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
2507 - KEYLYNK-010: Phase 3 Study of Pembrolizumab (pembro) Plus Olaparib (OLA) vs Enzalutamide (ENZA) or Abiraterone (ABI) in ENZA- or ABI-Pretreated Patients (pts) With Metastatic Castration-Resistant Prostate Cancer (mCRPC) Who Had Progression on Chemotherapy (CTx)
Presenter: Evan Yu
Session: Poster Display session 3
Resources:
Abstract
2944 - PROSTRATEGY: A Spanish Genitourinary Oncology Group (SOGUG) multi-arm multistage (MAMS) phase III trial of immunotherapy strategies in high-volume metastasic hormone-sensitive prostate cancer.
Presenter: Jose Arranz Arija
Session: Poster Display session 3
Resources:
Abstract
3535 - A phase 1 study of AMG 160, a half-life extended bispecific T cell engager (HLE BiTE) immuno-oncology therapy targeting PSMA, in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)
Presenter: Ben Tran
Session: Poster Display session 3
Resources:
Abstract
4951 - ProBio: An outcome-adaptive, multi-arm, open-label, multiple assignment randomised controlled biomarker-driven trial in patients with metastatic castration-resistant prostate cancer (EudraCT: 2018-002350-78, NCT03903835)
Presenter: Johan Lindberg
Session: Poster Display session 3
Resources:
Abstract
2892 - A phase 3 randomized, placebo-controlled, double-blind study of niraparib plus abiraterone acetate and prednisone versus abiraterone acetate and prednisone in patients with metastatic prostate cancer (NCT03748641)
Presenter: Kim Chi
Session: Poster Display session 3
Resources:
Abstract
2427 - The Extended/Phase II Study of Safety And Tolerability Of Proxalutamide (GT0918) In Subjects With Metastatic Castrate Resistant Prostate Cancer (mCRPC) Who Failed Either Abiraterone (Abi) Or Enzalutamide (Enza)
Presenter: Nicholas Vogelzang
Session: Poster Display session 3
Resources:
Abstract
3224 - Addition of an oral docetaxel treatment (ModraDoc006/r) to androgen deprivation therapy (ADT) and intensity-modulated radiation therapy (IMRT) in patients with high risk N+M0 prostate cancer
Presenter: Marit Vermunt
Session: Poster Display session 3
Resources:
Abstract
3312 - A phase II randomized, open-label study comparing salvage radiotherapy in combination with 6 months of androgen-deprivation therapy with LHRH agonist or antagonist versus anti-androgen therapy with apalutamide in patients with biochemical progression after radical prostatectomy.
Presenter: Piet Dirix
Session: Poster Display session 3
Resources:
Abstract
2829 - Health-Related Quality of Life (HRQoL) and Updated Follow-Up From KEYNOTE-057: Phase 2 Study of Pembrolizumab (pembro) for Patients (pts) With High-Risk (HR) Non–Muscle Invasive Bladder Cancer (NMIBC) Unresponsive to Bacillus Calmette-Guérin (BCG)
Presenter: Ronald de Wit
Session: Poster Display session 3
Resources:
Abstract
2673 - Clinical activity of vofatamab (V), an FGFR3 selective antibody in combination with pembrolizumab (P) in metastatic urothelial carcinoma (mUC), updated interim analysis of FIERCE-22
Presenter: Arlene Siefker-Radtke
Session: Poster Display session 3
Resources:
Abstract