Abstract
Abstract 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
Cancer research (Chicago, Ill.), Vol.81(13_Supplement), pp.LB180-LB180
07/01/2021
DOI: 10.1158/1538-7445.AM2021-LB180
Abstract
Abstract
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.
Citation Format: Kevin J. Harrington, Francesca Aroldi, Joseph J. Sacco, Mohammed M. Milhem, Brendan D. Curti, Ari M. Vanderwalde, Scott Baum, Adel Samson, Anna C. Pavlick, Jason A. Chesney, Jiaxin Niu, Terence D. Rhodes, Tawnya L. Bowles, Robert Conry, Anna Olsson-Brown, Douglas E. Laux, Pablo Nenclares, Lavita Menezes, Alex Deterding, Victoria Roulstone, Joan Kyula, Suzanne Thomas, Praveen K. Bommareddy, Selda Samakoglu, Andrea Pirzkall, Robert S. Coffin, Mark R. Middleton. 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 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB180.
Details
- Title: Subtitle
- Abstract 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
- Creators
- Kevin J. Harrington - The Institute for Cancer research/Royal Marsden Hospital, UK., London, United Kingdom;Francesca Aroldi - Churchill HospitalJoseph J. Sacco - Clatterbridge Cancer Centre NHS Foundation TrustMohammed M. Milhem - University of IowaBrendan D. Curti - Providence Portland Medical CenterAri M. Vanderwalde - West Cancer CenterScott Baum - West Cancer CenterAdel Samson - University of LeedsAnna C. Pavlick - NYU Langone HealthJason A. Chesney - University of LouisvilleJiaxin Niu - Banner MD Anderson Cancer Center, Gilbert, AZTerence D. Rhodes - Intermountain Medical CenterTawnya L. Bowles - Intermountain Medical CenterRobert Conry - University of Alabama at BirminghamAnna Olsson-Brown - Clatterbridge Cancer Centre NHS Foundation TrustDouglas E. Laux - University of IowaPablo Nenclares - The Institute for Cancer research/Royal Marsden Hospital, UK., London, United Kingdom;Lavita Menezes - Replimune Inc, Woburn, MA.Alex Deterding - Replimune Inc, Woburn, MA.Victoria Roulstone - The Institute for Cancer research/Royal Marsden Hospital, UK., London, United Kingdom;Joan Kyula - The Institute for Cancer research/Royal Marsden Hospital, UK., London, United Kingdom;Suzanne Thomas - Replimune Inc, Woburn, MA.Praveen K. Bommareddy - Replimune Inc, Woburn, MA.Selda Samakoglu - Replimune Inc, Woburn, MA.Andrea Pirzkall - Replimune Inc, Woburn, MA.Robert S. Coffin - Replimune Inc, Woburn, MA.Mark R. Middleton - Churchill Hospital
- Resource Type
- Abstract
- Publication Details
- Cancer research (Chicago, Ill.), Vol.81(13_Supplement), pp.LB180-LB180
- DOI
- 10.1158/1538-7445.AM2021-LB180
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Language
- English
- Date published
- 07/01/2021
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984362282002771
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