Abstract 129P
Background
Cancer immunotherapy has revolutionized cancer treatment by harnessing the immune system to target tumors. However, its clinical success is limited by low response rates, typically ∼20%. To address the challenge, we developed a transcriptome-based computational framework aimed at improving the efficacy of immunotherapy.
Methods
We established a computational framework to analyze similarities between transcriptome patterns associated with responsiveness or resistance to cancer immunotherapy. We then applied this computational framework to two applications: identifying predictive biomarkers for immunotherapy response and discovering synergistic compounds for combination therapy with immunotherapy. To identify predictive biomarkers, we investigated genomic and epigenomic changes and the transcriptional impact of gene knockouts or knockdowns that mimic the transcriptome pattern of responders. To identify synergistic compounds for combination therapy, we screened compounds in silico that reverse gene signatures associated with resistance to immunotherapy (e.g., T cell exclusion signature, cancer immune resistance program, and nivolumab resistance signature. Finally, we evaluated our computational results through in vitro and in vivo studies.
Results
Using this approach, we found genomic biomarkers that could enhance immunotherapy response. We also discovered three types of chemical compounds for combination therapy: I) known immunotherapy agents (POC verification), Ⅱ) unknown immunotherapy agents with known MoA (drug repurposing), Ⅲ) four clusters with new chemical structures (new drug candidates). We further studied a compound cluster from (Ⅲ) by reverse-docking and measuring structural similarity to identify potential drug targets. We finally demonstrated that co-administration of the compound with anti-PD1 significantly improved survival in a syngeneic mouse model.
Conclusions
We successfully identified both predictive biomarkers and novel synergistic compounds that enhance the efficacy of cancer immunotherapy. These findings hold promise for improving patient outcomes and developing more effective combination therapies. The newly identified compounds are now progressing through preclinical development.
Legal entity responsible for the study
The authors.
Funding
Korea Institute of Science and Technology Information (KISTI) (K24L2M1C4-01) The National Research Foundation of Korea (NRF-2022R1C1C1006162).
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
156P - Liver Metastases Correlate with Shortened Survival and Increased Dissociate Response in Patients Treated with T-Cell Engagers.
Presenter: Noé Herbel
Session: Poster Display session
Resources:
Abstract
157P - Preliminary results of a multicentric randomized phase I/IIa trial of an immunotherapy targeting dendritic cells (DC), CD40HVac, in patients with HPV16-positive oropharyngeal carcinoma (OPC)
Presenter: Caroline Even
Session: Poster Display session
Resources:
Abstract
158P - XCR1+ dendritic cell (DC) role in antitumoral response to anti PD-L1 antibody: Data from the phase Ib/II trial of DC vaccination in small cell lung cancer patients
Presenter: Maria Gonzalez Cao
Session: Poster Display session
Resources:
Abstract
159P - Unveiling the impact of DC vaccination on systemic immunity in advanced malignant melanoma: Preliminary results from the ABSIDE study
Presenter: Giada Sabatino
Session: Poster Display session
Resources:
Abstract
160P - Oral DNA vaccination targeting personalised neoantigens in immune checkpoint-inhibitor treated solid tumor patients: Interim results
Presenter: Domas Vaitiekus
Session: Poster Display session
Resources:
Abstract
161P - Safety of TrimelVax vaccine for patients with advanced melanoma: Clinical results
Presenter: ROBERTO ESTAY
Session: Poster Display session
Resources:
Abstract
162P - EO4010 (EO) + nivolumab (N) ± bevacizumab (B) in patients (pts) with microsatellite stable (MSS) metastatic colorectal carcinoma (mCRC)
Presenter: Romain Cohen
Session: Poster Display session
Resources:
Abstract
163P - Effect of split intravenous dosing of oncolytic adenovirus TILT-123 on normal tissue versus tumor macrophages and virus bioavailability in patients with advanced solid tumors
Presenter: Elise Jirovec
Session: Poster Display session
Resources:
Abstract
164P - Roginolisib (IOA-244), the first highly selective oral allosteric modulator of phosphoinositide 3-kinase inhibitor delta (PI3K_), has immuno-modulatory effects associated with clinical benefits in patients with metastatic uveal melanoma
Presenter: Anna Di Giacomo
Session: Poster Display session
Resources:
Abstract
165P - TIGIT inhibition in non-small cell lung cancer: Meta-analysis of clinical efficacy and biomarker correlation
Presenter: Hashim Talib Hashim
Session: Poster Display session
Resources:
Abstract