Tumor antigen expression and survival of patients with previously treated advanced non-small cell lung cancer (NSCLC) receiving viagenpumatucel-L (HS-110) plus nivolumab.

Abstract

9546 Background: Viagenpumatucel-L (HS-110) is an allogeneic cellular vaccine derived from a human lung adenocarcinoma cell line transfected with gp96-Ig fusion protein. Gp96-Ig functions as an antigen chaperone for dendritic cell activation and direct CD8+T cell expansion via cross presentation. DURGA is a multi-cohort study evaluating HS-110 plus anti-PD-1 mAbs in patients (pts) with advanced NSCLC. We report on Cohort A, which enrolled previously-treated pts who had not received an anti-PD(L)1 prior to study entry. Methods: Primary objectives were safety and objective response rate (ORR). Overall Survival (OS) was a secondary endpoint. Pts received 1 X 107 HS-110 cells intradermally every week for 18 wks and nivolumab until tumor progression. To determine cancer testis antigen (CTA) overexpression from baseline pt tumor samples, hybrid-capture RNA-seq libraries were prepared from macrodissected formalin fixed paraffin embedded tumor tissue and sequenced on an Illumina NovaSeq 6000. Gene-level transcripts were quantified using the Salmon software package. Results: 47 pts were enrolled into Cohort A. ORR and clinical benefit rate (CR + PR + SD) were 21% and 43%, respectively, with a 17.2 month median duration of response. Median OS was 28.7 months (mos), with a median follow up of 15.7 mos. One and 2-year survival were 57% and 36%, respectively. A prespecified exploratory analysis of CTA expression level in baseline pt tumor tissue was performed. 50% of pts shared at least 8 of the 39 total antigens overexpressed by HS110. Although there was no difference in ORR between these groups, mOS was higher in pts with tumors that shared ≥ 8 antigens with HS-110 (not reached (NR) [95%CI: 10.3 mos, NR] vs 6.7 mos [95%CI: 1.4 mos, NR]), p = 0.028. Pts whose tumors expressed the ZNF492 antigen also had improved OS (NR [95%CI: 11.6 mos, NR] vs 7.2 mos [95%CI: 1.6 mos, NR]), p = 0.03. All pts experienced at least one adverse event (AE), and the most common AEs were fatigue (28%), arthralgia (19%) and cough (17%). There were 2 grade 5 AEs not related to treatment. Conclusions: The combination of HS-110 and nivolumab appears safe and well tolerated. OS was improved in pts whose tumors express ≥ 8 shared antigens with HS110, as well as in those who specifically expressed ZNF492. Further exploration of antigen expression as a predictor for treatment outcome with HS110 plus nivolumab is ongoing. Clinical trial information: NCT02439450 .

Induction of SARS-CoV-2 Protein S-Specific CD8+ T Cells in the Lungs of gp96-Ig-S Vaccinated Mice

“…Cell-based secreted heat shock protein technology has been previously validated in numerous animal models and in humans ( 37 – 39 , 42 ). The secreted form of gp96 protein (gp96-Ig) was generated by replacing the c-terminal, KDEL-retention sequence of human gp96 gene, with hinge region and constant heavy chains (CH2 and CH3) of human IgG1 ( 43 ) ( Figure 1A ).…”

“…Human embryonic kidney (HEK)-293 cells, obtained from the American Tissue Culture Collection (ATCC, #CRL-1573) and human lung adenocarcinoma cell lines (AD100) ( 40 , 41 ) (source: University of Miami, FL, USA) were transfected with 2 plasmids: B45 encoding gp96-Ig (source: University of Miami) and pcDNA™ 3.1(–) (Invitrogen), encoding full-length SARS-CoV-2 protein S gene (Genomic Sequence: NC_045512.2; NCBI Reference Sequence: YP_009724390.1 GenBank Reference Sequence: QHD43416). A B45 plasmid expressing secreted gp96-Ig has been approved by the Food and Drug Administration and Office of Biotechnology Activities for human use and is currently employed in a clinical study for the treatment of nonsmall cell lung cancer (NSCLC) (NCT02117024, NCT02439450) ( 42 ). The histidinol-selected, B45 plasmid, replicates as multicopy episomes and provides high levels of expression.…”

Induction of SARS-CoV-2 protein S-specific CD8+ T cells in the lungs of gp96-Ig-S vaccinated mice

“…[37][38][39][46][47][48] Importantly, this vaccine strategy has shown success in delaying virus acquisition, as well as in improving the survival of NSCLC patients in clinical trials. 38,42 The principle of a cell-based vaccine relies on the ability of gp96-Ig to chaperone antigenic proteins to be efficiently endocytosed and cross-presented by activated dendritic cells (DC) to CD8+ T cells, thereby stimulating an avid, pathogen-specific T-cell response. 33,34,[37][38][39] We adapted this cell-based technology to create a vaccine that delivers SARS-CoV-2 spike (S) protein directly to DCs, so that primed and activated SARS-CoV-2 protein S-specific CD8+ T cells can identify and kill SARS-CoV-2 infected lung epithelial cells.…”

“…The B45 plasmid expressing secreted gp96-Ig has been approved by the Food and Drug Administration and Office of Biotechnology Activities for human use and is currently employed in a clinical study for the treatment of nonsmall cell lung cancer (NSCLC) (NCT02117024, NCT02439450). 42 The histidinol-selected, B45 plasmid, replicates as multicopy episomes and provides high levels of expression. Full-length SARS-CoV-2 protein S is based upon published SARS-CoV-2 protein S sequence from the original Wuhan strain (GenBank Reference Sequence: QHD43416) and cloned into the neomycinselectable eukaryotic expression vector, pcDNA 3.1(-).…”

“…Cell-based secreted heat shock protein technology has been previously validated in numerous animal models and in humans. [37][38][39]42 The secreted form of gp96 protein (gp96-Ig) was generated by replacing the c-terminal, KDEL-retention sequence of human gp96 gene, with hinge region and constant heavy chains (CH2 and CH3) of human IgG1 43 (Figure 1a). The Vaccine cells, 293-gp96-Ig-S and AD100-gp96-Ig-S, were generated by cotransfection of AD100 and HEK293 cells with plasmids encoding gp96-Ig (B45) and protein S (pcDNA 3.1) and selection with G418 and L-histidinol as described in Methods.…”