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
4021 - Prospective pathological experience with research biopsies in the context of clinical trials at Vall d’Hebron Institute of Oncology
Presenter: Paolo Nuciforo
Session: Poster Display session 3
Resources:
Abstract
5603 - Development of a comprehensive next-generation targeted sequencing assay for detection of gene-fusions in solid tumors
Presenter: Vinay Mittal
Session: Poster Display session 3
Resources:
Abstract
4952 - Next-generation sequencing for better treatment strategy of cancer of unknown primary (CUP)
Presenter: Kang Kook Lee
Session: Poster Display session 3
Resources:
Abstract
4590 - Circulating-free DNA analysis from long-term surviving metastatic colorectal cancer patients undergoing surgery for resectable disease.
Presenter: Michele Ghidini
Session: Poster Display session 3
Resources:
Abstract
3696 - Ultra-sensitive detection of circulating tumor DNA identifies patients in high risk of recurrence in early stages melanoma
Presenter: Filip Janku
Session: Poster Display session 3
Resources:
Abstract
4295 - Identification of the founder BRCA1 mutation c.4117G>T (p.Glu1373*) recurring in Abruzzo and Lazio regions of Central Italy and predisposing to breast/ovarian and BRCA1-related cancers
Presenter: Daniela Di Giacomo
Session: Poster Display session 3
Resources:
Abstract
2214 - Enzalutamide (ENZA) and Apalutamide (APA) In vitro chemical reactivity studies and Activity in a Mouse Drug Allergy Model (MDAM)
Presenter: Mausumee Guha
Session: Poster Display session 3
Resources:
Abstract
5044 - Influence of genetic variation in COMT on cisplatin-induced nephrotoxicity in cancer patients.
Presenter: Bram Agema
Session: Poster Display session 3
Resources:
Abstract
3293 - Cardioprotective and anti-inflammatory effects of Empagliflozin during treatment with Doxorubicin: a cellular and preclinical study
Presenter: Vincenzo Quagliariello
Session: Poster Display session 3
Resources:
Abstract
3324 - Breast Cancer Organoids Model Treatment Response of HER2 Targeted Therapy in HER2-mutant Breast Cancer
Presenter: Xuelu Li
Session: Poster Display session 3
Resources:
Abstract