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507 A phase 1 clinical trial of RP2, an enhanced potency oncolytic HSV expressing an anti-CTLA-4 antibody, as a single agent and combined with nivolumab in patients with advanced solid tumors
  1. Mark Middleton1,
  2. Joseph Sacco2,
  3. Kevin Harrington3,
  4. Anna Olsson-Brown2,
  5. Tze Chan4,
  6. Pablo Nenclares3,
  7. Isla Leslie3,
  8. Francesca Aroldi1,
  9. Praveen Bommareddy5,
  10. Imran Saleem5,
  11. Henry Castro5,
  12. Andrea Pirzkall5 and
  13. Robert Coffin5
  1. 1University of Oxford, Oxford, UK
  2. 2Clatterbridge Cancer Centre, Wirral, UK
  3. 3Institute of Cancer Research, London, UK
  4. 4Royal Liverpool University Hospital, Liverpool, UK
  5. 5Replimune, Woburn, MA, USA


Background RP2 is a first-in-class, enhanced potency oncolytic herpes simplex virus (HSV) -1 expressing GM-CSF, a fusogenic protein (GALV-GP R-), and an anti-CTLA-4 antibody-like molecule that is being tested in an open-label, multicenter, phase 1 study alone and combined with nivolumab (nivo). Preliminary data with RP2 as monotherapy has been presented previously [1–2]. We present updated safety, tolerability, and clinical activity data of RP2 alone and initial data in combination with nivolumab.

Methods Using a 3+3 dose escalation, patients (pts) received intratumoral injections of up to 10 mL RP2 to superficial and/or visceral tumors Q2W up to 5 times at two dose levels (Dose level 1: 10^5 PFU/mL then 4 doses of 10^6 PFU/mL; dose level 2: 10^6 PFU/mL then 4 doses of 10^7 PFU/mL). Following determination of the RP2D (10^6 PFU/mL, followed by subsequent doses of 10^7 PFU/mL, Q2W X 7), a combination cohort of 30 pts were dosed with RP2 up to 8 times combined with nivo (240 mg Q2W for 4 mos from the second RP2 dose, then 480 mg Q4W for 20 mos). Re-initiation of up to 8 additional RP2 doses is permitted in prespecified circumstances.

Results Nine pts were enrolled into the RP2 monotherapy phase (6 seropositive and 3 seronegative for HSV). Objective responses were observed in 3 pts, 1 ongoing CR for ≥15 months in mucoepidermoid carcinoma, 1 ongoing PR for ≥18 months in esophageal cancer with liver metastases, 1 PR in uveal melanoma with liver metastases that progressed at 15 months. As of June 3rd 2021, 27 patients had been enrolled and ongoing partial responses had been observed in 4/9 anti-PD-1 failed cutaneous melanoma, 1/3 uveal melanoma and 1/3 SCCHN pts. A further 8 patients remained on study with the opportunity for response. Biomarker analyses indicate T cell infiltration, increase in tumor inflammation signature, expansion of existing T cell clones and emergence of new T cell clones, together indicative of local and systemic anti-tumor activity. The combination was well tolerated and no new safety signals were identified.

Conclusions RP2 ± nivo demonstrated good tolerability and durable systemic responses in pts with difficult-to-treat, heavily pretreated and anti-PD-1 failed advanced cancers. These data continue to support the hypothesis that oncolytic delivery of anti-CTLA-4 into tumors, with accompanying antigen release, presentation and immune activation, can provide potent systemic anti-tumor effects. Updated data from the full 30 patient cohort will be presented.

Trial Registration NCT04336241


  1. Aroldi F, Sacco J, Harrington K, Olsson-Brown A, Nanclares P, Menezes L, Bommareddy P, Thomas S, Kaufman H, Samakoglu S, Coffin R and Middleton M. 421, Initial results of a phase 1 trial of RP2, a first in class, enhanced potency, anti-CTLA-4 antibody expressing, oncolytic HSV as single agent and combined with nivolumab in patients with solid tumors Journal for Immuno Therapy of Cancer 2020;8.

  2. Harrington KJ, Aroldi F, Sacco JJ, Milhem MM, Curti B, Vanderwalde A, et al. 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 Res 2021. LB-180

Ethics Approval The study was approved by institutional review board or the local ethics committee at each site. Informed consent was obtained from patients prior to enrollment.

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