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R. Pio
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MA09 - Immunotherapy Combinations (ID 390)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:M. Sebastian, E.B. Garon
- Coordinates: 12/06/2016, 14:20 - 15:50, Strauss 2
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MA09.01 - Dual Blockade of PD-1 and C5a/C5aR Synergistically Protects against Non-Small Cell Lung Cancer Tumor Growth (ID 5261)
14:20 - 14:26 | Author(s): R. Pio
- Abstract
- Presentation
Background:
Immunotherapy based on PD-1/PD-L1 immune checkpoint inhibitors has emerged as a powerful tool for the treatment of lung cancer. To further enhance the antitumor efficacy of individual treatments, numerous ongoing studies are trying to identify synergistic combinations that simultaneously block more than one immunomodulatory pathway. C5aR1 is a G protein-coupled receptor activated by C5a, an anaphylatoxin released during the activation of the complement system, a major component of innate immunity. We have previously shown in a murine model of lung cancer that pharmacological blockade of C5aR1 reduces cancer progression by reversing the immunosuppressive microenvironment. Thus, we hypothesized that a combined inhibition of C5aR1 and PD-1 may have a synergistic effect in the treatment of lung cancer.
Methods:
We characterized the immunosuppressive activity of C5aR1 and evaluated the therapeutic efficacy of the dual administration of PD-1 and C5a/C5aR1 antagonists in syngeneic non-small cell lung cancer mouse models. The RMP1-14 monoclonal antibody was used to block PD-1, and a PEG-modified L-aptamer, which binds to complement C5 and C5a, was used to inhibit the C5a/C5aR1 interaction.
Results:
Kras[G12D/+] mice deficient for C5aR (Kras[G12D/+];C5aR1[Δ/Δ]) had a lower lung tumor burden and survived longer than Kras[G12D/+];C5aR1[wt/wt] littermates. Interestingly, Kras[G12D/+];C5aR1[Δ/Δ] mice showed a significant reduction of myeloid-derived suppressor cells (MDSCs), a subpopulation of immune cells that profoundly influences the effectiveness of cancer immunotherapies. We therefore evaluated whether C5a/C5aR blockade may enhance the efficacy of anti-PD-1 therapy by reversing the immunosuppressive microenvironment. In the Kras/Tp53 mutant 393P syngeneic lung cancer model, the combination of C5a and PD-1 blockade dramatically reduced in vivo tumor growth, as compared to the effect of each treatment alone. Similarly, this combination showed a remarkable synergistic antitumor effect in Lewis lung carcinoma (3LL)-bearing mice. Survival analysis confirmed the benefit of the combined treatment. Finally, the therapeutic combination significantly diminished the in vivo metastatic capacity of the highly aggressive Lacun3 lung cancer cell line in syngeneic BALB/c mice, as compared to the effect of anti-PD-1 or anti-C5a drugs as monotherapy.
Conclusion:
Our study supports the notion that the efficacy of anti-PD-1 therapy is limited by the immunosuppressive tumor microenvironment. In this context, C5a/C5aR1 blockade concomitant to anti-PD1 therapy obliterates the resistance mechanisms mediated by MDSCs, improving antitumor immune responses. These findings provide a framework for the clinical evaluation of this therapeutic strategy.
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MA17 - Genetic Drivers (ID 409)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:M. Satouchi, G.R. Simon
- Coordinates: 12/07/2016, 14:20 - 15:50, Lehar 1-2
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MA17.10 - YES1 Kinase is a New Therapeutic Target in Non-small Cell Lung Cancer (ID 7159)
15:26 - 15:32 | Author(s): R. Pio
- Abstract
- Presentation
Background:
Next-generation sequencing techniques have allowed the discovery of driver mutations in non-small cell lung cancer (NSCLC) that can be translated into advances in cancer diagnosis and treatment. However, specific oncogenic alterations are still unknown in a high proportion of NSCLC patients, that therefore cannot benefit from targeted therapies. The challenge is to identify new genetic alterations that allow the use of molecular-targeted therapies. In previous studies from our group (Aramburu et al. BMC Genomics 2015), the analysis of tumor molecular profiles from patients with NSCLC allowed us to identify the DNA copy number amplification of YES1 kinase (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) as a prognostic marker in lung cancer. YES1 kinase is member of the Src family of non-receptor protein tyrosine kinases that are involved in the regulation of cell growth, apoptosis, cell-cell adhesion, cytoskeleton remodeling, and differentiation. The aim of this project is to evaluate if YES1 is a driver gene in NSCLC, and if targeting its activation may be a potential new therapeutic strategy.
Methods:
We first evaluated the prognostic role of YES1 protein expression in two independent series of 76 and 234 NSCLC patients, respectively. In both series, the multivariate analysis revealed that high YES1 expression is an independent poor prognostic factor for overall survival (CUN series HR: 3.416 [0.933-12.508]; MD Anderson series HR: 1.570 [1.032-2.391]). We next evaluated the effect of YES1 knockdown in 5 NSCLC cell lines with YES1 amplification and overexpression, and in 3 cell lines without YES1 amplification and with low protein expression. YES1 downregulation by two specific siRNAs decreased proliferation and cell survival only in those cells overexpressing YES1. Congruently, YES1 inhibition led to apoptosis only in those cells.
Results:
Consistent with these results, constitutive overexpression of YES1 in cells with low YES1 expression significantly enhanced cell proliferation. We next evaluated the effect of the multitarget Src kinase inhibitor dasatinib on the proliferation of NSCLC cell lines with high (8 cell lines) or low (4 cell lines) YES1 expression. Dasatinib dramatically inhibited proliferation in high YES1-expressing cell lines, whereas low YES1 cell lines were more resistant to dasatinib treatment (GI50s were four orders of magnitude higher in resistant cells).
Conclusion:
In conclusion, our results indicate that YES1 is a promising therapeutic target in NSCLC. Furthermore, amplification and high expression of YES1 may define a subset of patients who may potentially benefit from dasatinib treatment.
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.
