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Erik R. Rasmussen



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    OA13 - Therapeutics and Radiation for Small Cell Lung Cancer (ID 927)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 203 BD
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      OA13.02 - Two Novel Immunotherapy Agents Targeting DLL3 in SCLC: Trials in Progress of AMG 757 and AMG 119 (ID 14538)

      10:40 - 10:50  |  Author(s): Erik R. Rasmussen

      • Abstract
      • Presentation
      • Slides

      Background
      Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by initial response to chemotherapy and radiotherapy followed by relapse or progression with chemoresistant disease. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is specifically upregulated in SCLC. IHC profiling of tumor samples showed DLL3 expression in 86% of SCLC tumors and minimal expression in normal tissue.
      We are conducting clinical trials of two novel immunotherapy agents that target DLL3. AMG 757 is a half-life extended bispecific T cell engager (BiTE®) antibody construct that is designed to transiently crosslink DLL3-positive SCLC cells to CD3-positive T cells and induce T cell–mediated tumor cell lysis and concomitant T cell proliferation. AMG 119 is an adoptive cellular therapy that consists of a patient’s autologous T cells that have been genetically modified ex vivo to express a transmembrane chimeric antigen receptor that targets DLL3 on the surface of SCLC cells. Both AMG 119 and AMG 757 showed potent killing of SCLC cell lines with a broad range of DLL3 expression in vitro and inhibition of tumor growth in the SHP-77 human SCLC xenograft model in vivo. AMG 757 was well tolerated in a preclinical multi-dose GLP toxicology study, with no evidence of tissue damage at weekly doses as high as 4.5 mg/kg.
      a9ded1e5ce5d75814730bb4caaf49419 Method
      NCT03319940 is an open label, phase 1 study evaluating the safety, tolerability and pharmacokinetics of AMG 757 that will initially enroll adult patients with SCLC who have progressed or recurred following platinum-based chemotherapy. Key inclusion criteria: ECOG PS 0–2, life expectancy ≥12 weeks, at least 2 measurable lesions per modified RECIST 1.1 criteria, and adequate organ function. The study will later enroll patients with extended disease SCLC with ongoing clinical benefit following no more than 6 cycles of first-line platinum-based chemotherapy. AMG 757 will be administered as an intravenous infusion once every 2 weeks.
      NCT03392064 is an open-label, phase 1 study evaluating the safety, tolerability and efficacy of AMG 119 in adult patients with SCLC whose disease has progressed or recurred after at least one platinum-based regimen. Key inclusion criteria: ECOG PS 0–1, at least 2 measurable lesions per modified RECIST 1.1 criteria, no evidence of CNS metastasis, and adequate organ function. AMG 119 will be administered as a one-time intravenous infusion.
      Both of these studies are currently enrolling patients. For more information, please contact Amgen Medical Information: medinfo@amgen.com.
      4c3880bb027f159e801041b1021e88e8

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    P1.04 - Immunooncology (Not CME Accredited Session) (ID 936)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.04-07 - Pemetrexed Enhances Anti-Tumor Efficacy of PD-L1 blockade by Promoting Intra-Tumor Immune Response via Tumor and T Cell-Intrinsic Mechanisms (ID 14269)

      16:45 - 18:00  |  Author(s): Erik R. Rasmussen

      • Abstract
      • Slides

      Background

      The combination of pemetrexed/carboplatin with the PD-1 antibody pembrolizumab demonstrates a substantial increase in overall survival in NSCLC patients (hazard ratio 0.49) based on KEYNOTE-189 Phase III data (Gandhi et al., 2018), and represents the first chemoimmunotherapy combination ever approved in Oncology. However, the mechanisms underlying the efficacy of this combination remain largely unknown. Many chemotherapies in general and antifolates in particular have detrimental effects on immune homeostasis, and differ in their ability to induce immunogenic tumor cell death. Nevertheless, KEYNOTE-189 results suggest a positive interaction between pemetrexed-based chemotherapy and immunotherapy highlighting the importance to understand the role of pemetrexed in modulating antitumor immune response to assure rational application of this therapy to the appropriate patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      To characterize the effects of pemetrexed on intra-tumor immune response, murine syngeneic tumor models (MC38 and Colon 26) were treated with pemetrexed, paclitaxel with or without carboplatin, or anti-mouse PD-L1. Immune cell subsets and immune-related changes in tumor tissue and T cells were assessed by flow cytometry and gene expression analysis. Tumor and T cell-intrinsic effects of pemetrexed including ability to induce immunogenic cell death of tumor cells and enhance immune function through changes in mitochondrial respiration and gene expression in T cells were also evaluated.

      4c3880bb027f159e801041b1021e88e8 Result

      In MC38 syngeneic mouse tumor model, pemetrexed increases frequency of intratumor leukocytes and cycling (Ki67+) T cells accompanied by gene expression changes indicative of T cell inflamed phenotype. In contrast, paclitaxel exerts quantitatively and qualitatively different immune effects mainly associated with modest upregulation of myeloid cell-related genes whereas carboplatin barely exhibits any immune-related changes in monotherapy and appears to attenuate immunomodulatory effects induced by pemetrexed in MC38 tumors. Pemetrexed in combination with PD-L1 antibody demonstrates enhanced antitumor efficacy and pronounced inflamed/immune activation phenotype in Colon26 syngeneic mouse tumor model. In vitro data indicate that pemetrexed is a potent inducer of immunogenic tumor cell death as exemplified by marked release of HMGB1 in MC38 and Colon26 tumor cells and suggest T cell-intrinsic effects exemplified by enhanced mitochondrial content, oxidative respiration and increased expression of cell surface molecules and immune-related genes indicative of T cell activation.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pemetrexed promotes intra-tumor T cell-mediated immune response through immunogenic tumor cell death and increased activation and metabolic fitness of T cells leading to an enhanced anti-tumor efficacy in combination with PD-L1 antibody.

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