Virtual Library
Start Your Search
W.J. Lesterhuis
Author of
-
+
MINI 24 - Epidemiology, Early Detection, Biology (ID 140)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:J. Creaney, M. Carbone
- Coordinates: 9/08/2015, 16:45 - 18:15, 102+104+106
-
+
MINI24.14 - Use of Next Generation Sequencing to Improve Lung Tumor Immunotherapy (ID 1749)
18:00 - 18:05 | Author(s): W.J. Lesterhuis
- Abstract
- Presentation
Background:
Immunotherapy of pulmonary tumors is now a clinical reality, however most patients do not respond. To convert non-responders into responders one potential approach is to identify the tumor‐specific ‘neo‐antigens’ that arise from DNA mutations in order to follow tumor-specific responses and to design therapeutic vaccines to try to ‘enforce’ a response against these resistant tumors.
Methods:
First, in order to identify tumor neo-antigens we performed RNAseq and exome analysis to identify single nucleotide variants (SNV) in murine pulmonary tumors. An average of 485 SNVs was found. We focused on AB1 and AB1-HA (asbestos-induced mesotheliomas, which mimic human mesothelioma) and Line 1 (lung cancer). We used the NetMHCpan 2.8 algorithm to identify candidate mutation‐carrying peptides and screened them in an interferon‐γ ELISPOT assay. Second, to determine if more neo-antigens could be ‘unmasked’ by therapy, we tested three candidate therapies in our murine model then reanalyzed neo-antigen responses a) Treg depletion using Foxp3-DTR mice, b) gemcitabine, an immunogenic cytotoxic chemotherapy commonly used for pulmonary malignancies, and c) antiCTLA4 (a checkpoint blockade therapy).
Results:
We identified 20 candidate mutation‐carrying peptides in the ELISPOT assay. A strong spontaneous endogenous pre-treatment immune response was demonstrated to DUqcrc2, a component of the respiratory chain protein ubiquinol cytochrome complex. It was found to stimulate a strong response at a similar magnitude to the model neo-antigen viral haemagglutinin (HA). The DUqcrc2 peptide sequence (amino acid 405-413) is predicted to bind the H-2Kd, and the mutant has a proline to alanine substitution mutation at position 408. Treg depletion unmasked a second neo-antigen, DGANAB. GANAB is an alpha glucosidase which cleaves the 2 innermost alpha-1,3-linked glucose residues from the Glc-2-Man-9-GlcNAc-2 oligosaccharide precursor of immature glycoproteins. There is an arginine to glutamine substitution mutation at position 969 of DGANAB (965-972) sequence. This observation supports the theory that removing Treg cells may broaden the immune response to a greater number of neo-antigens, a response presumably otherwise restrained by Treg suppression. Gemcitabine and antiCTLA4 checkpoint blockade did not unmask any additional neo-antigens.
Conclusion:
Thus, removing some immune restraints may expose a greater number of neo-antigens as potential clinical targets. The results from these approaches suggest novel ways to improve the immunotherapy of lung tumor and are the basis for planning current clinical trials.
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.
-
+
P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
-
+
P2.04-075 - Network Analysis of Anti-CTLA4-Induced Regressing Tumours Identifies Novel Synergistic Drug Combinations (ID 1113)
09:30 - 09:30 | Author(s): W.J. Lesterhuis
- Abstract
Background:
Antibodies blocking immune checkpoint molecules such as CTLA-4 have been shown to be effective in several cancer types, with some patients displaying durable complete regression. However, many patients do not respond to treatment. It is not known what molecular events control the response nor which co-treatments are likely to combine effectively with checkpoint blockade. Current strategies involve empirically testing different combinations of checkpoint blocking antibodies with other immunotherapeutic strategies or conventional anti-cancer drugs. We provide an alternative approach.
Methods:
Through performing network analysis of gene expression data from responding versus non-responding AB1-HA mesothelioma tumours from mice treated with anti-CTLA-4, we identified genetic modules and hub genes within these modules that were associated with responsiveness. We subsequently identified synergistic anti-CTLA-4/drug combinations using two different approaches: first, by pinpointing drugs that modulated hub genes within these response-associated modules, and second, by interrogating overlaps in the modular response patterns and drug-perturbation signatures in drug repurposing databases. The approaches were validated by testing the identified drugs in vivo, in combination with anti-CTLA-4 in murine cancer models.
Results:
We identified and validated several drugs that increased the response rate to anti-CTLA-4 in a highly synergistic manner. We identified four drug classes with the capacity to increase the cure rate from 10% for anti-CTLA-4 alone to 60-80% as combination therapy. These repurposed drugs are normally used in completely unrelated conditions such as cardiovascular or skin diseases.
Conclusion:
Together, our results show that using network analysis of gene expression data from immunotherapy-responsive tumours generates testable hypotheses for the identification of novel synergistic drug combinations.
