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S. Albelda
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OA13 - Immunotherapy in Malignant Pleural Mesothelioma: Current Status of Trials and New Approaches (ID 392)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
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OA13.07 - Intrapleural Modified Vaccine Strain Measles Virus Therapy for Patients with Malignant Pleural Mesothelioma (ID 5655)
15:25 - 15:35 | Author(s): S. Albelda
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MM) remains an almost universally fatal disease with limited treatment options. Preclinical models indicate the preferential oncolytic activity of the modified vaccine strain measles virus carrying the gene for the human sodium-iodine symporter (NIS) – MV-NIS. Intraperitoneal and intravenous administration of MV-NIS was recently found to be potentially effective in patients with refractory ovarian cancer and multiple myeloma. However, whether MV-NIS is directly oncolytic or triggers an anti-tumor immune response remains unclear.
Methods:
We conducted a phase I dose escalation study with 3+3 design and ongoing maximal tolerated dose (MTD) expansion cohort. MV-NIS was administered as first or second line therapy via a tunneled intrapleural catheter to patients with MM. MV-NIS dose ranged from 10[8] TICID~50~ to 9 x 10[9] TICID~50~. In the absence of dose limiting toxicity and disease progression, patients received up to 6 cycles of MV-NIS therapy (Phase I). Currently additional patients are being randomized between a single and multiple cycles. MV-NIS infection and replication are monitored by Iodine[123] SPECT/CT (Phase I only) as well as by RT-PCR and/or plaque-assay. Anti-tumor immunity is monitored in the blood and pleural fluid and patients are followed clinically by chest CT using the modified RECIST criteria.
Results:
Twelve patients (3/dose level) received MV-NIS therapy. There were no dose limiting adverse events and therapy was well tolerated. The best therapeutic response was stable disease, which was achieved at 1 month by 8/12 evaluable patients (67%). Median overall survival was 449 days (95%CI: 221, 484) (~15 months) (4/12 patients remain alive), and median progression free survival was 63 days (95% CI: 33, 174) (~2 months). MV infection and replication were detectable by RT-PCR and plaque assay in the pleural fluid between 24-72 hours after treatment. I[123] SPECT-CT demonstrated only marginal viral gene expression in a single patient treated with the highest dose level. MV-NIS therapy effectively boosted pre-existing anti-MV neutralizing antibody responses in the plasma and pleural fluid of most patients. We observed a transient inflammatory response in the pleural space after MV-NIS administration. In addition, induction or boosting of anti-tumor antibody responses was observed.
Conclusion:
The intrapleural administration of MV-NIS is safe, resulted in stable disease for 67% of patients and may be associated with favorable overall survival in MM. While there was only transient infection and viral replication, we observed the induction of anti-tumor immune responses supportive of potential long-term therapeutic impact. The study continues with the MTD expansion cohort.
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P3.03 - Poster Session with Presenters Present (ID 473)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.03-027 - Growth Factor and Inflammatory Signaling Pathway Interactions Influence Outcomes Following Multimodality Therapy for Mesothelioma (ID 6406)
14:30 - 14:30 | Author(s): S. Albelda
- Abstract
Background:
Photodynamic therapy (PDT) and external beam radiotherapy (RT) have been used as adjuvant therapies directed at increasing local control in patients undergoing surgical resection for malignant pleural mesothelioma (MPM). In patients with MPM treated with a surgically-based multimodality treatment program that involves intraoperative PDT and postoperative RT for MPM, we have previously demonstrated that expression/activation of epidermal growth factor receptor (EGFR)/STAT3 signaling correlates with increased pleural recurrence rates and decreased overall survival. We assessed if activation of STAT3 through EGFR pathway activation mediates resistance of lung cancer cells to either PDT or ionizing RT.
Methods:
Tumor samples from patients with MPM undergoing lung-sparing surgery/intraoperative PDT and postoperative RT were analyzed for expression of growth factor and inflammatory signaling pathways using both IHC and Nanostring techniques. For in vivo assays, Balbc mice with syngeneic Ab12 MPM tumors were treated with partial surgical resection followed by PDT. In vitro studies involved human MPM cell lines derived from subjects enrolled on tissue acquisition with a pTRIPZ expression vector designed to allow doxycycline-induced STAT3 or EGFR shRNA expression.
Results:
Ninety-three consecutive patients were assessed. Patients undergoing surgery/PDT and RT with median time to local recurrence of <12 months demonstrated elevated EGFR/STAT3 expression levels and increased plasma IL-6 after tumor resection as compared to patients with a median time to local recurrence of > 12 months. In vivo studies in Balbc mice undergoing incomplete surgical resection of Ab12 MPM flank tumors demonstrated activation of STAT3 and EGFR signaling as well as increased plasma IL-6. Moreover, this activation was associated with decreased efficacy of postoperative PDT as compared to mice bearing equivalent sized tumors undergoing PDT without surgery and the effects of surgery on PDT were abolished by pretreating animals with the Cox-2 inhibitor celecoxib. Finally, using a novel 3D in vitro MPM cell culture system, we found that activation of EGFR/STAT3/Cox-2 signaling pathways significantly decreased PDT and RT mediated cellular cytotoxicity. Conversely, inhibition of these pathways enhanced PDT and RT efficacy.
Conclusion:
Both EGFR and STAT3 are activated in the wound healing/inflammatory response to surgical injury, and EGFR/STAT3 activation leads to increased cox-2 expression. Taken with the above results, this suggests that surgically mediated activation of these pathways, possibly through STAT3-mediated growth factor/inflammatory signaling pathways, impairs the potential efficacy of intraoperative/post-operative PDT and RT and that inhibition of this response to surgery might enhance clinical outcomes in patients with MPM.
