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Daniel H. Sterman
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MA 10 - Immunotherapy I (ID 664)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:S. Wang, Robert Pirker
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 303 + 304
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MA 10.10 - Tumor Draining Lymph Node Immunophenotype Corresponds with Primary Tumor Characteristics in Patients with Non-Small Cell Lung Cancer (ID 10343)
12:05 - 12:10 | Presenting Author(s): Daniel H. Sterman
- Abstract
- Presentation
Background:
There is growing appreciation for the role of tumor-draining lymph nodes (TDLN) in the dynamic of immunoediting orchestrated by non-small cell lung cancers (NSCLC). By comparing T-cell subsets and gene expression in TDLN and non-draining lymph nodes (NDLN), we aim to determine whether there is tumor-regional variation in immunophenotype.
Method:
Patients undergoing endobronchial ultrasound-guided transbronchial needle aspiration for the diagnosis/staging of NSCLC were recruited. Aspirates were obtained from TDLN (N1/N2 nodes with increased fluorodeoxyglucose-F-18 (FDG) avidity and/or enlarged >1cm) and NDLN (non-enlarged/non-FDG-avid N2/N3 nodes) along with peripheral blood. Samples were stained with fluorophore-conjugated antibodies (CD4-FITC, CD8-V450, CD25-PECy7, CD127-APCR700, CD45RO-PECF594) and analyzed by flow cytometry. CD4+CD25- and CD8+ effector T-cells (Teff) were sorted. Gene expression profiling was performed on sorted Teff using the Nanostring™ platform to measure differential expression between TDLN and NDLNs.
Result:
We compared T-cell subpopulations in TDLN and paired NDLN from 16 subjects. There were significantly fewer CD4+ T-cells in TDLN vs NDLN (10.1% vs 28.9%, p=0.0039), with more Tregs (12.1% vs 7.3%, p=0.1563) suggesting a pattern of tumor-regional immunosuppression in the TDLN. This was more consistent when tumor histology was adenocarcinoma compared to squamous cell cancer with respect to both depletion of Teff and higher proportion of Tregs (Figure 1). A more immunosuppressive TDLN phenotype was also observed with high tumor PD-L1 expression (>50%), with 36% fewer CD4+ T-cells in TDLN relative to paired NDLN when PD-L1 expression was high relative to just 3.2% fewer CD4+ T-cells with low PD-L1 expression. Gene expression in Teff has preliminarily demonstrated upregulation of genes mediating T-cell exhaustion (CTLA-4, PD-1, TGF-β) and downregulation of co-stimulatory/recruitment factors (CD28, ICOS, ICAM2) in TDLN suggesting impaired activation of tumor-regional Teff. Figure 1
Conclusion:
Our findings suggest that TDLNs in patients with NSCLC display a tolerogenic phenotype, with more marked immunosuppression in the setting of adenocarcinoma and high tumor PD-L1 expression.
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OA 02 - Mesothelioma: Challenges For New Treatment (ID 653)
- Event: WCLC 2017
- Type: Oral
- Track: Mesothelioma
- Presentations: 1
- Moderators:S. Hasegawa, Anna Nowak
- Coordinates: 10/16/2017, 11:00 - 12:30, F205 + F206 (Annex Hall)
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OA 02.04 - Discussant - OA 02.01, OA 02.02, OA 02.03 (ID 10827)
11:30 - 11:45 | Presenting Author(s): Daniel H. Sterman
- Abstract
- Presentation
Abstract not provided
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P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-059 - Phase I Trial of Gene Mediated Cytotoxic Immunotherapy (GMCI) for Malignant Pleural Effusion (MPE) and Malignant Pleural Mesothelioma (MPM) (ID 10269)
09:30 - 09:30 | Presenting Author(s): Daniel H. Sterman
- Abstract
Background:
GMCI is a tumor-specific immune-stimulator through local delivery of aglatimagene besadenovec, an adenovirus-based vector expressing the HSV-1 thymidine kinase gene (AdV-tk) followed by anti-herpetic prodrug. We conducted a phase I dose escalation trial of intrapleural administration of aglatimagene besadenovec followed by standard chemotherapy in patients with MPE.
Method:
The primary end-point of this dose escalation trial was safety. Eligibility included patients with MPE or MPM with a clinical indication for placement of pleural catheter, age > 18 yrs, ECOG PS 0-1, FEV1> 40% predicted and adequate end organ function. Intra-pleural (IP) AdV-tk was administered at doses of 1x 10[12 ]viral particles (vp) (Cohort 1); 1x10[13 ]vp (Cohort 2); and 1x10[13 ]vp plus celecoxib (Cohort 3). Three patients were treated per cohort with 10 patients in the expansion phase. Valacyclovir (2 gm PO TID x 14 days) started the day after AdV-tk followed by chemotherapy. Secondary end-points included response rate, progression free survival, overall survival and immune response.
Result:
From 2013 to 2015, 19 patients were enrolled and completed therapy: median age 69.5 years (range 41-89), 14 malignant mesothelioma (MM) (9 epithelioid, 3 sarcomatoid, 2 biphasic), 4 non-small cell lung cancer (NSCLC) and 1 breast cancer. Eight patients received IP AdV-tk upon diagnosis, 7 prior to 2[nd] line and 4 prior to 3[rd] line chemotherapy. Safety results have previously been reported. Response according to RECIST was evaluable for 17 pts. Best response was PR in 4 patients (3 with MM, and one pt with NSCLC), 9 SD and 4 PD. As of 05/2017, three patients are alive and in active follow up (one with NSCLC, and 2 with MM), range of follow up 21-32 months. Of the 4 patients with NSCLC, 3 had prolonged disease stabilization (median overall survival 25.7 months post-GMCI), and one patient is still alive 3.6 years from initial diagnosis (29 month post-GMCI).
Conclusion:
We previously reported that GMCI can be safely administered at high-doses IP in combination with chemotherapy. With median follow up of 31 months, we report that the majority of the patients experienced clinical benefit and sustained disease stabilization was seen in patients with NSCLC. Three patients are still alive and in active follow up. Phase II studies are warranted to further determine efficacy based on these preliminary encouraging observations; NCT01997190.
