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T. Hilton



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    O08 - Preclinical Therapeutic Models I (ID 92)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      O08.01 - A novel autophagosome non-small cell lung cancer vaccine (DRibbles) contains short-lived proteins, defective ribosomal products, at least nine NCI-prioritized antigens, and agonists for TLR 2, 3, 4, 7, and 9. (ID 2612)

      16:15 - 16:25  |  Author(s): T. Hilton

      • Abstract
      • Presentation
      • Slides

      Background
      Tumor-derived autophagosomes, referred to as DRibbles, are novel cancer vaccines that have been shown to be effective against 5 preclinical models of established tumors. We hypothesize that DRibbles’ efficacy stems from their ability to present stabilized tumor-derived short-lived proteins (SLiPs) and defective ribosomal products (DRiPs) that are, due to their short-lived nature, normally not processed and presented by professional antigen presenting cells. These SLiPs and DRiPs represent a potential pool of tumor antigens against which the host is not tolerant. A pilot clinical trial of an autologous DRibble vaccine demonstrated feasibility and suggested immune effects in 4 patients with advanced NSCLC (WCLC 2013, submitted). In order to expand the DRibble strategy to patients without an autologous tumor source, we have produced an allogeneic DRibble vaccine (DPV-001) from two NSCLC cell lines and developed a panel of 13 NSCLC cell lines expressing relevant antigenic targets that will be used to monitor induction of tumor-specific immunity.

      Methods
      The two NSCLC cell lines used to produce the DPV-001 vaccine (UbiLT3 and 6) were cultured with bortezomib and ammonium chloride to block the proteasome and prevent lysosomal degradation of SLiPs and DRiPs. Gene expression profiles were performed for each lot produced (Human Gene 1.0 ST arrays). Stability of indicator tumor antigens was assessed by Western blots. Toll-like receptor (TLR) agonist activity was assessed using HEK blue cells transfected with specific TLRs. After informed consent, a panel of NSCLC cell lines was established from 13 patients (tumor tissue or pleural fluid). These cell lines were HLA-typed for use in immunologic monitoring studies. cDNA was synthesized in triplicate from total RNA extracted from each cell line in log phase growth. Samples were then analyzed using human microarrays containing approximately 17,000 oligonucleotides (CBER array). Data files were uploaded into the mAdb database and analyzed by software provided by the Center for Information Technology (CIT), NIH. Group t-test was used to compare gene expression differences between NSCLC and normal lung tissues and between cell lines.

      Results
      Analyses confirm reproducible gene expression profiles from both cell lines during DPV-001 manufacture, and stability studies demonstrate that the vaccine remains stable for 23 months. The vaccine contains at least nine NCI-prioritized cancer antigens and agonists for 5 TLRs. Gene expression profiles of the 13 NSCLC cell lines identified 46 commonly overexpressed genes, all of which are expressed in the DPV-001 vaccine.

      Conclusion
      The DPV-001 vaccine provides a source of broad-spectrum relevant NSCLC antigens. We are conducting a multicenter, randomized, phase II trial of adjuvant DPV-001 vaccine in patients with definitively treated stage IIIA/B NSCLC. T-cell immune responses will be monitored using HLA matched cell lines from the indicator panel of 13 NSCLC cell lines. NIH grants R21 CA123864 (WJU) and R43/44 CA121612 (SA, TH), Kuni Foundation (WJU), Murdoch Trust, Robert Franz, Wes and Nancy Lematta, Lyn and Jack Loacker, and the Chiles Foundation. Clinicaltrials.gov study identifier pending

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-032 - A pilot single institution study of autologous tumor autophagosome (DRibble) vaccination with docetaxel in patients (pts) with stage IV non-small cell lung cancer (NSCLC) (ID 2486)

      09:30 - 09:30  |  Author(s): T. Hilton

      • Abstract

      Background
      DRibbles are tumor-derived autophagosomes containing short-lived proteins (SLiPs) and defective ribosomal products (DRiPs). Vaccination with DRibbles produces tumor regression and provides cross-protection against syngeneic MCA sarcomas in preclinical models. Docetaxel can expose hidden tumor antigens and induces relative lymphopenia, potentially enhancing specific immune response. Sargramostim (GM-CSF) augments priming of tumor-specific T cells when administered at the site of DRibble vaccine in mice. This pilot study of autologous NSCLC DRibble vaccination with GM-CSF and docetaxel enrolled patients with advanced incurable NSCLC with malignant pleural effusion.

      Methods
      Pts had NSCLC with malignant pleural effusion, ECOG PS ≤ 2, and up to 2 prior chemotherapy regimens. Prior cancer-related vaccine therapy, active autoimmune disease, HIV, viral hepatitis, or chronic steroid use were not permitted. Pts with rapid clinical deterioration after enrollment were not eligible for vaccination. After informed consent, cells from malignant pleural fluid were cultured with bortezomib to block degradation of SLiPs and DRiPs and ammonium chloride to prevent lysosomal degradation of the autophagosome. DRibble vaccines were irradiated and passed sterility and endotoxin release criteria. Pts received docetaxel 75 mg/m[2] IV on day 1 and 29 for antitumor effect and to unmask tumor antigens and produce relative lymphopenia. Vaccination was scheduled for days 14, 43, 57, 71 and 85. GM-CSF (50 ug/d) was given via mini pump for 6d after each vaccination with immune monitoring pretreatment and at each vaccination.

      Results
      Six pts (3M, 3F, average age 65) with PS 1 and adenocarcinoma were enrolled. All received d1 docetaxel. Two did not receive further therapy due to clinical decline. Four pts were vaccinated (2-4 vaccines). One of 4 pts exhibited autologous tumor-specific immune response (IFN-γ, TNF-α, IL-5, IL-10) and 3 of 4 pts generated B cell responses (>5 fold specific antibody), with 1 patient not evaluable (Table 1). Figure 1

      Conclusion
      DRibble vaccine given with GM-CSF and chemotherapy is feasible. Small patient numbers preclude further conclusions. In order to translate this strategy to a larger number of pts in a more feasible population, we have developed an allogeneic DRibble vaccine from two NSCLC cell lines expressing at least 9 NCI-prioritized cancer antigens and including agonists for TLR 2, 3, 4, 7 & 9, HSPs and a dendritic cell-targeting molecule. A phase II trial of adjuvant DRibble vaccine alone or combined with GM-CSF or imiquimod is open in patients with definitively treated stage IIIA/B NSCLC. Support R21 CA123864-02 (WJU), R444 CA121612-01 (SA/TH) and Kuni Foundation (WJU).