Abstract 4426
Background
The use of immunotherapy in multiple cancer types is becoming mainstay along with next-generation sequencing (NGS) to identify potential actionable targets. We hypothesized that some immunoregulatory molecules are often found upregulated with certain gene mutations regardless of cancer subtype.
Methods
2740 TCGA patients were identified to have at least one potentially oncogenic mutation (mt) within an established 50-gene hotspot panel, including stomach/esophageal carcinoma (N = 255), skin cutaneous melanoma (N = 226), stomach adenocarcinoma (N = 163), breast invasive carcinoma (N = 143), and lung adenocarcinoma (N = 139), among others. Differential expression of 10 immunoregulatory molecules (IRM) was analyzed between mt vs. wt. To ensure observed significant associations were not confounded by tumor-type, differential IRM expression within mt-enriched tumor-types was compared to that of mt vs. wt.
Results
19/50 gene mutations were found to be significantly associated with ≥1 IRM expression. This included elevated CTLA4in CDKN2A mt (adj. p = 1.9e-9), elevated IDO1in FBXW7 mt (adj. p = 0.007), and decreased PDL1 in APCmt (adj, p = 0.02). In many, the mt effect-size was larger than that of tumor-type; e.g. head & neck carcinomas (HNSCC) are highly enriched for CDKN2Amt (OR = 4.9, p = 4.3e-9), yet CDKN2Amt are more associated with CTLA4expression than HNSCC location (t = 7.0 vs. 5.4). Similarly, FBXW7mt are more associated with high IDO1 than colorectal adenocarcinoma (CRC) (t = 4.3 vs. 0.9), and APC mt are more associated with low PDL1 (t=-4.1 vs. -3.2) than CRC. In total, 15 strong mt-gene/immune-regulator associations were identified.
Conclusions
The presented differential checkpoint expression patterns are strongly associated with mutation status and are not primarily driven by tissue type. NGS data continues to drive agnostic approvals while immunotherapeutic efforts work to replace chemotherapy providing better efficacy with milder toxicities. This data hopes to shed light on the future studies that may analyze optimization of concomitant versus sequential therapies in various genomic-driven targeted therapies combined with immunotherapy trials.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
NantWorks.
Disclosure
C.W. Szeto: Full / Part-time employment: NantCell. S.K. Reddy: Full / Part-time employment, Officer / Board of Directors: NantHealth. All other authors have declared no conflicts of interest.
Resources from the same session
5650 - Tissue-based activation of mucosal-associated invariant T (MAIT) cells in combination ipilimumab and nivolumab checkpoint inhibitor (CI) colitis.
Presenter: Sarah Sasson
Session: Poster Display session 3
Resources:
Abstract
5944 - Significance of severe immune-related adverse effects (irAE) on patients with advanced tumors treated with immune checkpoint inhibitors being admitted for secondary toxicity: Clinical relevance and next steps
Presenter: Leyre Zubiri
Session: Poster Display session 3
Resources:
Abstract
5989 - Implementation of a dedicated immuno-oncology toxicity service reduces the acute impact of immune-related adverse events
Presenter: Anna Olsson-Brown
Session: Poster Display session 3
Resources:
Abstract
3267 - Cardiotoxic and pro-inflammatory effects induced by the association of immune checkpoint inhibitor Pembrolizumab and Trastuzumab in preclinical models
Presenter: Nicola Maurea
Session: Poster Display session 3
Resources:
Abstract
3417 - Interstitial lung disease associated with immune-checkpoint inhibitors in malignant diseases
Presenter: Akira Yamagata
Session: Poster Display session 3
Resources:
Abstract
2071 - A Phase 1 Study of Intraperitoneal MCY-M11 Anti-Mesothelin CAR for Women with Platinum Resistant High Grade Serous Adenocarcinoma of the Ovary, Primary Peritoneum, or Fallopian Tube, or Subjects with Peritoneal Mesothelioma with Recurrence after Prior Chemotherapy
Presenter: Christina Annunziata
Session: Poster Display session 3
Resources:
Abstract
4935 - Trial in progress: First-in-human study of a novel anti-NY-ESO-1–anti-CD3, TCR-based bispecific (IMCnyeso) as monotherapy in NY-ESO-1/LAGE-1A-positive advanced solid tumors (IMCnyeso-101)
Presenter: Juanita Lopez
Session: Poster Display session 3
Resources:
Abstract
5613 - Nimotuzumab-Cisplatin-Radiation versus Cisplatin-Radiation in HPV negative oropharyngeal cancer
Presenter: Kumar Prabhash
Session: Poster Display session 3
Resources:
Abstract
2576 - Interim analysis of a single arm phase 2 study of adjuvant nivolumab after salvage resection in head and neck squamous cell carcinoma patients previously treated with definitive therapy.
Presenter: Trisha Wise-draper
Session: Poster Display session 3
Resources:
Abstract
4758 - A Phase I Study of the CDK4/6 Inhibitor, Palbociclib in combination with Cetuximab and Intensity Modulated Radiation Therapy (IMRT) for Locally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN); A Result of Dose Escalation Cohort
Presenter: Nuttapong Ngamphaiboon
Session: Poster Display session 3
Resources:
Abstract