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M. Zeltsman
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MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA04.11 - Mechanistic Insights into CAR T-Cell Efficacy in the Treatment of Heterogenous Antigen Expressing Lung Adenocarcinoma (ID 6039)
17:12 - 17:18 | Author(s): M. Zeltsman
- Abstract
- Presentation
Background:
Our laboratory has translated (NCT02414269, NCT02792114) mesothelin (MSLN), a cancer-antigen, targeted chimeric antigen receptor (CAR) T-cell therapy to solid tumors including for lung adenocarcinoma (ADC) patients. The goal of this study is to investigate the anti-tumor efficacy of MSLN CAR T cells against lung ADC with heterogenous MSLN expression, and further develop mechanistic insights to potentiate the therapy.
Methods:
Human CAR T cells transduced with M28z, MSLN CAR with CD28 costimulation, were tested in vitro (cytotoxicity by [51]Cr release assay, proliferation, cytokine secretion, LFA-1/ICAM-1 [lymphocyte function associated antigen-1/intercellular adhesion molecule 1] adhesion assay, and flow cytometry) and in vivo (tumor and T-cell bioluminescence imaging [BLI], survival) against low-, high- or a mixture (50:50 or 70:30) of MSLN-expressing A549 human lung ADC.
Results:
MSLN CAR T cells demonstrate antigen-intensity dependant cytotoxicity against both low- and high- MSLN-expressing A549 cells with additive bystander cytotoxicity against [51]Cr-labelled low-MSLN A549 cells in the mixture both in vitro (Figure Panel A) and in vivo (22 days delay in tumor progression by low-MSLN A549 cells). Flow cytometry demonstrated ICAM-1 overexpression on low-MSLN A549 cells when treated with effector cytokine-rich supernatant collected by exposure of CAR T cells to high-MSLN A549 cells (Panel B), LFA-1 expression by MSLN-activated CAR T cells (Panel B). Activated CAR T cells adherence to ICAM-Fc coated plates compared to controls (Panel C). LFA-1/ICAM-1 expression promoted adherence of antigen-activated CAR T cells to low antigen-expressing tumor cells (Panel D), which is inhibited in the presence of LFA-1 blocking antibody (Panel E). Figure 1
Conclusion:
We provide a mechanistic reason for the antigen-specific, bystander efficacy of CAR T cells against low-antigen expressing lung cancer cells. Strategies to augment LFA-ICAM interactions between CAR T cells and cancer cells can effectively translate mesothelin-targeted CAR T-cell therapy against heterogenous antigen-expressing solid tumor, lung cancer.
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MA13 - Modern Technologies and Biological Factors in Radiotherapy (ID 395)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Radiotherapy
- Presentations: 1
- Moderators:M. Thomas, P. Mitchell
- Coordinates: 12/06/2016, 16:00 - 17:30, Stolz 1
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MA13.07 - Tumor-Targeted Radiation Promotes Abscopal Efficacy of Regionally Administered CAR T Cells: A Rationale for Clinical Trial (ID 5456)
17:24 - 17:30 | Author(s): M. Zeltsman
- Abstract
- Presentation
Background:
Our laboratory has demonstrated the augmented anti-tumor efficacy of intrapleurally administered cancer-antigen mesothelin (MSLN)-targeted chimeric antigen receptor (CAR) T cells (Sci Transl Med 2014), and translated the approach to a clinical trial (NCT02414269) for thoracic malignancies. We hypothesized that regionally administered MSLN CAR T cells can circulate systemically to achieve abscopal anti-tumor efficacy in an antigen-specific manner, and the abscopal efficacy can further be promoted by tumor-targeted radiation therapy (RT).
Methods:
Using optimized protocols that would permit non-necrotic, well-vascularized tumor growth in pleura, chest wall, peritoneum and flank, tumors were established in immunodeficient (NOD/SCID gamma) mice using mesothelioma or lung adenocarcinoma (LAC) cells. Tumor burden progression, MSLN-targeted CAR T-Cell accumulation at primary and distant tumors was monitored by noninvasive bioluminescence imaging (BLI) and tumor volume measurements.
Results:
A single dose of MSLN CAR T cells administered intrapleurally proliferated (Figure 1A left panel), circulated extrapleurally and accumulated at abscopal sites, including the lymph nodes, chest wall, peritoneum, and flank within 3-5 days, with subsequent T-cell proliferation at abscopal sites (Figure 1A right panel). Primary tumor-targeted, single-dose, thoracic RT prior to T-cell administration augmented T-cell accumulation as demonstrated by BLI (Figure 1B) and tumor T-cell quantification (p<0.01). In a mouse model of primary pleural, abscopal antigen-expressing and non-expressing flank tumors (Figure 1C), a single, low-dose, non-cytotoxic thoracic RT enhanced abscopal site CAR T-cell accumulation that resulted in tumor regression (p=0.01; Figure 1D). Figure 1
Conclusion:
Regionally administered mesothelin-targeted CAR T cells proliferate and eradicate the primary tumor, accumulate and demonstrate anti-tumor efficacy at abscopal sites prior to eradication of the primary tumor in an antigen-specific manner. A single low-dose primary tumor-targeted radiation therapy promotes scopal and abscopal anti-tumor efficacy. These results provide rationale to initiate a clinical trial of combination regional therapies with radiation therapy and CAR T cells.
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P1.08 - Poster Session with Presenters Present (ID 460)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Surgery
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.08-047 - Decreasing Use of Epidural Analgesia with Increasing Minimally Invasive Lobectomy: Impact on Postoperative Morbidity (ID 4941)
14:30 - 14:30 | Author(s): M. Zeltsman
- Abstract
Background:
The goal of this study is to assess the impact of the decreasing use of epidural analgesia (infusion ≥24 hours) on the incidence of postoperative morbidity following minimally invasive surgical (MIS; includes VATS and robotic-assisted) lobectomy in patients with non-small cell lung cancer (NSCLC).
Methods:
We reviewed 1206 patients who underwent MIS lobectomy for pathological stage I-III NSCLC in 2009-10 (n=506) and 2014-15 (n=700) at our institution. Clinical data was obtained from a prospectively maintained database and by review of individual patient medical records. Patients with induction therapy (n=225) or conversion from MIS to thoracotomy (n=99) were excluded. Postoperative morbidity (≤30 days) was graded based on the Common Terminology Criteria for Adverse Events (CTCAE). Statistical comparison was performed using Chi-squared analysis and Fisher’s exact test.
Results:
A total of 884 patients were included in this study (2009-10, n=401; 2014-15, n=483). The rate of MIS lobectomy significantly increased in 2014-15 compared to 2009-10 (74% vs. 53%, p<0.001) with a simultaneous decrease in the use of epidural analgesia (92.9% vs. 53.6%, p<0.001; Figure 1A and 1B). In the MIS group, there was no difference in age, sex, or pathological stage between the 2009-10 and 2014-15 cohorts. There was no significant change in the incidence of any, severe respiratory or cardiovascular morbidity (CTCAE grade ≥3) following MIS lobectomy between the two time periods evaluated (Figure 1C). However, the incidence of CTCAE grade ≥2 respiratory morbidity in 2014-15 was higher than that in 2009-10 (7.1% vs. 12.6%, p=0.047).Figure 1
Conclusion:
In our study cohort, the observed decrease in use of epidural analgesia with the increasing rate of MIS lobectomy did not affect the incidence of severe postoperative morbidity.
