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Grace Dy
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EP1.04 - Immuno-oncology (ID 194)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.04-23 - Ongoing Phase II Trial of Anti-PD1 Therapy in Combination with CIMAvax-EGF in Patients with Advanced NSCLC or Squamous Cell Head and Neck Cancer (Now Available) (ID 2668)
08:00 - 18:00 | Presenting Author(s): Grace Dy
- Abstract
Background
CIMAvax-EGF (CE) is a novel EGF-depleting immunotherapy consisting of human recombinant EGF conjugated to recombinant P64k derived from Neisseria meningitidis, that elicits an anti-EGF antibody response, resulting in reduction of circulating EGF levels. A randomized phase III study of CIMAvax-EGF administered after first-line platinum-based chemotherapy as switch maintenance therapy, in patients with advanced NSCLC, demonstrated improved overall survival versus best supportive care alone, particularly in patients with high baseline serum EGF levels. A recently completed phase I trial combining CE with nivolumab (N), an anti-PD1 immune checkpoint inhibitor, as second-line therapy for advanced NSCLC, demonstrated the combination is safe and induces a higher frequency of good anti-EGF antibody responses compared to the historical experience with CE alone (Figure 1). In addition, promising efficacy was observed in patients with PD-L1 low (< 1%) tumors. These results led to the initiation of this multi-arm phase II trial.
Method
CIMAvax-EGF (2.4 mg IM every 2 weeks x 4 doses, then every 4 weeks thereafter) in combination with Nivolumab (240mg IV every 2 weeks) is being evaluated in this multi-arm phase II study (NCT02955290) as second-line therapy in patients with advanced NSCLC (cohort A), advanced/recurrent head and neck squamous cell cancer (cohort B) and is also being tested as first-line therapy in combination with pembrolizumab (200 mg IV every 4 weeks) in patients with advanced NSCLC with PD-L1 ≥ 50% (cohort C). The primary and secondary endpoints are to evaluate 12-month OS and PFS in cohorts A and B, and to evaluate objective response rate, PFS and 12-month OS in cohort C. Exploratory objectives include characterizing tissue-based immune and EGFR signaling as well as serum EGF levels, anti-EGF antibody levels and other blood-based biomarkers in relation to clinical outcomes.
Result
A total of 10 patients have been enrolled to this ongoing study with a planned enrollment of up to 127 patients. An update on accrual along with interim safety, efficacy and correlative data will be presented.
Conclusion
To date, the combination of CIMAvax-EGF with anti-PD1 therapy has been safe and well tolerated. Enrollment to the phase II portion of this study is ongoing at Roswell Park and is in the process of being expanded to additional U.S. sites.
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P1.04 - Immuno-oncology (ID 164)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.04-10 - Identification of Immunotherapy Targets in STK11 Mutant Non-Squamous Non-Small Cell Lung Cancer (ID 2403)
09:45 - 18:00 | Author(s): Grace Dy
- Abstract
Background
The use of PD-1/PD-L1 checkpoint inhibitors (CPI) has dramatically altered the treatment of advanced Non-Small Cell Lung Cancer (NSCLC). However, a large proportion of patients with NSCLC do not derive clinical benefit from CPI treatment. Recent studies have identified STK11 mutations leading to loss of LKB1 in non-squamous NSCLC as drivers of primary resistance to CPI treatment. Using a clinical cohort of patients whose tumors underwent comprehensive genomic and immune transcriptomic analysis, we characterized the immune gene expression profile of STK11 mutant non-squamous NSCLC tumors and identified potential novel immunotherapy targets in STK11 mutant non-squamous NSCLC.
Method
We performed comprehensive analysis of the genomic and immunological landscape of 204 formalin-fixed, paraffin-embedded tumor samples (obtained prior to CPI treatment) from advanced stage non-squamous NSCLC patients treated at Roswell Park Comprehensive Cancer Center using a CLIA-certified laboratory test that included targeted NGS genomic sequencing, gene fusion analysi,s and RNA-seq of 394 immune transcripts. Differential gene expression analysis was performed using R/Bioconductor package limma with Benjamini-Hochberg adjusted p-values reported . This study was approved by Roswell Park internal review board review (protocol BDR 091817) according to institutional policy for nonhuman subjects research.
Result
Among the cohort of 204 cases, 30 contained truncating STK11 mutations. STK11 mutant cases showed an immunosuppressive environment with decreased PD-L1 mRNA expression (p=0.01) and decreased T-cell inflammation gene expression signature (p=0.0029). Analysis of differentially expressed immune genes signatures showed significant decreases in antigen presentation (p=0.015) and processing (p=0.044), NK cell activation (p=0.039), chemokine and cytokine signaling (p=0.044), immune checkpoint pathways (p=0.015), and Interferon gamma signaling (p=0.039). The top upregulated gene was TRIM29 (p=0.024). Other overexpressed targets included CD276 (p=0.024) also known as B7-H3, ID3 (p=0.002), KRT7 (p=0.008), and NOTCH3 (p=0.006). Interrogation of the TCGA LUAD dataset also demonstrated elevated TRIM29 expression (p=0.006) in KRAS/STK11-mutant (KL) compared to KRAS/STK11-wild-type samples. We also confirmed elevated TRIM29 expression in a panel of KL human cell lines. TRIM29 is an E3 ubiquitin ligase known to play a role in innate immune responses to DNA viral infections through targeting STING for degradation. Given recent studies implicating decreased STING expression in STK11 mutant cell line panels, TRIM29 represents a potential novel therapeutic candidate in this cohort of patients resistant to CPI treatment.
Conclusion
Using a large clinical cohort of non-squamous NSCLC patients we characterized the immunsuppressive environment of STK11 mutant tumors and identified the E3 ubiquitin ligase TRIM29 as a potential therapeutic target.
