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Moshe Giladi
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Lunch & Poster Display session (ID 58)
- Event: ELCC 2019
- Type: Poster Display session
- Track:
- Presentations: 3
- Moderators:
- Coordinates: 4/11/2019, 12:30 - 13:00, Hall 1
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187TiP - Tumor treating fields concurrent with standard of care therapy for stage IV NSCLC following platinum failure: Phase III LUNAR study (ID 391)
12:30 - 13:00 | Author(s): Moshe Giladi
- Abstract
Background
Tumor Treating Fields (TTFields), a non-invasive anti-mitotic treatment, added to temozolomide significantly extended survival in newly diagnosed glioblastoma. TTFields is eficacious in preclinical in vitro and in vivo NSCLC models. A phase I/II study [NCT00749346] of advanced NSCLC of TTFields plus pemetrexed detected no serious adverse events; median overall survival (OS) of 13.8 months. The Phase 3 LUNAR study [NCT02973789] investigates if TTFields added to immune checkpoint inhibitors or docetaxel following platinum failure will increase overall survival (OS).
a9ded1e5ce5d75814730bb4caaf49419 Trial design
Patients (N = 534) with squamous or non-squamous NSCLC, are stratified by therapy (immune checkpoint inhibitors or docetaxel), histology (squamous vs. non-squamous) and geographical region. Key inclusion criteria: disease progression on or after platinum-based therapy, ECOG 0-2, no electronic medical devices in upper torso, and absence of brain metastases. Docetaxel or immune checkpoint inhibitors are given at standard doses. TTFields (150 kHz) are applied to the upper torso for >18 hours/day. TTFields are continued until progression in the thorax and/or liver. Follow up is performed once q6 weeks, including CT scans of the chest and abdomen. On progression in the thorax and/or liver, patients have 3 post-progression follow up visits and are then followed monthly for survival. The primary endpoint is superiority in OS between patients treated with TTFields in combination with the standard of care treatments versus standard of care treatments alone. Key secondary endpoints compare the OS in patients treated with TTFields and docetaxel versus docetaxel alone, and patients treated with TTFields and immune checkpoint inhibitors vs those treated with immune checkpoint inhibitors alone. An exploratory analysis will test non-inferiority of TTFields with docetaxel compared to checkpoint inhibitors alone. Secondary endpoints include progression-free survival, radiological response rate, quality of life based on the EORTC QLQ C30 questionnaire and severity and frequency of adverse events. The sample size is powered to detect a HR of 0.75 in TTFields-treated patients versus control group.
d9b324a48b043b3d87bc9b3fe620f260 Clinical trial identification
NCT02973789.
7a6a3ffa2dadc03a6151ee2c4d6fa383 Legal entity responsible for the study
Novocure.
213f68309caaa4ccc14d5f99789640ad Funding
Novocure.
682889d0a1d3b50267a69346a750433d Disclosure
U. Weinberg, O. Farber, M. Giladi, Z. Bomzon, E. Kirson: Full time employee, stock options: Novocure.
cffcb1a185b2d7d5c44e9dc785b6bb25 -
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198P - Efficacy of 150 kHz tumor treating fields (TTFields) and cisplatin or pemetrexed for the treatment of mesothelioma cells in vitro (ID 363)
12:30 - 13:00 | Author(s): Moshe Giladi
- Abstract
Background
Malignant pleural mesothelioma (MPM) is a rare and aggressive thoracic cancer that has been strongly linked to asbestos exposure. The standard of care treatment for unresectable mesothelioma is cisplatin plus pemetrexed chemotherapy, which offers modest outcomes. Thus, there is an urgent need to identify more effective treatments for mesothelioma patients. Tumor Treating Fields (TTFields) therapy is an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. We explored the potential use of TTFields alone and in combination with cisplatin or pemetrexed as a treatment for mesothelioma.
a9ded1e5ce5d75814730bb4caaf49419 Methods
NCI-H2052 and MSTO-211H cells were treated at various TTFields frequencies for 72 hours using the inovitro system.
20c51b5f4e9aeb5334c90ff072e6f928 Results
The optimal TTFields frequency leading to the highest reduction in cell counts was 150 kHz for both NCI-H2052 and MSTO-211H cells. TTFields application (1.1 V/cm, 72 hours) at 150 kHz led to 45%, 51% reduction in cell counts and 64%, 46% reduction in clonogenic potential in NCI-H2052 and MSTO-211H cells, respectively. Efficacy of the combined treatment of TTFields and cisplatin or pemetrexed was tested by applying TTFields at the optimal frequency together with various drug concentrations. The combined treatment of TTFields and cisplatin or pemetrexed led to a significant reduction in cell count, induction of apoptosis and reduced clonogenic potential as compared to either modality alone (2-way ANOVA, p < 0.0001(. Safety studies did not reveal any adverse event associated with 150 kHz TTFields application to the rat torso.
fd69c5cf902969e6fb71d043085ddee6 Conclusions
These results demonstrate that TTFields can be an effective treatment against mesothelioma cells and that the combination with cisplatin or pemetrexed may further enhance treatment efficacy. These results are supported by a recent phase 2 study, which reported that MPM patients treated with the combination of TTFields with pemetrexed and platinum experienced improved overall survival as compared to historical control with no increase in systemic toxicity.
b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study
Novocure Israel.
213f68309caaa4ccc14d5f99789640ad Funding
Novocure Israel.
682889d0a1d3b50267a69346a750433d Disclosure
U. Weinberg, M. Munster, R.S. Schneiderman, Y. Porat, T. Voloshin Sela, A. Shteingauz, E. Zeevi, M. Giladi, A. Kinzel, Y. Palti: Full time employee, stock options, stock ownership: Novocure Israel. K. Gotlib, S. Davidi, N. Kaynan: Full time employee, stock options: Novocure Israel. E. Kirson: Full time employee stock options, stock ownership: Novocure Israel; Holds senior leadership position: Novocure Israel.
cffcb1a185b2d7d5c44e9dc785b6bb25 -
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7P - Immunomodulatory effects of Tumor Treating Fields (TTFields) on lung cancer models (ID 436)
12:30 - 13:00 | Author(s): Moshe Giladi
- Abstract
Background
Tumor Treating Fields (TTFields) are a clinically approved anti-mitotic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. In this study, we evaluated whether TTFields-induced cell death can be perceived as immunogenic.
a9ded1e5ce5d75814730bb4caaf49419 Methods
Human and murine lung carcinoma cell lines were treated with TTFields using the inovitro system. Immunogenic cell death was evaluated by changes in the levels of calreticulin (CRT) on the surface of treated cells, phosphorylation of the translation initiation factor eIF2α, and secretion of ATP and High mobility group box 1 (HMGB1). Activation of immune cells was evaluated using co-culture of bone marrow derived dendritic cells (DCs) with TTFields treated cells. For in-vivo studies, mice orthotopically implanted with lung tumors were treated with TTFields, the immune checkpoint inhibitor anti-PD-1 or a combination of the two modalities. Tumor volume was monitored and flow cytometry analysis was performed for phenotypic characterization of infiltrating immune cells.
20c51b5f4e9aeb5334c90ff072e6f928 Results
We demonstrate that cancer cells that died under TTFields application exhibited release of HMGB1, ATP secretion from cells, and ER stress leading to CRT translocation to the cell surface, all of which are cardinal signs of immunogenic cell death. TTFields treated cells promoted in vitro phagocytosis by DCs and DC maturation as well as initiation of inflammation in vivo. The combined treatment of lung tumor-bearing mice with TTFields plus the immune checkpoint inhibitor anti-PD-1 led to a significant decrease in tumor volume compared to anti-PD-1 alone or to the control group. Significant increases in CD45+ tumor infiltrating cells were observed in the TTFields plus anti-PD-1 group. These infiltrating cells demonstrated upregulation of surface PD-L1 expression. Correspondingly, cytotoxic T-cells isolated from these tumors showed higher levels of IFN-γ production relative to untreated mice.
fd69c5cf902969e6fb71d043085ddee6 Conclusions
Our results demonstrate the potential of TTFields therapy to induce immunogenic cell death and increase the efficacy of anti PD-1 therapy by further enhancing antitumor immunity.
b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study
Novocure Israel.
213f68309caaa4ccc14d5f99789640ad Funding
Novocure Israel.
682889d0a1d3b50267a69346a750433d Disclosure
U. Weinberg, T. Voloshin Sela, Y. Porat, M. Munster, R.S. Schneiderman, C. Tempel Brami, S. Cahal, M. Giladi, A. Kinzel, Y. Palti: Full time employee: Novocure Israel; Stock options, stocks: Novocure. N. Kaynan, S. Davidi, A. Shteingauz, K. Gotlib, E. Zeevi: Full time employee: Novocure Israel; Stock options: Novocure. E. Kirson: Full time employee: Novocure Israe; Stock options, stocks: Novocure; Senior leadership position: Novocure.
cffcb1a185b2d7d5c44e9dc785b6bb25
