F1 - Cancer - Immunotherapy and Cancer Vaccines
5: Personalized Neoantigen DNA Vaccine (GNOS-PV02) and Pembrolizumab Develop Antitumor Poly-Functional Neoantigen-Specific CD4+ and CD8+ Effector T Cells in Advanced Hepatocellular Carcinoma Therapy
Type: Oral Abstract Session
Presentation Details
Session Title: Clinical Trials Spotlight Symposium
A personalized therapeutic cancer vaccine (PTCV) tailored against neoantigens identified in an individual’s tumor may enhance responses to PD-1 inhibitors through the induction of tumor-specific immunity. Here, we present results from a single-arm Phase Ib/2a trial evaluating a DNA plasmid (GNOS-PV02) encoding up to 40 neoantigens co-administered with plasmid-encoded IL-12 (pIL12) in combination with pembrolizumab (PEMBRO) in patients (pts) with advanced HCC.
Pts were eligible for study therapy upon progression or intolerance with a 1L tyrosine kinase inhibitor (TKI). The PTCV [GNOS-PV02 (1mg) and pIL12 (0.34mg)] was administered intradermally via in vivo electroporation Q3w x 4 doses, and Q9w thereafter. PEMBRO was administered at 200mg IV Q3w. The primary endpoints were safety and immunogenicity. The data cut date was August 18, 2023.
Among the 36 enrolled pts who received at least one dose of treatment, there were no DLTs or treatment-related grade ≥3 events. ORR (mITT) per RECIST 1.1 was 30.6% (11/36; 9 confirmed and 2 unconfirmed) with 8.3% (3/36) of pts achieving a CR. A complete molecular response (100% ctDNA clearance) was detected in 7 pts including the 3 radiographic CRs, and 4 additional pts who continue to show durable tumor control (3PR, 1 SD). Immunological analyses confirmed the induction of neoantigen-specific T cell responses by IFNγ-ELISpot in 19/22 (86.4%) evaluable pts, and pts with a larger ELISpot response showed a trend towards longer OS. PTCV immunization resulted in a significant increase of positive epitopes in both clinically responding and non-responding patients. The expression of T cell- biomarkers - CD8A, CD8B, CCL5, CXCR6, LCK, and TIGIT was significantly increased in the responding patients. Multi-parametric cellular profiling and single-cell analysis revealed active, proliferative, and cytolytic vaccine-specific CD4+ and CD8+ effector T cells in the blood of immunized pts, with a higher CD8-to-CD4 ratio. In 14/14 (100%) of pts with paired pre- and on-treatment blood and tumor biopsies, we identified by TCRβ bulk sequencing expanded T cell clones in the peripheral blood that also trafficked into the tumor.
Our data shows that the personalized DNA-based vaccine (GNOS-PV02) in combination with pembrolizumab generates a significant poly-functional neoantigen-specific antitumor CD8+ and CD4+ T cell responses, including T cell clonal expansion and infiltration to the tumor. These features could explain the mechanism of action behind the clinical activity observed in advanced HCC patients.
Plain Language Summary
PD-1 inhibitors have modest efficacy as monotherapy in hepatocellular carcinoma. A personalized therapeutic cancer vaccine tailored against neoantigens identified in an individual’s tumor may enhance responses to PD-1 inhibitors through the induction of tumor-specific immunity. Here, we present results from a single-arm Phase Ib/2a trial evaluating a DNA plasmid encoding up to 40 neoantigens co-administered with plasmid-encoded IL-12 in combination with pembrolizumab in patients with advanced HCC. Our data shows that the personalized DNA-based vaccine in combination with pembrolizumab generates a significant poly-functional neoantigen-specific antitumor CD8+ and CD4+ T cell responses, including T cell clonal expansion and infiltration to the tumor. These features could explain the mechanism of action behind the clinical activity observed in advanced HCC patients.
Renzo Perales1, Jian Yan2, Mark Yarchoan3, Edward Gane4, Thomas Marron5, Neil Cooch1, Daniel Shu6, Elana Fertig7, Luciane Kagohara8, Gabor Bartha9, Josette Northcott9, John Lyle9, Sarah Rochestie1, Joann Peters1, Jason Connor10, Elizabeth Jaffee11, Alfredo Perales-Puchalt1, David B. Weiner12, Ildiko Csiki1, Niranjan Y. Sardesai1
1Geneos Therapeutics, Philadelphia, PA,2Research & Development, Geneos Therapeutics, Philadelphia, PA,3Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD,4New Zealand Liver Transplant Unit, University of Auckland, Auckland, New Zealand,5Early Phase Trials Unit, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY,6Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD,7Department of Applied Mathematics and Statistics, Johns Hopkins University Whiting School of Engineering, Baltimore, MD,8Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD,9Personalis, Inc., Fremont, CA,10ConfluenceStat, LLC, Orlando, FL,11The Johns Hopkins University School of Medicine, Baltimore, MD,12The Wistar Institute, Philadelphia, PA"
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