Virtual Library

 x 
My Library Virtual Library FAQ

Start Your Search

A. Varghese



Author of

  • +

    MO13 - SCLC I (ID 118)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
    • +

      MO13.10 - Prospective Molecular Evaluation of Small Cell Lung Cancer (SCLC) Utilizing the Comprehensive Mutation Analysis Program at Memorial Sloan-Kettering Cancer Center (MSKCC) (ID 3137)

      11:25 - 11:30  |  Author(s): A. Varghese

      • Abstract
      • Presentation
      • Slides

      Background
      Oncogenic events in adenocarcinoma and squamous cell cancers of the lung are well described. In contrast, the repertoire of possible molecular targets in SCLC still is unclear. Recent studies using next generation sequencing on rare resected SCLC specimens have provided insights into the molecular heterogeneity of this disease. Comprehensive, prospective molecular profiling of patients with SCLC using the biopsy specimens available in clinical practice has not been performed.

      Methods
      Utilizing an IRB-approved protocol to prospectively test SCLC tumors (Small Cell Lung Cancer Mutation Analysis Program, “SCLC-MAP”), these biopsies are evaluated by: FISH for FGFR1 and MET amplification; immunohistochemistry (IHC) for MGMT and PTEN loss; point mutation genotyping with Sequenom for PIK3CA (and others); and next-generation sequencing with our MSK-IMPACT assay (Integrated Mutation Profiling of Actionable Cancer Targets). MSK-IMPACT uses exon capture followed by massively parallel sequencing to profile all protein-coding exons and select introns of 279 cancer-associated genes, enabling the identification of mutations, indels, and copy number alterations of these genes. First, we tested the feasibility of this approach in a series of SCLC patients that were identified retrospectively as they had banked matched tumor and normal pairs. We performed next generation sequencing with MSK-IMPACT, with findings confirmed by FISH on these samples. We are prospectively collecting and evaluating SCLC tumors of our patients in active treatment, as detailed above.

      Results
      For our feasibility cohort, we identified 21 patients with SCLC with FFPE samples available from both matched normal tissue and small tumor biopsies. After histologic review and DNA extraction, 10 patients had adequate tissue for MSK-IMPACT (3 core biopsies, 7 fine needle aspirates). The following were noted: recurrent mutations in Rb1 (N=7) and p53 (N=8), FGFR1 amplification (N=2), and MET amplification (N=1), using as little as 15 nanograms of DNA. FGFR1 and MET amplification were confirmed by FISH testing. We have initiated this prospective SCLC-MAP program for our SCLC patients undergoing active treatment. Since 2/2013, 25 patients have provided consent and tumor tissue for analysis (8 surgical resections, 12 core biopsies, 3 lymph node dissections, 2 fine needle aspirates). Preliminary data are available for 16 patients: AKT1 E17 mutation by Sequenom (N=1), MGMT loss by IHC (N=1); and PTEN loss by IHC (N=2).

      Conclusion
      As adequate biopsy specimens are necessary to match lung cancer patients and treatments, increased number of patients with SCLC are presenting with more tissue. Comprehensive molecular evaluation of SCLC is feasible on clinically available specimens, as seen in our feasibility cohort. Prospective collection of SCLC tumor samples and mutational analyses are ongoing. Such analyses will allow us to characterize the molecular diversity of this disease and identify patients who will be candidates for targeted therapies. Funded, in part, by the Lung Cancer Research Foundation.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    P3.13 - Poster Session 3 - SCLC (ID 202)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
    • +

      P3.13-007 - Pilot trial of an adjuvant pentavalent vaccine for patients with small cell lung cancer (SCLC) (ID 2830)

      09:30 - 09:30  |  Author(s): A. Varghese

      • Abstract

      Background
      Despite initial responses to chemotherapy, SCLC typically progresses within a few months. Targeting residual disease has the potential to improve outcomes. A number of tumor specific glycolipid antigens have been identified and are potential targets for immune therapies. In a series of phase I clinical trials, vaccination with each of these antigens individually was safe and induced antibody responses in the majority of patients. Preclinical data indicate that combining these antigens will expand the immunogenicity across a broader array of SCLC tumor cells. We conducted this pilot trial to determine the safety and immunogenicity of a vaccine combining five of these antigens.

      Methods
      Patients with limited or extensive stage SCLC who have completed initial chemotherapy +/- thoracic or cranial irradiation with a maintained response are eligible. Vaccinations must start within 3-8 weeks of the last chemotherapy, and at least 1 week after radiation. Patients receive KLH-conjugates of GD2L, GD3L, Globo H, fucosyl GM1, and N-propionylated polysialic acid (30mcg each) plus OPT-821 adjuvant (150mcg) subcutaneously on weeks 1, 2, 3, 9, 20, and 32. One cycle of etoposide/platinum chemotherapy was administered in week 6. A significant immune response is defined as an antibody titer of ≥ 1:80 by ELISA against a given antigen or a ≥ 8 fold increase over baseline for patients with a detectable baseline titer. The vaccine would be deemed worthy of further study if >5 patients had an immune response to 3 or more antigens.

      Results
      Ten patients were treated, including 9 with extensive stage, 4 women, 7 with prior brain radiation. The number of vaccinations administered was: 1 (1pt), 3 (2), 4 (3), 5 (2), and 6 (2). Toxicity was limited to mild skin reactions. One patient was taken off study after he developed aphasia the day after the first vaccination; MRI brain was unremarkable and symptoms resolved spontaneously. No patients met the predefined criteria for immune response. Six patients had increases in IgM titers to 1-2 antigens. The median time to progression was 4 months. The two patients with the strongest IgM responses to Globo H and fucosyl GM1, and also the only IgG responses to fucosyl GM1, had progression of disease 7 and 9 months after starting the vaccines, and both progressed initially in the brain only.

      Conclusion
      The polyvalent vaccine is safe, but fewer patients than expected had a significant immune response, Two patients with immune responses experienced a longer than expected time to progression. A second cohort of patients is now receiving the vaccinations over a shorter period of time and without the added cycle of chemotherapy. Five out of 10 of those patients have been enrolled, and preliminary data will be available on those patients for the meeting. Following completion of this pilot trial, a multicenter randomized trial is planned. Supported by MabVax Therapeutics’s NIH grant R41 CA128363 and a grant from FAMRI.