Abstract 3089
Background
MTL-CEBPA is a myeloid modifier saRNA therapy which upregulates CEBPalpha and is the first saRNA therapy to enter clinical trials. We hypothesise that targeting myeloid-derived suppressor cells (MDSCs) with MTL-CEBPA and T cells with PD-1 antibody may enhance the therapeutic efficacy of each individual therapy.
Methods
CT26 syngeneic mice were randomised into 4 groups (n = 10) and treated with vehicle control, PD-1 antibody (10mg/kg, i.p., d1/d4 schedule, 7 doses), MTL-CEBPA (5mg/kg, i.v, d1/d3 schedule, 7 doses) or a combination of both compounds. RNA extracted from tumours at termination were analysed by Nanostring IO360 and myeloid innate immunity codeset.
Results
At 21 days of treatment, the average tumonur volumes in the MTL-CEBPA/PD-1 treated group were smallest and 3.0-fold smaller (p < 0.05) than the closest group. Nanostring analysis shows that only tumours from the combination group display significant increase in tumour infiltrating lymphocytes (2.4-fold versus control, p < 0.05) and pathway analysis reveals that 5 of the 6 tumours in this group have the highest increase in expression of genes for various immune pathways including lymphoid compartment, antigen presentation and cytotoxicity when compared against all tumour samples. At the level of individual genes, we observed synergy in gene expression changes in combination of PD-1 antibody and MTL-CEBPA as illustrated in table.Table:
1230P Individual genes that show synergistic effect. Calcilated as fold versus vehicle control. * p < 0.05 and ** p < 0.01
PD-1 mAb | MTL-CEBPA | Combination | |
---|---|---|---|
Cd4 | 1.81 | 1.53 | 7.63 (*) |
Cd8a | 1.29 | 1.22 | 3.68 (*) |
Cd8b1 | 1.51 (*) | 1.02 | 4.62 (*) |
Cd3e | 1.22 | 1.11 | 4.48 (*) |
Gzma | 1.38 | 1.14 | 2.39 (*) |
Gzmb | 1.76 | 1.51 (*) | 3.86 |
Ifng | 2.20 | 1.24 | 4.71 (**) |
Vegfa | 1.18 | 1.04 | 0.94 |
Mki67 | 1.00 | 0.84 (**) | 0.62 (**) |
Conclusions
The study indicates enhanced anti-tumour activity when combining MTL-CEBPA with PD-1 antibody in the immunocompetent mouse CT26 colorectal cancer model. The combination treatment appears to result in increased penetration of TILs through modulation of immune activity in the tumour microenvironment.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
MiNA Therapeutics.
Funding
MiNA Therapeutics.
Disclosure
M. Sodergren: Research grant / Funding (self): MiNA Therapeutics. C. Tan: Honoraria (self), Research grant / Funding (self): MiNA Therapeutics. V. Reebye: Honoraria (self), Leadership role, Research grant / Funding (self): MiNA Therapeutics. R. Habib: Honoraria (self), Leadership role: MiNA Therapeutics. D. Blakey: Honoraria (self), Leadership role: MiNA Therapeutics. N. Habib: Leadership role, Research grant / Funding (self): MiNA Therapeutics.
Resources from the same session
4634 - Comparative molecular analyses between microsatellite stable BRAFV600E mutant colorectal cancers and BRAFV600E mutant melanomas.
Presenter: Mohamed Salem
Session: Poster Display session 3
Resources:
Abstract
3264 - A novel preclinical model of RAF-independent MEK1 mutant tumors and its treatment with novel ATP competitive MEK inhibitor
Presenter: Luca Hegedus
Session: Poster Display session 3
Resources:
Abstract
4918 - HER2 inhibition in Aggressive Squamous Cell Carcinomas driven by a common MET Sema Domain Polymorphism
Presenter: Nur Afiqah Mohamed Salleh
Session: Poster Display session 3
Resources:
Abstract
2426 - ADAM9 as a target for lung cancer treatment
Presenter: Yuh-pyng Sher
Session: Poster Display session 3
Resources:
Abstract
5537 - Novel polyurea/polyurethane nanocapsules loaded with a tambjamine analog to improve cancer chemotherapy delivery and safety in lung cancer
Presenter: Marta Perez Hernandez
Session: Poster Display session 3
Resources:
Abstract
1597 - Discovery of Clinical Candidate DBPR112, a Furanopyrimidine-based Epidermal Growth Factor Receptor Inhibitor for the Treatment of Non-Small Cell Lung Cancer
Presenter: Hsing-pang Hsieh
Session: Poster Display session 3
Resources:
Abstract
3543 - Molecular characteristics in lung squamous cell carcinomas dependent on TP53 status – putative targets
Presenter: Vilde Haakensen
Session: Poster Display session 3
Resources:
Abstract
4111 - Comparison of molecular profiles between primary tumour and matched metastasis in non-small cell lung cancer
Presenter: Asuka Kawachi
Session: Poster Display session 3
Resources:
Abstract
4559 - Treatment with BLU-667, a potent and selective RET inhibitor, provides rapid clearance of ctDNA in Patients with RET-altered Non-Small Cell Lung Cancer (NSCLC) and Thyroid Cancer
Presenter: Giuseppe Curigliano
Session: Poster Display session 3
Resources:
Abstract
2501 - Triple MET/SRC/PIM inhibition in MET addicted tumors
Presenter: Ilaria Attili
Session: Poster Display session 3
Resources:
Abstract