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T. D'Amico

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    MINI 26 - Circulating Tumor Markers (ID 148)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI26.05 - Immunophenotyping of Circulating T Cells and TILs with Chemotherapy and Phased Ipilimumab in Non-Small Cell Lung Cancer (ID 2787)

      16:45 - 18:15  |  Author(s): T. D'Amico

      • Abstract
      • Presentation
      • Slides

      Ipilimumab (Ipi) is a humanized CTLA-4 antibody that blocks binding of CTLA-4 with its cognate ligands, permitting T cell activation through CD28 binding. There is evidence that phased in Ipi added to chemotherapy (C) may enhance efficacy in non-small cell lung cancer NSCLC. This trial was undertaken to gain a better understanding of the changes that occur in T cells, regulatory T cells (Tregs), and myeloid-derived suppressor (MDSC) in both the blood and tumor micro-environment with CTLA-4 blockade.

      Patients with stage T > 4 cm and/or N1, N2 NSCLC were offered neoadjuvant carboplatin AUC6 plus paclitaxel 200 mg/m[2] every 21 days 3 cycles with ipilimumab 10 mg/kg day 1 cycles 2 and 3. Blood for immune profiling of circulating T cells was collected prior to cycle 1, after cycle 1 chemotherapy alone, and after cycle 3 chemotherapy plus Ipi. If patients underwent tumor resection and excess tumor was available, viable tumor infiltrating lymphocytes (TILS) were disaggregated and stored for later analysis. Phenotypic and functional polychromatic flow cytometry (PFC) analyses were performed on peripheral blood mononuclear cells (PBMC).

      Blood was successfully collected at all 3 time points for the first 17/18 patients who initiated trial therapy. Excess tumor (0.96-5 gms) was collected on 5 patients and ample viable CD45+ TIL cells (9.4-26x10[6]) were isolated and viably cryopreserved. Phenotypic analyses revealed that both CD4+ and CD8+ cells from all 17 patients were highly activated following two cycles of ipilimumab (cycle 3) as evidenced by greatly increased frequencies of CD28, HLA-DR, PD-1, and intracellular CTLA-4 expressing cells. The frequencies of Tregs, defined by CD4+CD25+FoxP3+ expression, were highly variable among the 17 participants, with 8 showing increased Tregs, 7 showing decreased frequencies, and 2 remaining unchanged over the course of therapy. Seven of the 17 participants had levels of MDSC cells at or above 5%, with two patients achieving MDSC levels of 13% and 26.7%. Tumor associated antigen (TAA)-specific CD4+ or CD8+ cells were detected at baseline on 4 patients (24%), but their relative frequencies were unaltered by Ipi therapy. The most commonly recognized TAA was Survivin, followed by MAGEA3 and PRAME. No patients developed detectable de novo TAA reactivities while on Ipi therapy. We will report the phenotypic and functional parameters of TILs isolated from 5 tumors of the patients enrolled on the current trial at the time of presentation.

      TAA-specific CD4+ or CD8+ cells were unexpectedly detected in the blood at baseline in a subset of patients. We were able to determine what common NSCLC antigens the circulating CD4+ or CD8+ T cells were activated against, and this has the potential to be a blood based biomarker for trials studying immunotherapy such as vaccines. Neoadjuvant ipilimumab therapy neither facilitated the development of anti-TAA reactivities nor enhanced the frequencies of existing TAA-reactive T cells in PBMC. Neoadjuvant ipilimumab therapy effectively enhanced the frequencies of highly activated T cells, but had no consistent effect of the frequencies of Tregs.

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