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R. Kratzke
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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): R. Kratzke
- 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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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-057 - Viroimmunotherapy with Vesicular Stomatitis Virus Expressing Interferon-β (Vsv-IFNβ) in a Murine Model of NSCLC (ID 6217)
14:30 - 14:30 | Author(s): R. Kratzke
- Abstract
Background:
VSV-IFNβ is a live, replicating oncolytic virus with activity against NSCLC. We have previously shown that VSV-IFNβ leads to an inflamed tumor microenvironment and enhances anti-tumor immunity in a syngeneic mouse model. Furthermore, we have observed increased PDL-1 expression on tumor cells after intratumoral injection with VSV-IFNβ. Here, we have further explored the mechanisms by which VSV-IFNβ exerts its immunologic effects and combined therapy with anti-PD1 and anti-PDL1 antibodies.
Methods:
VSV-human and murine IFNβ (hIFNβ and mIFNβ, respectively) and VSV-IFNβ-NIS are manufactured by the Imanis Life (Rochester, MN) and titered on Vero cells by limiting dilution method. H460, H2009, H838, H2030, and A549 human NSCLC cells were grown in RPMI with 10% serum. LM2 cells (murine lung adenocarcinoma cells) were grown in DMEM with 10% serum. For cytotoxicity assays, NSCLC cells are treated with VSV-IFNβ at varying MOI. CCK8 assay was used to estimate cell viability 72 hours later. For in vivo experiments, A/J mice are injected with 2x10[6] LM2 cells in the flank. After tumors form, unilateral intratumoral injections are given at varying doses on days 1,3, and 5. For combination experiments, VSV-IFNβ is given in combination with intraperitoneal anti-PD1 or PDL1 antibodies or Isotype IgG or with JAK inhibitor, ruxolitinib. Tumor infiltrating leukocytes (TIL) were analyzed by flow cytometry for presence of CD8/CD4 T cells, Tregs, and MDSCs after VSV-IFNβ infection.
Results:
VSV-IFNβ treatment on human NSCLC cells induced PDL-1 expression by Western blot and flow cytometry, but not VSV-GFP which is abrogated by pretreatment with ruxolitinib. Furthermore, viral replication was enhanced by pretreatment with ruxolitinib. In vivo immune effects of combination ruxolitinib and VSV-IFNβ are ongoing. TILs were examined by flow cytometry after intratumoral injection of VSV-mIFNβ or VSV-hIFNβ. There was increased T-cell infiltration, decreased Tregs and increased PDL-1 expression in both groups. Antitumor activity was similar between VSV-mIFNβ and VSV-hIFNβ suggesting that effects observed are mediated by the virus rather than exogenous IFNβ. CD4 T cell depletion had no effect on antitumor responses or on immune infiltration of CD8 T cells in the tumor microenvironment. CD8 T cell depletion experiments and combination treatments of VSV-IFNβ and VSV-IFNβ-NIS with Anti-PD1/PDL1 antibodies are ongoing.
Conclusion:
VSV-IFNβ is a promising oncolytic agent for non-small cell lung cancer and induces an inflamed tumor microenvironment in a process that is independent of exogenous IFNβ and CD4 T cells. Our data support clinical testing of VSV-IFNβ with checkpoint blockade for NSCLC.
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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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P3.03-036 - Prognostic Model for Mesothelioma Based on Cancer and Leukemia Group B (CALGB) Trials (Alliance) (ID 3976)
14:30 - 14:30 | Author(s): R. Kratzke
- Abstract
Background:
Prognostic models play an important role in the design and analysis of mesothelioma treatment trials. The European Organisation for Research and Treatment of Cancer (EORTC) developed a well-known tool in 1998 to predict overall survival (OS) in patients with malignant mesothelioma. In this study, we built and assessed the performance of a new mesothelioma prognostic model OS using data from multiple CALGB clinical trials data.
Methods:
This study included 595 mesothelioma patients from fifteen completed CALGB treatment trials accrued between June 1984 and August 2009. We split the cohort of patients into two parts - 67% of patients as training and 33% as testing. We developed a Cox model using the training set with PS, age, WBC count, and platelet count as prognostic variables. To compare the EORTC and our new models, the concordance of predicted survival times and risk scores were estimated by concordance C (c-index) (Harrell et al. 1996) and AUC score at 6-months (Patrick et al. 2000). 95% confidence intervals were calculated for the c-index. Based on the prediction model fit from training set, we partitioned testing set patients into high-risk and low-risk groups using the median for their risk score values for the new model. For the EORTC model, the cut off of 1.27 from the original paper was used to assign the high-risk and low-risk groups. A Log-rank test was used to compare the survival curves of these two groups. We also compared our results with a model using PS alone.
Results:
For OS, the EORTC model c-index was 0.55 (0.52, 0.58) and P = 0.0007 comparing high- and low- risk patients for testing set. The new model c-index was 0.60 (0.56, 0.64), with P < 0.000001 for testing set. Using the new model, the median OS in the high-risk and low-risk groups in the testing set were 5.16 (4.70, 6.37) and 10.41 (7.95, 14.32) months, respectively. PS alone produced c-index of 0.55 (0.53, 0.57) and P = 0.0002 for testing set. The AUC scores at 6-months for testing set generated by EORTC and PS alone models are 0.62 and 0.66. The new model generated AUC scores at 6-months of 0.70.
Conclusion:
Our new model performs better than the EORTC model or PS alone for survival prognostication in patients with mesothelioma.
