Background Liver metastases (mets) have been linked to resistance to checkpoint inhibitors.1-2 Intratumoral (IT) oncolytic immunotherapy is intended to provide immunogenic killing of tumors by inducing local and systemic immune responses to convert immunologically cold tumors into hot.3 RP1, RP2 and RP3 (RPx) are oncolytic immunotherapies that are currently being investigated in Phase 1-2 clinical trials, either alone or in combination with anti-PD1 therapy (nivolumab [nivo] and cemiplimab). RP1 is an enhanced potency oncolytic HSV-1 which expresses GALV-GP R- and GM-CSF, RP2 additionally expresses an anti-CTLA-4 antibody-like molecule and RP3 additionally 4-1BBL and CD40L, but does not express GM-CSF. Here we present safety data following direct IT injection of RP1-2 into liver mets.
Methods Patients enrolled into the clinical trials with RPx ± nivo are included in this analysis. Patients received up to 10 mL of RPx intratumorally into one or more superficial or deep seated/visceral lesions (Dose: 1x106 PFU/mL × 1 followed by 1x107 PFU/mL × 7, Q2W). From the second dose of RPx, nivo was also administered via intravenous injection for the combination groups.
Results As of March 2022, 26 and 10 patients had been injected with RP1 and RP2 into liver mets respectively. For RP1, 9/26 (34.6%) and 4/26 (15.4%) patients were refractory to anti-PD-1/PD-L1 and anti-CTLA-4 (including combined with anti-PD1) respectively. With RP2, 6/10 (60%) and 4/10 (40%) were refractory to anti-PD-1/PD-L1 and anti-CTLA-4 (including combined with anti-PD1) respectively. The most common any grade adverse events were pyrexia (65.4% with RP1 and 70% with RP2), nausea (53.8% and 20%), chills (61.5% and 20%) and fatigue (46.2% and 20%). This compares to pyrexia (26.3% and 60%), nausea (36.8.8% and 60%), chills (21.1% and 80%) and fatigue (42.1% and 40%) in patients with liver mets who did not receive RP1 (n=19) or RP2 (n=5) into the liver; which is consistent with patients without liver mets who received superficial injections.
Conclusions Direct injection of RP1 and RP2 into liver mets was safe and demonstrated good feasibility and tolerability in patients with difficult-to-treat, heavily pretreated and anti-PD-1/anti-CTLA failed advanced cancers. While the frequency of common side effects appeared to be moderately increased following injection into liver lesions as compared to other sites, no new safety signals were identified following liver injection as compared to patients administered RP1-2 by the superficial route. Together, these data support the safety and feasibility of direct IT injection of RP1-3 into liver mets.
Riihimäki, M, Thomsen, H, Sundquist, K, Sundquist, J, Hemminki, K. Clinical landscape of cancer metastases. Cancer Med. 2018;7:5534–5542.
Yu J, Green MD, Li S, Sun Y, Journey SN, Choi JE, Rizvi SM, Qin A, Waninger JJ, Lang X, Chopra Z, El Naqa I, Zhou J, Bian Y, Jiang L, Tezel A, Skvarce J, Achar RK, Sitto M, Rosen BS, Su F, Narayanan SP, Cao X, Wei S, Szeliga W, Vatan L, Mayo C, Morgan MA, Schonewolf CA, Cuneo K, Kryczek I, Ma VT, Lao CD, Lawrence TS, Ramnath N, Wen F, Chinnaiyan AM, Cieslik M, Alva A, Zou W. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat Med. 2021 Jan;27(1):152–164.
Harrington K, Freeman DJ, Kelly B, Harper J, Soria JC. Optimizing oncolytic virotherapy in cancer treatment. Nat Rev Drug Discov. 2019 Sep;18(9):689–706.
Ethics Approval The study was approved by institutional review board or the local ethics committee at each participating site. Informed consent was obtained from patients before participating in the trial.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.