Abstract 75P
Background
We have previously shown that a large gene set can classify the tumor immune microenvironment (TIME) of patients with epithelial tumors into one of three phenotypes: immune inflamed (immune hot), immuno-suppressive (immune cold), or immune inert (immune cold). Given that the tumor is constantly evolving, identifying key genes where changes in mutation or cell signaling is associated with a change in phenotypes can lead to identification of potential new targets. Here we show three bioinformatic methodologies for this purpose.
Methods
The first approach to identifies genes hypermethylated in one phenotype and hypomethylated in another as methylation patterns can be surrogates for mutations that drive a transition across the TIME. Second, MUTECT2 annotation was used to detect high impact mutations which were associated with the phenotypes. Third, the IntAct database was used to identify potential cell signaling pairings where one gene was associated with patients classified as hot and a second gene classified patients as cold. All three of these approaches yielded genes with known targeted therapies in active clinical trials.
Results
The methylation approach identified VEGFR2 as a gene where mutations could likely affect TIME phenotypes. VEGFR2 is routinely used in clinical trials and has an approved drug on the market (ramucirumab), and mutations in VEGFR2 are seen to affect patient prognosis and drug sensitivity. With the MUTECT2 approach, mutations in STK11 were identified. Several clinical trials are examining the role that mutations in STK11 can play in altering the treatment paradigm between immunotherapy and KRAS targeted therapy. Finally, the IntAct approach identified the interaction between CRCX4 and CXCL12, known to be involved in TIME evolution and with several clinical trials being conducted designed to disrupt this interaction.
Conclusions
Utilizing a curated gene list to classify patients into TIME phenotypes and then using bioinformatic methods to find genes which may be driving transition across immune of phenotypes resulted in identifying known and well validated targets from current clinical trials. The results argue for a more careful examination of other genes that resulted from this methodology as potential targets for immunotherapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Oncocyte.
Disclosure
R. Seitz: Financial Interests, Personal, Advisory Role: Oncocyte, Inc. B. Ring, C. Cronister: Financial Interests, Personal, Full or part-time Employment: Oncocyte, Inc.
Resources from the same session
24P - Fibroblast growth factor receptor (FGFR) as a target for epigenetic therapies: A case review for a new approach to target tumors with somatic mutations/amplifications of FGFR
Presenter: M. Nezami
Session: Cocktail & Poster Display session
Resources:
Abstract
25P - Relationship between aberrant methylation of CpG islands of microRNA gene promoters and changes in their expression in epithelial ovarian cancer
Presenter: Irina Pronina
Session: Cocktail & Poster Display session
Resources:
Abstract
26P - 3MST: A potential workhorse in H2S signaling trimmed by microRNA-548 in breast cancer
Presenter: Alyaa Dawoud
Session: Cocktail & Poster Display session
Resources:
Abstract
29P - A phase I, open-label, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics, antitumor activity of QL1604, a humanized anti-PD-1 mAb, in patients with advanced solid tumors
Presenter: Yun Fan
Session: Cocktail & Poster Display session
Resources:
Abstract
30P - Deep learning approach for discovering new predictive histological features of immunotherapy response
Presenter: Saima Ben Hadj
Session: Cocktail & Poster Display session
Resources:
Abstract
32P - Clinical efficacy and safety of an immune checkpoint inhibitor in combination with regorafenib therapy as second-line regimen for patients with unresectable hepatocellular carcinoma
Presenter: Jinpeng Li
Session: Cocktail & Poster Display session
Resources:
Abstract
33P - Nomogram to predict survival of patients with unresectable melanoma receiving immune checkpoint inhibitors
Presenter: Eftychia Chatziioannou
Session: Cocktail & Poster Display session
Resources:
Abstract
34P - Targeting LSD1 rescues MHC-I antigen presentation and overcomes resistance to PD-L1 checkpoint blockade in small cell lung cancer
Presenter: Evelyn Nguyen
Session: Cocktail & Poster Display session
Resources:
Abstract
36P - Therapeutic vaccination with HPV-16 oncoproteins fused into a checkpoint modifier of early T cell activation protects against HPV-associated tumors in a preclinical model
Presenter: Susan Currie
Session: Cocktail & Poster Display session
Resources:
Abstract
37P - Dose transition pathways for time-to-event continual reassessment method (TITE-CRM): Will imposing a waiting time result in better performance?
Presenter: Zhulin Yin
Session: Cocktail & Poster Display session
Resources:
Abstract