Virtual Library
Start Your Search
J. Hegmans
Author of
-
+
MINI 18 - Radiation Topics in Localized NSCLC (ID 139)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
-
+
MINI18.03 - Immune Activation in Early Stage Non-Small Cell Lung Cancer (NSCLC) following Stereotactic Ablative Radiotherapy (SABR) and Surgery (ID 2123)
16:55 - 17:00 | Author(s): J. Hegmans
- Abstract
- Presentation
Background:
An anatomical surgical resection is considered to be the standard of care in fit patients, but non-randomized comparative effectives studies suggest that survival outcomes may be similar following SABR. An antitumor immune microenvironment was found to be a prognostic factor in surgically resected early stage NSCLC. SABR has been reported to activate the immunesystem in malignant diseases via a number of mechanisms. We investigated the impact of both surgery and SABR in early stage NSCLC on the immunesystem, studied in peripheral blood over time.
Methods:
This is a non-randomised trial. Treatment by either surgery or SABR treatment for early stage (cT1-T2aN0M0) were determined by an institutional multi-disciplinary tumorboard, and in accordance with the patient’s preference . SABR was typically delivered in 3-8 fractions in 1-2 weeks, based on risk-adapted radiotherapy schemes that delivered a biologically effective dose of >100 Gy. Surgery generally involved a VATS lobectomy. Blood was collected prior to treatment, and at weeks 1, 2, 3 and 6 after start of treatment. The peripheral blood mononuclear cell (PBMC) fraction was isolated and was stimulated for 4 hours with phorbol 12-myristate 13-acetate (PMA) and ionomycin, to activate the T cells. Subsequently, the T-cells cells were harvested and analyzed by flow cytometry on the expression of CD4 and/or CD8, granzyme B and interferon (IFN) γ. As PD-1 expression is induced in T-cells after antigen exposure the expression of PD-1 was determined. Changes of population proportions between the different time points were analyzed with the related-samples Wilcoxon signed rank test.
Results:
23 early stage non-small cell lung cancer (NSCLC) patients were included in the study. Of these, 13 patients underwent surgical resection at a mean age (±standard deviation) of 62,9± 8,4 years, and 10 patients who underwent SABR at a median age of 70,0 ±10,4 years. SABR patients had more comorbidities, and a poorer WHO performance score, but clinical tumor stage was comparable. A significant increase in the proportion of IFNγ[+]Granzyme B[+] CD8 T cells (p<.05) was observed at week 2 in the SABR treated group, whereas no difference was found after surgical resection. The PD1[+] fraction of CD4[+] T cells was significantly increased at week 2 in the SABR treated group (p<.05), whereas no differences were seen at two weeks after surgical resection. Proportions of PD1[+ ]CD4 T cells remained elevated in the SABR group at week 3 and 6. A similar trend was observed in the CD8[+] T cell population, although this did not reach statistical significance (p<.1).
Conclusion:
SABR but not surgery, enhances T-cell activation and PD-1 upregulation. The results of our study warrant further investigation as to whether SABR induces an anti-tumor response in patients with early stage NSCLC . The upregulation of PD-1 inherently accompanied with this activation of the immune system potentially warrants combination treatment with PD-(L)1 blockade.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
ORAL 40 - Biology 1 (ID 154)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:C. Brambilla, R. Bueno
- Coordinates: 9/09/2015, 16:45 - 18:15, 702+704+706
-
+
ORAL40.03 - Combination Therapy with a CD40-Agonist and Dendritic Cell Immunotherapy Has Synergistic Effects in a Murine Mesothelioma Model (ID 2643)
17:07 - 17:18 | Author(s): J. Hegmans
- Abstract
- Presentation
Background:
The potential of immunotherapy in mesothelioma has recently been demonstrated in multiple (pre)clinical studies. The success of immunotherapy relies on the induction of an anti-tumor immune response which has to overcome the local immunosuppressive environment in established tumors. Tumor-associated macrophages (TAMs) are an important part of the suppressive environment in mesothelioma and reprogramming these TAMs towards a more pro-inflammatory phenotype using a CD40-agonist has shown promising results in multiple solid tumors. Dendritic cell (DC) immunotherapy has been shown to elicit anti-tumor T-cell responses and is currently being studied in mesothelioma patients at our institution. We hypothesize that the combination treatment with a CD40-agonist and DC therapy has synergistic effects and the aim of the current study is to investigate the efficacy of this combinatorial approach.
Methods:
Wildtype Balb/c mice were injected intraperitoneally (i.p.) with the AB1 murine mesothelioma cell line. Different treatment regimens were compared as follows: untreated control group (n=6), monotherapy with CD40-agonist (FGK4.5 monoclonal antibody, n=5), monotherapy with DC immunotherapy (n=5) and combination therapy of DC immunotherapy followed by treatment with the CD40-agonist (n=5). Three days after completion of the treatment regimens, blood was drawn and analyzed using flow cytometry to investigate peripheral immune activation. All mice were monitored and sacrificed when showing signs of severe illness. After sacrifice, tumors are investigated using flow cytometry to determine the local immunological composition.
Results:
Blood analysis revealed that peripheral monocytes of the CD40-agonist group and the combination therapy group showed an increase in expression of MHC-II and PD-L1 compared to the mice in the control group and the DC immunotherapy group. In addition, the combination therapy induced a profound increase in effector CD8 T-cells and proliferating CD8 T-cells compared to the monotherapies. The interim survival analysis at day 40 post tumor cell injection demonstrates a 17% survival of the control group, 80% survival of the monotherapies and 100% survival of the combination therapy. The final survival analysis will be presented at the conference.
Conclusion:
Combination therapy of DC immunotherapy and a CD40-agonistic antibody induces synergistic immune activation in the peripheral blood of mesothelioma-bearing mice compared to the monotherapies. Although the final survival data are awaited, the presented data demonstrate the potential of the combination of cellular immunotherapy and targeting of the local tumor microenvironment in mesothelioma.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
