Abstract 5713
Background
Historically, immunotherapies have been tested in syngeneic mouse models and until now only limited CRC syngeneic cells are available. Animal models with functioning human immune systems are critically needed to more accurately evaluate checkpoint blockers delivery, therapeutic response, and to better define biomarker expression in the presence of a competent immune system.
Methods
To better address the efficacy of immune checkpoint therapy specifically in relation to presence of a BRAFmutation, we developed a novel platform for the generation of somatic mosaic models of CRC enabling (i) high-throughput generation of genetically complex syngeneic models of cancer, (ii) tracing studies through fluorescence reporters.
Results
Cdx2Cre/+ mice, expressing the Cre recombinaseunder the control of a human Cdx2 promoter/enhancer sequence have been crossed with the R26LSL-Cas9-Gfp strain to generate models allowing for tissue specific activation of Cas9 and Gfpreporter only in CDX2 positive cells. This strain has been crossed with BRAFFSF-V600E mice to generate the final model. 6-8 weeks old mice have then been transduced with AAV constructs expressing the FLPO recombinasethat can be activated by Cre recombinase and sgRNAs targeting APC, TP53, MLH1, MSH2and ARID1Aalone or combined, in order to model MSI CRC (APC-TP53-MLH1and ARID1A-MLH1conditional mosaic knock-outs) and MSS CRC (APC-TP53 conditional mosaic knock-out). Viral particles have been surgically delivered via subserosal cecal injection and mice monitored for tumor formation by IVIS imaging. 35 mice injected with 3 combinations of tumor suppressors provide a diverse immunology repetoire. Cell lines isolated from genetically modified mice will provide a physiologic relevant and feasible means to study the mechanisms of response and resistance to immunotherapies and to understand biological and molecular differences between BRAFmutated MSI and MSS tumors.
Conclusions
This project focuses on the identification and characterization of the functional drivers of CMS1CRC tumors leveraging in vivomosaic genome editing technologies and functional genetic labeling of malignant sub-populations emerging during disease progression and in response to therapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
MD Anderson Cancer Center.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
4370 - Continental differences in pathologic response with neoadjuvant ipilimumab (IPI) plus nivolumab (NIVO) in patients with macroscopic stage III melanoma in the phase 2 OpACIN-neo trial.
Presenter: Irene Reijers
Session: Poster Display session 3
Resources:
Abstract
3230 - Comparable responses of melanoma at primary site and synchronous lymph node metastases upon neoadjuvant ipilimumab (IPI) and nivolumab (NIVO)
Presenter: Judith Versluis
Session: Poster Display session 3
Resources:
Abstract
3171 - Adjuvant Therapies for Stage III Melanoma: Benchmarks for Bringing Clinical Trials to Clinical Practice
Presenter: Tina HIEKEN
Session: Poster Display session 3
Resources:
Abstract
3493 - Mixture-cure modeling for resected stage III/IV melanoma in the phase 3 CheckMate 238 trial
Presenter: Jeffrey Weber
Session: Poster Display session 3
Resources:
Abstract
3036 - An open-label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib for patients with unresectable advanced BRAFV600-mutant melanoma: a subgroup analysis of patients with brain metastasis
Presenter: Caroline Dutriaux
Session: Poster Display session 3
Resources:
Abstract
2233 - Adverse event (AE) kinetics in patients (pts) treated with dabrafenib + trametinib (D + T) in the metastatic and adjuvant setting
Presenter: Jean Jacques Grob
Session: Poster Display session 3
Resources:
Abstract
2435 - A Single Arm, Open Label, Phase II, Multicenter Study to Assess the Detection of the BRAF V600 Mutation on cfDNA from Plasma in Patients with Advanced Melanoma
Presenter: Piotr Rutkowski
Session: Poster Display session 3
Resources:
Abstract
1766 - Efficacy and Safety of Dabrafenib and Trametinib in Patients with Metastatic BRAFV600 Mutation-positive Melanoma in the Real-World Setting – Interim results of the non-interventional COMBI-r study
Presenter: Carola Berking
Session: Poster Display session 3
Resources:
Abstract
2131 - Trial update: A randomized Phase Ib/II study of the selective small molecule Axl inhibitor Bemcentinib (BGB324) in combination with either dabrafenib/trametinib (D/T) or pembrolizumab in patients with metastatic melanoma
Presenter: Oddbjørn Straume
Session: Poster Display session 3
Resources:
Abstract
4074 - Analysis of pyrexia in patients (pts) treated with dabrafenib (D) and/or trametinib (T) across clinical trials
Presenter: Caroline Robert
Session: Poster Display session 3
Resources:
Abstract