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H.J. Ross



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    MO20 - Preclinical Therapeutic Models II (ID 93)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO20.01 - Protein Kinase C iota is required for maintenance of a tumor initiating cell phenotype in lung squamous cell carcinoma (ID 2644)

      10:30 - 10:35  |  Author(s): H.J. Ross

      • Abstract
      • Presentation
      • Slides

      Background
      We discovered that PKCι is an oncogene in non-small cell lung cancer (NSCLC), elucidated a major oncogenic PKCι signaling mechanism, and identified therapeutic agents that target oncogenic PKCι signaling. We have shown that PKCι signaling is genetically activated in approximately 70% of lung squamous cell carcinomas (LSCCs) through tumor-specific amplification of the PKCι gene, PRKCI. More recently, we have investigated the role of PKCι in bronchio-alveolar stem cells (BASCs), which are putative lung tumor-initiating cells (TICs). We demonstrated that PKCι is required for Kras-mediated transformation of BASCs in a mouse model of Kras-mediated lung adenocarcinoma. We hypothesize that PKCι plays a critical role in the development and maintenance of the TIC phenotype in LSCC by activating cell autonomous proliferative signaling mechanisms.

      Methods
      We isolated “oncospheres” from four human LSCC cell lines (H1703, H1299, Calu-1, and ChagoK1) grown in non-adherent culture in defined stem cell medium using established protocols. Lentiviral shRNA techniques were used to genetically knock down expression of PKCι to assess the effect of PKCι depletion on the TIC phenotype. Non-target (NT) and PKCι RNAi TICs were assessed for the ability to grow as non-adherent oncospheres, to clonally expand, express stem marker genes, form colonies in soft agar, and initiate tumors in immune deficient mice. The effect of the selective and potent PKCι signaling inhibitor auranofin on TIC behavior and PKCι signaling activity was assessed as was the mTOR inhibitor, rapamycin.

      Results
      LSCC oncospheres exhibited characteristics of cancer stem or tumor-initiating cells including the ability to redifferentiate into bulk tumor cells when returned to adherent culture. Oncosphere cells express elevated levels of stem genes, clonally expand, exhibit enhanced transformed growth, and efficiently initiate and maintain lung orthotopic tumors and metastases. Biochemical studies indicate that the oncogenic PKCι-Rac1-Ect2-MMP10 signaling axis is activated in LSCC TICs. To assess the role of PKCι in TIC growth, we knocked down PKCι in TIC cultures derived from the four LSCC cell lines described above. Whereas TICs expressing NT RNAi grew efficiently as anchorage-independent colonies in soft agar and clonally expanded, PKCι RNAi TICs were severely impaired in soft agar growth, clonal expansion, and tumorigenicity in vivo. Treatment of TICs with the potent and selective PKCι inhibitor auranofin (ANF) likewise led to inhibition of PKCι signaling, TIC growth, clonal expansion, and tumorigenicity. Combined inhibition of PKCι and mTOR with ANF plus rapamycin was synergistic against TIC proliferation in vitro.

      Conclusion
      Our data demonstrate that PKCι signaling is activated in LSCC TICs and that PKCι signaling is important for maintaining the TIC phenotype. We showed that the selective PKCι inhibitor ANF potently inhibits LSCC TIC behavior. Taken together, our data support the targeting of LSCC TICs through selective inhibition of PKCι for treatment of patients with LSCC. Based on these and earlier results showing synergistic tumor inhibition with combined PKCι and mTOR inhibition, a phase I clinical trial of auranofin with the mTOR inhibitor sirolimus has been instituted as maintenance therapy for LSCC patients who have completed initial chemotherapy.

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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): H.J. Ross

      • 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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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-033 - Safety and Resource Use in PRONOUNCE: A randomized, phase 3, open-label study of Pemetrexed plus Carboplatin with maintenance Pemetrexed (PemC) and Paclitaxel plus Carboplatin plus Bevacizumab with maintenance Bevacizumab (PCB) in patients with advanced non-squamous (NS) non-small-cell lung cancer (NSCLC) (ID 1680)

      09:30 - 09:30  |  Author(s): H.J. Ross

      • Abstract

      Background
      Two combination chemotherapy regimens were compared in a Phase 3, randomized, open-label United States only study. The two-drug regimen of pemetrexed/carboplatin followed by maintenance pemetrexed (PemC) was compared to the three-drug regimen of paclitaxel/carboplatin/bevacizumab followed by maintenance bevacizumab (PCB). The primary endpoint of improved progress-free survival (PFS) without Grade 4 toxicity (G4PFS) for PemC over PCB was not met in PRONOUNCE, as reported by Zinner et al. (ASCO, 2013). No difference in PFS or overall survival (OS) for PemC vs. PCB was observed. Both regimens demonstrated tolerability, but toxicity profiles differed.

      Methods
      Patients 18+ years of age with Stage IV chemonaïve non-squamous non-small-cell lung cancer (NS-NSCLC) were randomized to PemC (n=182) or PCB (n=179). Safety data were compared for patients who received ≥1 dose of study treatment (PemC:171; PCB:166), and resource use including concomitant medications, transfusions, and hospitalizations was recorded. Measures were compared between arms using Fisher’s exact test, if not otherwise specified. Protocol-defined chemotherapy infusion time was 0.7 hours for PemC and 4-5 hours for PCB. For the primary endpoint of G4PFS, the G4 events were reported regardless of drug causality.

      Results
      Of 152 G4PFS events for PemC, 37 (24.3%) resulted from first occurrence of a G4 event. Of 144 G4PFS events for PCB, 64 (44.4%) resulted from first occurrence of a G4 event. The safety profile for the entire study demonstrated that patients on PemC experienced significantly more drug-related Grade 3/4 anemia (18.7% vs. 5.4%; p<0.001), Grade 3/4 thrombocytopenia (24.0% vs. 9.6%; p<0.001), and Grade 1/2 nausea (46.8% vs. 28.9%; p<0.001). Patients on PCB experienced significantly more drug-related Grade 3/4 neutropenia (24.6% vs. 48.8%; p<0.001) and Grade 1/2 alopecia (8.2% vs. 28.3%; p<0.001). There was a significantly higher rate of drug-related Grade 1/2 sensory neuropathy (8.2% vs. 30.1%; p<0.001), Grade 1/2 hypertension (0.0% vs. 9.6%; p<0.001), Grade 1/2 hemorrhage in pulmonary/upper respiratory (1.8% vs. 13.3%; p< 0.001) and Grade 1/2 joint pain (1.8% vs. 13.9%; p<0.001) with PCB. Patients on PemC required more red blood cell (RBC) transfusions (34.5% vs. 11.4%; p<0.001), but there was no difference in platelet transfusions (p=0.621). Erythropoietic stimulating agents (ESAs) were used more frequently (19.9% vs. 7.2%; p<0.001) in PemC, and granulocyte colony-stimulating factor (G-CSF) use was significantly higher with PCB (17.0% vs. 30.1%; p=0.005). Requirement for antibiotics (p=0.323) and antiemetics (p=0.574) did not differ between PemC and PCB. There were no differences between PemC and PCB in the number of patients with at least one hospitalization (34.5% vs. 31.9%; p=0.645), and the mean length of stay between PemC (8.2d +/- 6.79) and PCB (8.8d +/- 7.33) did not differ (p=0.682;Wilcoxon rank sum test).

      Conclusion
      The toxicity profiles of PemC and PCB were consistent with previous reports. Toxicities documented as important to patients were split, with mild-to-moderate nausea more common for PemC and alopecia, infection and neuropathy more frequent for PCB. Resource intense toxicities were also divided. Hospitalizations did not differ between treatments. ESAs and RBC transfusions were more common with PemC, and G-CSF use was more common with PCB. ClinicalTrials.gov identifier:NCT00948675

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    P2.07 - Poster Session 2 - Surgery (ID 190)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P2.07-046 - Effect of airway stenting on quality of life (QoL) in patients with malignant airway obstruction: A single institutional experience at Mayo Clinic Arizona (MCA) (ID 3203)

      09:30 - 09:30  |  Author(s): H.J. Ross

      • Abstract

      Background
      Malignant airway obstruction is associated with severe respiratory distress and poor outcome. Airway stents have been used to relieve malignant airway obstruction and may provide significant palliation of symptoms, but quality of life data after airway stenting is lacking. We report the Mayo Clinic Arizona experience with the Boston Scientific Ultra Flex stent in the management of malignant airway obstruction.

      Methods
      A single center study evaluating quality of life before and after placement of the Boston Scientific Ultra Flex stent for malignant airway obstruction. Quality of life data (SF-36 questionnaires) before and after stent placement were obtained prospectively. Charts were reviewed retrospectively. Patients were enrolled from 2007-2011 at Mayo Clinic Arizona. The study was approved by the Mayo Foundation IRB. Informed consent was obtained and documented in the clinical record. SF-36 questionnaires were completed by the patients in the outpatient clinic before (baseline) and after stent placement.

      Results
      From 2007 to 2011, 19 patients underwent placement of Boston Scientific Ultraflex non covered tracheobronchial stents for airway obstruction. 3 of the 19 patients underwent stent placement for benign etiologies and were excluded from the analysis. Of the remaining 16 patients, 8 were male and 8 were female. The median age was 64.5 years. Non-small cell lung cancer was the most common underlying diagnosis (11 patients). The remaining patients had head and neck cancer (2 patients), esophageal cancer (1 patient), metastatic Hurthle cell thyroid cancer (1 patient) and metastatic renal cell carcinoma (1 patient). The most common presenting symptom of airway obstruction was dyspnea. Data from SF36 forms were available in 8 of 16 patients. There was a significant improvement in the physical component score (PCS) (10.4±10.1, P=0.02), and a non-significant improvement in the mental component score (MCS) (1.4±6.2, P=0.54) after stent placement.

      Conclusion
      Placement of airway stents for malignant bronchial obstruction resulted in significant palliation of symptoms and improvement in patient quality of life.

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    P2.13 - Poster Session 2 - SCLC (ID 201)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.13-002 - Randomized Phase II Study of Single Agent OSI-906, an Oral, Small Molecule, Tyrosine Kinase Inhibitor (TKI) of the Insulin Growth Factor-1 Receptor (IGF-1R) Versus Topotecan for the Treatment of Patients with Relapsed Small Cell Lung Cancer (SCLC) (ID 920)

      09:30 - 09:30  |  Author(s): H.J. Ross

      • Abstract

      Background
      SCLC typically presents with advanced (extensive stage) disease. Despite an initial response to chemotherapy, they all relapse and rarely survive beyond 2 years. Treatment of relapsed SCLC is limited (topotecan) and dependent on the response to initial chemotherapy (sensitive vs. refractory relapse). Downstream activation of PI3K-AKT, through IGF-1R pathway signaling plays a role in both, growth/survival and resistance to chemotherapy in SCLC. Growth inhibition and chemosensitization with IGF-1R inhibitors correlates with the PI3K-AKT inhibitory signaling and suggests AKT activation as a potential biomarker. OSI-906, is a well tolerated oral, small molecule, potent inhibitor of IGF-1R

      Methods
      A phase II randomized study comparing the efficacy of OSI-906 vs topotecan in patients with rSCLC is currently being conducted. Primary endpoint is PFS, summarized with the K-M method. An increase in median PFS from 2.5 to 4.175 months (in the experimental arm B) is proposed. A total of 95 patients are planned. Biomarkers of IGF-1R inhibition are explored in plasma, PBMC and using Radiomics. Eligible patients must have proven rSCLC, platinum sensitive (sen) or resistant (res) disease, ECOG PS 0-2 and adequate hematologic, renal and hepatic function. Fasting glucose <160 mg/dl, QTc < 450 msec and measurable disease by RECIST v1.1 are required. Pregnant, breast-feeding, diabetic and cirrhotic patients as well as those taking insulin/insulinotropic agents are excluded. Patients are randomized (2:1) to the experimental arm (B): OSI-906, 150 mg PO BID, until progression or to the standard arm (A): topotecan, 1.5 mg/m[2] IV daily x5 OR 2.3 mg/m[2] PO daily x5, for 4 cycles. Crossover to OSI-906 is allowed.

      Results
      Figure 1 Thirty-three patients have been enrolled; A=10 (res=6, PS 2=2) and B=23 (res=15, PS 2=4). M/F= 13/20; ECOG PS 0/1/2 = 8/19/6. Platinum sen/res = 12/21. Two patients were not treated (A/B = 1/1). Adverse events are described in Table 1. No responses have been observed. Only 2/6 and 1/15 patients in arms A and B respectively achieved SD at 6 weeks. Median PFS (A/B) was 2.1 (95% CI; 0.6, 3.6) and 1.3 (95% CI; 1.0, 1.4) months respectively (p = 0.0149). OS was not reached in arm A and 2.7 (95% CI; 1.5, …) months in arm B (p = 0.1716).

      Conclusion
      OSI-906 is safe in rSCLC patients. In our unselected, high risk population, efficacy in both arms, but particularly in arm B appears suboptimal. The study continues to accrue to reach the sample size and follow up time needed for more robust conclusions.

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    P3.08 - Poster Session 3 - Radiotherapy (ID 199)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P3.08-018 - Stereotactic body radiotherapy for oligometastatic disease to the lung (ID 2371)

      09:30 - 09:30  |  Author(s): H.J. Ross

      • Abstract

      Background
      With the increasing penetration of stereotactic body radiotherapy (SBRT) into cancer practice, there is growing interest in applying this technique to patients with limited metastatic disease. We reviewed our single institution experience using SBRT in the treatment of oligometastatic pulmonary disease.

      Methods
      A retrospective review was performed to identify patients treated at our institution with SBRT for pulmonary metastases between 3/2008 and 1/2013. Treatment decisions were multidisciplinary and a biopsy was performed when feasible. The gross tumor volume (GTV) was non-uniformly expanded to create an internal target volume (ITV) to encompass tumor motion based on 4-dimensional computed tomography (CT). A 5 mm uniform expansion of the ITV was then applied to create the planning target volume (PTV). The most common dose/fractionation schedule was 48-50 Gy in 4-5 fractions. Cone beam CT was used for daily image guidance. Overall survival (OS), time to distant failure (TTDF), and local control (LC) were estimated from the end of the first SBRT procedure using the Kaplan-Meier method. Toxicity was scored based on CTCAEv4. Median follow up was 15 months (range 3-60).

      Results
      64 patients underwent 66 SBRT procedures to treat 74 lesions. There were 36 males (56%) and 28 females (44%) with a median age of 71 years (range 42-90). The most common primary disease sites were lung (n=23; 36%), colorectal (n=10; 16%), melanoma (n=9; 14%), and head and neck (n=5; 8%). The target lesion represented the only site of metastatic disease in 32 patients (50%); 20 patients (31%) had additional pulmonary metastases but no extra-thoracic disease; 12 patients (19%) had both pulmonary and non-pulmonary sites of metastases. Median lesion size was 2.3 cm (range 0.6-6.8). Median, 1-year, and 2-year OS was 21 months, 73%, and 49%, respectively. Distant metastatic disease progression was observed in 37 patients (58%) at a median time interval of 12 months. Patients (n=52) with no extra-thoracic disease at the time of SBRT had a significantly longer TTDF compared to patients (n=12) with concurrent extra-thoracic disease (median 13 vs. 5 months; 1-year failure rate 47 vs. 73%; p = 0.02) without a difference in OS (median OS not reached vs. 20 months; 1-year OS 75 vs. 63%; p=0.1). Local failure was observed for 4 lesions resulting in an 18-month LC rate of 88%. There were 11 toxicities observed in 10 patients including fatigue (n =1, grade 1), dyspnea (n=1, grade 1), dermatitis (n=1, grade 2), rib fracture (n=1, grade 2), and pneumonitis (n= 5, grade 2; n=2, grade 3).

      Conclusion
      SBRT is a reasonable treatment for patients with pulmonary metastases. High rates of local control can be achieved with acceptable toxicity. Only 2 patients (3%) developed grade 3 pneumonitis (oxygen indicated). In this high risk population, new distant metastatic progression was common, especially among patients who present for SBRT with known extra-thoracic sites of disease at the time of SBRT. However, among patients with solitary lung lesions or oligometastatic disease limited to the chest, survival was encouraging. We will continue to utilize SBRT in this population of oligometastatic disease with careful patient selection.