-associated viral (AAV) capsid at receptor binding sites can re-target AAV2-derived vectors to alternative cell types. Also, the use of serotypes AAV8 and -9 is more efficient than AAV2 for gene transfer to certain tissues in vivo. Consequently, re-targeting of these serotypes by ligand insertion could be a promising approach but has not been explored so far. Here, we generated AAV8 and -9 vectors displaying peptides in the threefold spike capsid domain. These peptides had been selected from peptide libraries displayed on capsids of AAV serotype 2 to optimize systemic gene delivery to murine lung tissue and to breast cancer tissue in PymT transgenic mice (PymT). Such peptide insertions at position 590 of the AAV8 capsid and position 589 of the AAV9 capsid changed the transduction properties of both serotypes. However, both peptides inserted in AAV8 did not result in the same changes of tissue tropism as they did in AAV2. While the AAV2 peptides selected on murine lung tissue did not alter tropism of serotypes 8 and -9, insertion of the AAV2-derived peptide selected on breast cancer tissue augmented tumor gene delivery in both serotypes. Further, this peptide mediated a strong but unspecific in vivo gene transfer for AAV8 and abrogated transduction of various control tissues for AAV9. Our findings indicate that peptide insertion into defined sites of AAV8 and -9 capsids can change and improve their efficiency and specificity compared to their wild type variants and to AAV2, making these insertion sites attractive for the generation of novel targeted vectors in these serotypes

Abstract P2-11-06: Safety and clinical activity of atezolizumab (anti-PDL1) in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer

Abstract Background: Metastatic triple-negative breast cancer (mTNBC) is associated with poor prognosis, and chemotherapy remains the mainstay of treatment. Cancer immunotherapy represents a promising treatment approach for mTNBC, which is characterized by a high mutation rate, increased levels of tumor-infiltrating lymphocytes and high programmed death ligand-1 (PD-L1) expression levels. Atezolizumab (atezo; MPDL3280A) is a humanized monoclonal antibody that can restore tumor-specific T-cell immunity by inhibiting the binding of PD-L1 to PD-1. Atezo has demonstrated durable responses as monotherapy in mTNBC (Emens et al, AACR 2015). In addition, high objective response rates (ORRs) and durable responses have been observed with atezo plus chemotherapy in patients with non-small cell lung cancer (Liu et al, ASCO 2015). This study is the first combination trial of a checkpoint inhibitor with chemotherapy in patients with mTNBC. Methods: This arm of a multicenter, multi-arm Phase Ib study (NCT01633970) evaluated atezo in combination with weekly nab-paclitaxel in patients with mTNBC. Primary endpoints were safety and tolerability, with secondary endpoints of PK and clinical activity. Key eligibility criteria included measurable disease, ECOG PS 0/1 and ≤ 2 prior cytotoxic regimens. Patients received atezo 800 mg q2w (days 1 and 15) with nab-paclitaxel 125 mg/m2 q1w (days 1, 8 and 15) for 3 weeks in 4-week cycles, continued until loss of clinical benefit. If nab-paclitaxel was discontinued due to toxicity, atezo could be continued as monotherapy. ORR was assessed by RECIST v1.1. PD-L1 expression was scored at 4 diagnostic levels based on PD-L1 staining on tumor cells and tumor-infiltrating immune cells with the SP142 immunohistochemistry assay. Results: As of February 10, 2015, 11 patients were evaluable for safety. All patients were women with a median age of 58 y (range, 32-75 y). No unexpected or dose-limiting toxicities were observed. The median duration of safety follow-up was 79 days (range, 27-182 days). The efficacy-evaluable population consisted of 5 patients who had ≥ 1 scan and ≥ 3 months follow-up. Four PRs and 1 SD were observed. By the next data cutoff of June 15, 2015, 21 patients will have been enrolled (7 in the safety cohort and 14 in the expansion cohort). All patients in the expansion cohort were required to undergo serial biopsies for correlative analyses. Approximately 21 and 19 patients will be evaluable for safety and efficacy, respectively. Updated safety, efficacy and biomarker data will be presented. Conclusions: Preliminary results indicate that the combination of atezo plus nab-paclitaxel is tolerable with promising activity in patients with mTNBC. Based on these results and the observed activity of single-agent atezo in these patients, the combination of atezo and nab-paclitaxel is being evaluated in a Phase III study (NCT02425891) of patients with previously untreated mTNBC. Sponsor: Genentech, Inc. ClinicalTrials.gov: NCT01633970. Citation Format: Adams S, Diamond J, Hamilton E, Pohlmann P, Tolaney S, Molinero L, Zou W, Liu B, Waterkamp D, Funke R, Powderly J. Safety and clinical activity of atezolizumab (anti-PDL1) in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-11-06.</jats:p