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E.D. Kirson
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Poster Display Session (ID 63)
- Event: ELCC 2017
- Type: Poster Display Session
- Track:
- Presentations: 3
- Moderators:
- Coordinates: 5/07/2017, 12:30 - 13:00, Hall 1
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133P - The influence of body composition on TTFields intensity in the lungs (ID 466)
12:30 - 13:00 | Author(s): E.D. Kirson
- Abstract
Background:
Tumor Treating Fields (TTFields) are low intensity, alternating electric fields in the intermediate frequency range that disrupt mitosis. The therapy is FDA approved for the treatment of glioblastoma, and a pivotal study testing the efficacy of TTFields in non-small cell lung cancer is planned. TTFields are delivered through two pairs of transducer arrays (TL) placed on the patient's skin. Since the efficacy of TTFields increases with intensity, it is important to identify factors that influence field intensity in the lungs. Therefore, it is important to understand how body shape and composition influence the field intensity. Here we present a computer-simulation-based study investigating the effect of body size, shape and composition on the field distribution in the lungs.
Methods:
The study was performed using the Sim4Life software package and realistic computational phantoms of a female (ELLA), male (DUKE) and obese male (FATS). Various array layouts were placed on the models, and the distribution of TTFields within their lungs were calculated and compared.
Results:
For all models, uniform field distributions within the lungs were obtained when the arrays were axially-aligned with the parenchyma as much as anatomically possible. The layouts that generated the highest average field intensities were those in which one pair of arrays delivered an electric field from the anterolateral to the posterior-contralateral aspect of the patient, with the second pair inducing the field from the antero-contralateral to the posterolateral aspect of the patient. In all models, these layouts led to average field intensities in the lungs of above the therapeutic threshold (>1 V/cm). The highest field intensities developed in DUKE's lungs and the lowest field intensities developed in FATS's lungs. Analysis suggests that field attenuation was caused primarily by layers of fat. Hence, the lower field intensities in the lungs of ELLA and FATS can be largely attributed to the thick layers of fat present in FATS and the fatty tissue in ELLA's breasts.
Conclusions:
This study provides insights into how TTFields distribution in the lungs is influenced by body composition. These insights will help to optimize TL placement and design in the future.
Clinical trial identification:
Legal entity responsible for the study:
Novocure
Funding:
Novocure
Disclosure:
U. Weinberg, N. Urman, H.S. Hershkovich, E.D. Kirson: Employee of Novocure. Z. Bomzon: Paid employee of Novocure Ltd. Y. Palti: The author is a shareholder in Novocure.
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145TiP - TTFields combined with PD-1 inhibitors or docetaxel for 2nd line treatment of non-small cell lung cancer (NSCLC): Phase 3 LUNAR study (ID 408)
12:30 - 13:00 | Author(s): E.D. Kirson
- 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.
Trial design:
We hypothesize that adding TTFields to 2nd line therapies in advanced NSCLC will increase OS. 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.
Clinical trial identification:
NCT02973789
Legal entity responsible for the study:
Novocure Ltd
Funding:
Novocure Ltd
Disclosure:
U. Weinberg, O. Farber, M. Giladi, Z. Bomzon: Full time employee of Novocure. E.D. Kirson: Full time employee of Novocure Ltd
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39P - Efficacy of Tumor Treating Fields (TTFields) and anti-PD-1 in non-small cell lung cancer (NSCLC) preclinical models (ID 457)
12:30 - 13:00 | Author(s): E.D. Kirson
- Abstract
Background:
Tumor Treating Fields (TTFields) are an effective anti-neoplastic treatment modality delivered via non-invasive application of low intensity, intermediate frequency, alternating electric fields. TTFields is approved for the treatment of both newly diagnosed and recurrent glioblastoma. TTFields interrupt mitosis in cancer cells by disrupting microtubules and septin filaments, which play key roles in mitosis. The mitotic effects of TTFields include abnormal chromosome segregation that trigger different forms of cell death. We evaluated TTFields’ effect on immunogenic cell death and its efficacy when combined with an immune checkpoint inhibitor (αPD1) in NSCLC.
Methods:
Murine Lewis lung carcinoma (LLC) cells were treated with TTFields using the inovitro[TM] system. Levels of cell surface calreticulin (CRT) and intracellular ATP levels were evaluated using flow cytometry. High mobility group box 1 (HMGB1) secretion was measured using an ELISA assay. Mice inoculated with LLC cells were treated with isotype control, TTFields, αPD-1, or TTFields + αPD-1. Tumor volume monitoring and intra-tumor immune cell profiling were performed.
Results:
TTFields induced elevated cell surface expression of CRT, decreased ATP levels, and promoted HMGB1 secretion. In vivo, the combined treatment of TTFields + α-PD-1 led to a significant decrease in lung tumor volume compared to all three other groups (P < 0.001). Significant increase in CD45+ tumor infiltrating cells was observed in the TTFields + αPD-1-treated mice. Infiltrating cells demonstrated a significant upregulation of surface PD-L1 expression. Both F4/80+CD11b+ cells and CD11c+ cells exhibited higher tumor infiltration and elevated PD-L1 expression, as compared to the control group. These findings indicate enhanced inflammatory antitumor environment conferred by the combination of TTFields + αPD-1.
Conclusions:
Our results demonstrate that TTFields treatment potentiates immunogenic cell death in NSCLC cancer cells. Combining TTFields with specific immunotherapies such as anti-PD-1 may enhance antitumor immunity and result in increased tumor control. A phase III clinical study on TTFields in combination with either PD-1 inhibitors or docetaxel in NSCLC is underway.
Clinical trial identification:
Not applicable. Preclinical research.
Legal entity responsible for the study:
Novocure Ltd
Funding:
Novocure Ltd
Disclosure:
U. Weinberg: Full time employee of Novocure. T. Voloshin, O.T. Yitzaki, N. Kaynan, M. Giladi, A. Shteingauz, M. Munster, S. Cahal, E.D. Kirson: Full time employee of Novocure Ltd. Y. Palti: Shareholder at Novocure Ltd, NY.
