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Moshe Giladi
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-088d - TTFields Combined with PD-1 Inhibitors or Docetaxel for 2nd Line Treatment of Non-Small-Cell Lung Cancer (NSCLC): Phase 3 LUNAR Study (ID 7563)
09:30 - 09:30 | Author(s): Moshe Giladi
- Abstract
Background:
Tumor Treating Fields (TTFields) are a non-invasive, anti-mitotic treatment modality. TTFields disrupt the formation of the mitotic spindle, and dislocation of intracellular constituents. TTFields significantly extend the survival of newly diagnosed glioblastoma patients when combined with temozolomide. Efficacy of TTFields in NSCLC has been shown preclinically and in a phase I/II pilot study with pemetrexed, where overall survival (OS) improved by > 5 months vs historical controls. We hypothesize that adding TTFields to 2nd line therapies in advanced NSCLC will increase OS.
Method:
Patients (N=512) with squamous or non-squamous NSCLC are enrolled in this Phase 3 study LUNAR [NCT02973789]. Patients are stratified by 2[nd] line therapy (PD-1 inhibitor or docetaxel), histology (squamous vs. non-squamous) and geographical region. Key inclusion criteria are 1st disease progression (RECIST 1.1), ECOG 0-1, no prior surgery or radiation therapy, no electronic medical devices in the upper torso, and absence of brain metastasis.Docetaxel or PD-1 inhibitors (either nivolumab or pembrolizumab) are given at standard doses. TTFields are applied to the upper torso for at least 18 hours/day, allowing patients to maintain daily activities. TTFields are continued until progression in the thorax and/or liver according to the immune-related response criteria (irRC). Follow up is performed once q6 weeks, including CT scans of the chest and abdomen. On progression in the upper torso, patients are followed monthly for survival. The primary endpoint is superiority in OS between patients treated with TTFields in combination with either docetaxel or PD-1 inhibitors, compared to docetaxel or PD-1 inhibitors alone. A co-primary endpoint compares the OS in patients treated with TTFields and docetaxel to those treated with PD-1 inhibitors alone in a non-inferiority analysis. Secondary endpoints include progression-free survival, radiological response rate based on the irRC, quality of life based on the EORTC QLQ C30 questionnaire and severity & frequency of adverse events. The sample size is powered to detect a HR of 0.75 in TTFields-treated patients versus control group.
Result:
Section not applicable
Conclusion:
Section not applicable
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P3.07 - Immunology and Immunotherapy (ID 723)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.07-013d - Tumor Treating Fields Induce Immunogenic Cell Death and Enhance Antitumor Effects of Anti-PD1 in NSCLC In-Vivo Models (ID 8952)
09:30 - 09:30 | Author(s): Moshe Giladi
- Abstract
Background:
Tumor treating fields (TTFields) exert directional forces on microtubules and dielectrophoretic forces on charged molecules leading to abnormal spindle formation. As a result, Cells may die in mitotic arrest or divide into abnormal daughter cells which can die during the following interphase or proliferate to be re-exposed to TTFields. Studies have shown cancer cell type specific frequency dependence for TTFields effects, and that some of the outcomes of abnormal mitosis under TTFields may trigger different forms of cell death. In this study we determined the optimal frequency of TTFields in NSCLC cell lines, and evaluated whether cell death induced by TTFields is potentially immunogenic. Finally, we explored the combination of TTFields with anti-PD1 therapy in-vivo.
Method:
We investigated the effect of TTFields in-vitro using four human NSCLC cell lines and two murine cell lines. Inhibition of tumor cell growth was analyzed by cell count. Survival fractions were calculated relative to control. We also evaluated the induction of immunogenic cell death by TTFields in vitro. Lewis lung carcinoma (LLC) were treated with TTFields. Levels of calreticulin on the surface of treated cells and intracellular ATP levels were evaluated using flow cytometry. High mobility group box 1 (HMGB1) secretion was measured using an ELISA assay. The effect of TTFields and anti-PD1 was tested on mice orthotopically implanted with LLC cells and treated with TTFields, anti-PD1, or the combination. Tumor volume was monitored; flow cytometry analysis was performed for phenotypic characterization of infiltrating immune cells.
Result:
TTFields therapy was found to induce a frequency-dependent reduction in viability in all six cell lines, with a common peak effective frequency at 150 kHz. TTFields induced elevated cell surface expression of calreticulin, decreased intracellular ATP levels, and promoted HMGB1 secretion. The combined treatment of tumor-bearing mice with TTFields plus anti-PD1 led to a significant decrease in tumor volume compared to anti-PD1 alone or to the control group. Significant increases in CD45+ tumor infiltrating cells were observed in the TTFields plus anti-PD1 group. These infiltrating cells demonstrated a significant up-regulation of surface PD-L1 expression. Specifically, both F4/80+CD11b+ cells, and CD11c+ cells exhibited higher tumor infiltration and elevated PD-L1 expression versus infiltrating immune cells in the control group.
Conclusion:
The inhibitory effects of TTFields were maximal at 150 kHz for all NSCLC cell lines tested. TTFields treatment potentiates immunogenic cell death in cancer cells. Combining TTFields with anti-PD1 may enhance antitumor immunity and result in increased tumor control.
