LB180 - Clinical biomarker studies with two fusion-enhanced versions of oncolytic HSV (RP1 and RP2) alone and in combination with nivolumab in cancer patients indicate potent immune activation
AACR Annual Meeting
oregon; portland; chiles
Introduction:RP1 and RP2 are novel, enhanced potency oncolytic versions of HSV1 engineered to express human GM-CSF and the gibbon ape leukemia virus membrane R- glycoprotein (GALV-GP R-), providing constitutive fusion activity and increased immunogenic cell death. RP2 further expresses an anti-CTLA-4 antibody-like molecule. Murine versions of RP1 and RP2 exhibited synergy in combination with anti-mouse-PD-1 leading to enhanced regression of both injected and un-injected tumors in mice (Thomas et al JITC 2019). RP1 and RP2 are currently being evaluated in clinical trials in a range of solid tumors alone and combined with anti-PD1 therapy, where deep and durable responses have been demonstrated (SITC 2020). Here we present biomarker data from the Phase 1/2 clinical trial of RP1 alone and combined with nivolumab (NCT03767348) and from the Phase 1 portion of the clinical trial with RP2 alone (NCT04336241).
Methods: In the Phase 1/2 studies tumor biopsies and peripheral blood mononuclear samples (PBMCs) were collected at screening and at D43 for biomarker analysis, after combination therapy with nivolumab for RP1 and following single agent treatment for RP2. Immunohistochemistry (IHC) was performed for CD8 (SP57 clone, Ventana) and for PD-L1 (28-8 clone, pharmDx assay). Gene expression was analysed using NanoString to assess effects on a range of genes. The tumor inflammation signature score (TIS) was also calculated.
Results:Preliminary Phase 1/2 biomarker data from paired tumor biopsies include the following: Immunohistochemistry for CD8 and PD-L1 (n=30) indicated robust and increased infiltration of CD8+ T cells and PD-L1 expression, both after combined treatment with RP1 and nivolumab and after single agent RP2 across different tumor types, and including reversal of T cell exclusion following prior combined treatment with ipilimumab and nivolumab in melanoma. Gene expression analysis (n=15) demonstrated a significant increase in the expression levels of genes associated with innate and adaptive immune activation and genes previously reported to be associated with responsiveness to anti-PD1 therapy, particularly CD8, CXCL9, CD27 and TIGIT, as well as consistently increased TIS.
Conclusion:Consistent with the pre-clinical data, preliminary clinical biomarker data indicate substantial increase in CD8 T cell infiltration and PD-L1 expression, as well as increased TIS score in the majority of patients treated with RP2 alone or RP1 and nivolumab combination. Particularly marked effects were seen in some patients with clinical responses which occurred independent of both baseline PD-L1 and prior anti-PD1 therapy status, which suggests potential broad utility of the RP1/2 treatment approach in igniting an anti-tumor immune response. Tumor mutation burden analysis and T cell receptor sequencing are currently underway and further updates of the dataset will be presented.
Earle A. Chiles Research Institute
Harrington, Kevin J.; Aroldi, Francesca; Sacco, Joseph J.; Milhem, Mohammed M.; Curti, Brendan; Vanderwalde, Ari M.; Baum, Scott; Samson, Adel; Pavlick, Anna C.; Chesney, Jason A.; Niu, Jiaxin; Rhodes, Terence D.; Bowles, Tawnya L.; Conry, Robert; Olsson-Brown, Anna; Laux, Douglas E.; Nenclares, Pablo; Menezes, Lavita; Deterding, Alex; Roulstone, Victoria; Kyula, Joan; Thomas, Suzanne; Bommareddy, Praveen K.; Samakoglu, Selda; Pirzkall, Andrea; Coffin, Robert S.; and Middleton, Mark R., "LB180 - Clinical biomarker studies with two fusion-enhanced versions of oncolytic HSV (RP1 and RP2) alone and in combination with nivolumab in cancer patients indicate potent immune activation" (2021). Articles, Abstracts, and Reports. 4785.