Phase I trial of intratumoral PVSRIPO in patients with unresectable, treatment-refractory melanoma

Abstract

Background: While programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) antagonists have improved the prognosis for many patients with melanoma, around 60% fail therapy. PVSRIPO is a non-neurovirulent rhinovirus:poliovirus chimera that facilitates an antitumor immune response following cell entry via the poliovirus receptor CD155, which is expressed on tumor and antigen-presenting cells. Preclinical studies show that oncolytic virus plus anti-PD-1 therapy leads to a greater antitumor response than either agent alone, warranting clinical investigation.

Methods: An open-label phase I trial of intratumoral PVSRIPO in patients with unresectable melanoma (American Joint Committee on Cancer V.7 stage IIIB, IIIC, or IV) was performed. Eligible patients had disease progression on anti-PD-1 and V-raf murine sarcoma viral oncogene homolog B (BRAF)/mitogen activated protein kinase kinase (MEK) inhibitors (if BRAF mutant). The primary objective was to characterize the safety and tolerability of PVSRIPO. Twelve patients in four cohorts received a total of 1, 2 or 3 injections of PVSRIPO monotherapy, with 21 days between injections.

Results: PVSRIPO injections were well tolerated with no serious adverse events (SAEs) or dose-limiting toxicities (DLTs) reported. All adverse events (AEs) were grade (G) 1 or G2 (G1 pruritus most common at 58%); all but two PVSRIPO-treatment related AEs were localized to the injected or adjacent lesions (n=1 G1 hot flash, n=1 G1 fatigue). Four out of 12 patients (33%) achieved an objective response per immune-related response criteria (two observations, 4 weeks apart), including 4/6 (67%) who received three injections. In the four patients with in-transit disease, a pathological complete response (pCR) was observed in two (50%) patients. Following study completion, 11/12 patients (92%) reinitiated immune checkpoint inhibitor-based therapy, and 6/12 patients (50%) remained without progression at a median follow-up time of 18 months.

Conclusion: Intratumoral PVSRIPO was well tolerated. Despite the limited number of PVSRIPO treatments relative to the overall lesion burden (67% patients>5 lesions), intratumoral PVSRIPO showed promising antitumor activity, with pCR in injected as well as non-injected lesions in select patients.

Trial registration number: NCT03712358.

Keywords: melanoma; oncolytic virotherapy.

Conflict of interest statement

Competing interests: SKN owns intellectual property related to this research, which has been licensed to Istari Oncology, Inc. DDB and MG have financial interest in Istari Oncology, Inc. Duke University (Licensor of PVSRIPO) has a financial interest in Istari Oncology, Inc.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

CD155 expression in melanoma tissue. Immunohistochemistry staining for the poliovirus receptor (CD155) was conducted on pretreatment tumor tissue for patients with available tumor biopsies. No tissue was available for patient 10. In patient 11 (J), the sample consisted of abundant macrophages; image shows the magnified region of the small region of viable tumor from a punch biopsy, which is negative for CD155. The brown staining in patient 11’s tumor is melanoma pigmentation and not CD155 staining. The intensity of the stain as reported by a pathologist (+lowest intensity to +++highest intensity) is listed in the table and the percent viable tumor on the slide staining positive is reported as % total.

Figure 2

Event history plot. Visual depiction of patients’ therapies prior to and after PVSRIPO. Patients are grouped on the basis of physician-assessed benefit of initial anti-PD-1 therapy, noted on the left side of the panel. Left top panel shows patients who had an initial benefit from anti-PD-1 (programmed cell death protein 1) therapy while left bottom panel shows patients who did not have initial benefit from anti-PD-1 therapy. The X-axis shows time in months before PVSRIPO and then months after PVSRIPO except where d is indicated. The duration of treatment is indicated by length of the block,;red dots indicate time of disease progression. Light blue is assessed benefit to PD-1; dark blue is no benefit to PD-1; dark green is PD-1 plus anti-CTLA-4 (cytotoxic T -lymphocyte-associated protein 4) therapy for which response could not be assessed (limited time or limited exposure); light green is benefit from PD-1 plus anti-CTLA-4 therapy; and purple indicates therapy stopped due to toxicity. Patients were censored (X) and deceased (black circle). Non-checkpoint therapies included BRAF (v-raf murine sarcoma viral oncogene homolog B1)/MEK (mitogen-activated protein kinase kinase) inhibition, radiation, T-VEC, and surgery. Orange indicates other clinical trials in which patients were enrolled that included anti-PD-1 as part of the experimental regimen. The single asterisk (patients 4, 5, and 2) indicates patients who received therapies for the treatment of metastatic melanoma greater than 24 months prior to PVSRIPO. The double asterisk indicates patient 4 was on anti-PD-1-based therapy plus chemotherapy. Patient number in the trial is listed under ID; patients underlined and bolded with R are those who had an objective response to PVSRIPO. d, day; PD-1, programmed cell death protein 1; T-VEC, talimogene laherparepvec.

Figure 3

Patient 9 clinical photographs. (A) Pre-PVSRIPO, (B) 9 days after first PVSRIPO injection, (C) 63 days after first PVSRIPO injection, (D) 5 months after first PVSRIPO injection, and (E) 12 months after first PVSRIPO injection.

Figure 4

Patient 8 clinical photographs and corresponding CT scans. (A) Photograph of lesions pre-PVSRIPO treatment; the subcutaneous lesions to be injected are outlined in purple. (B) Pre-PVSRIPO treatment CT scan; the red circle outlines subcutaneous lesions. (C) Photograph of lesions 63 days after first PVSRIPO injection. (D) CT scan 63 days after first PVSRIPO injection; the red circle outlines remaining subcutaneous lesions.