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
2664 - Phase (Ph) II study of MBG453 + spartalizumab in patients (pts) with non-small cell lung cancer (NSCLC) and melanoma pretreated with anti–PD-1/L1 therapy
Presenter: Nicholas Mach
Session: Poster Display session 3
Resources:
Abstract
1285 - Preliminary results of STELLAR-001, a dose escalation phase I study of the anti-C5aR, IPH5401, in combination with durvalumab in advanced solid tumors.
Presenter: Christophe Massard
Session: Poster Display session 3
Resources:
Abstract
3808 - GOLFIG chemo-immunotherapy in metastatic colorectal cancer (mCRC) patients: A fifteen year retrospective analysis
Presenter: Pierpaolo Correale
Session: Poster Display session 3
Resources:
Abstract
5677 - Immune correlates in peripheral blood samples in a preoperative window of opportunity randomized trial of nivolumab with or without tadalafil in resectable squamous cell carcinoma of the head and neck (SCCHN)
Presenter: Larry Harshyne
Session: Poster Display session 3
Resources:
Abstract
4854 - Phase 1 evaluation of AB928, a novel dual adenosine receptor antagonist, combined with chemotherapy or AB122 (anti-PD-1) in patients (pts) with advanced malignancies
Presenter: John Powderly
Session: Poster Display session 3
Resources:
Abstract
4344 - Phase 1 Trial of CV301 in Combination with Anti-PD-1 Therapy in Non-squamous NSCLC
Presenter: Arun Rajan
Session: Poster Display session 3
Resources:
Abstract
4555 - Safety and efficacy results of the combination of DPX-Survivac, pembrolizumab and intermittent low dose cyclophosphamide (CPA) in subjects with advanced and metastatic solid tumors: preliminary results from the hepatocellular carcinoma (HCC), NSCLC, bladder cancer, & MSI-H cohorts
Presenter: Henry Conter
Session: Poster Display session 3
Resources:
Abstract
3012 - Excellent CBR and Prolonged PFS in Non-Squamous NSCLC with Oral CA-170, an Inhibitor of VISTA and PD-L1
Presenter: Vivek Radhakrishnan
Session: Poster Display session 3
Resources:
Abstract
2536 - Phase Ib/II trial of TG4001 (Tipapkinogene sovacivec), a therapeutic HPV-vaccine, and Avelumab in patients with recurrent/metastatic (R/M) HPV-16+ cancers
Presenter: Christophe Le Tourneau
Session: Poster Display session 3
Resources:
Abstract
1845 - Induction of tumor-infiltrating functional CD8 positive cells and PD-L1 expression in esophageal cancer by S-588410
Presenter: Takashi Kojima
Session: Poster Display session 3
Resources:
Abstract