Replimune is pioneering a novel class of cancer treatments based on oncolytic immunotherapies—herpes simplex viruses engineered to replicate within tumors, kill cancer cells directly, and spark systemic anti-tumor immunity ([Replimune][1]).
The RPx Platform
Replimune’s RPx platform uses modified HSV-1 backbones enhanced with immune‑stimulating transgenes:
RP3: Adds co‑stimulatory ligands (CD40L and 4‑1BBL) to further stimulate immune responses in solid tumors ([Replimune][3]).
RP1: HSV‑1 expressing GM‑CSF and the fusogenic GALV‑GP R‑ protein—designed for immunogenic tumors like melanoma and non‑melanoma skin cancers ([Replimune][2]).
RP2: Builds on RP1 by adding an anti‑CTLA‑4 antibody‑like component—targeting more immunologically “cold” tumors (e.g., uveal melanoma) ([Replimune][2]).
Key Clinical Trials
1. IGNYTE & IGNYTE‑3 (RP1 + Nivolumab in Melanoma)
- Phase 1/2 IGNYTE, in patients with unresectable melanoma, MSI‑H/dMMR tumors, NMSC, and NSCLC (Replimune).
- June 2024 topline data: ~33% overall response rate (ORR), durable responses > 6 months, well‑tolerated safety profile (AIM at Melanoma Foundation).
- June 2025 ASCO preview: ORR ≈ 32.9%, with 15% complete responses; deeper injections (visceral organs) showed higher response rates (~42.9%) and systemic shrinkage in non‑injected lesions (Clinical Trial Vanguard).
- The FDA granted Breakthrough Therapy designation and accepted a Biologics License Application (BLA) with priority review; PDUFA target date is July 22, 2025 (ir.replimune.com).
- Phase 3 IGNYTE‑3 is underway across 100+ global sites comparing RP1 + nivolumab vs. physician’s choice in advanced melanoma (Oncodaily).
2. RP2 (RP2 ± Nivolumab)
- Phase I studies initially launched in advanced solid tumors, including combination with Opdivo (nivolumab) (Clinical Trials Arena).
- Encouraging phase II results in uveal melanoma—ORR ~29% (across 17 patients); responses seen regardless of HLA‑A2 status (Oncology Pipeline).
- A planned Phase 2/3 RP2 vs. Opdivo+Yervoy in checkpoint‑naïve metastatic uveal melanoma launched Jan 2025 (Oncology Pipeline).
3. RP2/RP3 combo with Atezolizumab + Bevacizumab in CRC
- A Phase 2 trial (NCT05733611) is testing intratumoral RP2 or RP3 alongside atezolizumab (PD‑L1 inhibitor) and bevacizumab (anti‑VEGF) in advanced microsatellite-stable colorectal cancer (ClinicalTrials).
4. ARTACUS and CSCC (RP1 Monotherapy & Combo Trials)
- The ARTACUS Phase 1/2 trial in organ-transplant-associated skin cancers reported interim RP1 monotherapy data in late 2023 (ir.replimune.com).
- Additional collaboration efforts are underway—e.g., RP1 with INCB99280 in resectable cutaneous squamous cell carcinoma (Clinical Trials Arena).
What This Means
- Clinical momentum: RP1 has delivered strong efficacy (~33% ORR, durable >6 months), leading to its BLA review in advanced melanoma.
- Mechanistic depth: Adding immune modulators (anti‑CTLA‑4, co-stimulatory ligands) in RP2/RP3 may help treat immunologically “cold” cancers.
- Strategic combos: Trials pairing oncolytic agents with checkpoint inhibitors and anti-angiogenics underscore a push toward multi-modal synergy.
- Global reach: Replimune’s trials span the US, Europe, and more, highlighting global ambition.
Summary Table
| Therapy | Indications | Phase | Highlights |
|---|---|---|---|
| RP1+Nivolumab | Advanced melanoma | Phase 3 / BLA | ORR ~33%, durable response, priority FDA review |
| RP2+/-Nivolumab | Uveal melanoma, other solid tumors | Ph1/2 & Ph2/3 | ORR ~29% in uveal melanoma, broader trial begun |
| RP2/RP3 + Atezolizumab + Bevacizumab | MSS CRC | Phase 2 | Combines immune/angiogenic targeting |
| RP1 Mono / Combos | Skin cancers, CSCC | Ph1/2 | Ongoing evaluation of RP1’s standalone use |
Looking Ahead
- July 22, 2025: FDA decision on RP1 + nivolumab in melanoma—if approved, this marks a milestone as the first HSV-based immunotherapy of this kind.
- Late 2025: Potential readouts from RP2/3 combo trials in uveal melanoma and colorectal cancer.
- Strategic expansion into investigator-led studies—Replimune supports independent trials and expanded access programs (Replimune, AIM at Melanoma Foundation, ClinicalTrials, Replimune, Oncology Pipeline).
Final Thoughts
Replimune’s RPx platform is at the cutting edge of oncolytic immunotherapy. With RP1 poised for approval and RP2/RP3 advancing through strategic combo trials, they are redefining how the immune system can be harnessed to tightly target, eradicate, and immunologically “educate” tumors. If late-stage trial results hold, RP1’s approval could catalyze a new era of virus‑based cancer therapies.
This article is based on publicly available information including Replimune’s clinical trial listings and press releases.
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