Oncolytic Immunotherapy: New Insights

Educational Objectives

The goal of this program is to improve the management of melanoma with oncolytic immunotherapy (OI). After hearing and assimilating this program, the clinician will be better able to:

1. Use T-VEC in patients with metastatic melanoma.
2. Optimize use of pembrolizumab in patients with unresectable stage 3 and 4 disease.

Summary

Introduction: treatment for cancer has evolved from intralesional therapy to oncolytic immunotherapy (OI); the abscopal effect — the inflammatory response produced by the oncolytic agents at the local site elicits a systemic immune response, which reduces the size of distant uninjected tumors; OI technology is now mainstream in melanoma treatment

Goals of OI: a locally ablative therapy for local disease control; induction of a systemic host immune antitumor activity with responses at uninjected distant and regional metastases; eliciting a systemic adjuvant effect that would prevent the development of distant disease and treat micrometastatic disease in patients with high-risk tumors or large local or regional recurrences (with limited systemic toxicity); overcoming programmed cell death protein 1 (PD-1) resistance

Cancer immunity cycle: step 1 — tumor lysis after injection of oncolytic therapy and release of tumor-derived antigens; step 2 — processing of the antigens (at the level of dendritic cells); steps 3 and 4 — T-cell priming and activation and generation of memory T-cells that circulate to distant sites; step 5 — T-cell infiltration into the tumor; step 6 — recognition of the tumor by T-cells; step 7 — tumor lysis

Key point: the cancer immunity cycle hypothesis gives the rationale for combinations of oncolytic therapy with immune checkpoint inhibitors (ICIs), ie, anti-cytotoxic T-lymphocyte-associated protein 4 (eg, ipilimumab) acts on step 2 and anti-PD-1 acts on steps 6 and 7

Immunotherapy agents in development: talimogene laherparepvec (T-VEC) is the only approved oncolytic viral immunotherapy; other therapies in development include toll-like receptor (TLR) agonists (eg, TLR9 agonists) and antibody cytokine fusion molecules, eg, daromun, a combination of 2 antibody-cytokine fusions, ie, L19 antibody linked to interleukin-2 (IL-2) and L19 antibody linked to tumor necrosis factor (TNF); the antibodies in daromun target the receptors on the tumor causing the release of IL-2 and TNF

T-VEC monotherapy: T-VEC is a type 1 herpes simplex virus (HSV) that has been genetically altered; when the virus replicates in the tumor, it releases granulocyte macrophage colony-stimulating factor (GM-CSF) that enhances the local and systemic responses

The OPTiM randomized controlled trial (RCT): in patients with stage 3B through stage 4 melanoma, T-VEC (previously known as OncoVEX) improved durable response rate, overall response, and objective response rate (26.4%) when compared with GM-CSF; 41% of the objective responses were complete clinical responses (Andtbacka et al [2019]); a good local inflammatory response is essential to obtain a good systemic abscopal response

Survival benefit: patients who received T-VEC had better overall survival (OS) when compared with GM-CSF; patients with stages 3B and C to 4M1a had better OS benefit

Systemic adjuvant response: in the patients who did not have stage 4 disease in visceral sites (stages 3B and 3C and 4M1a), T-VEC monotherapy reduced the risk for visceral or bony metastasis (59% lower risk); a strong local response triggers a systemic adjuvant response, reducing the risk for distant disease; the responses were durable; T-VEC is approved for patients with unresectable disease in the United States

Predictors of a pathologic complete response (pCR): Stahlie et al (2021) — among 93 patients with stage 3B and 3C in-transit disease, the overall response rate with T-VEC monotherapy was 79%; the durable response rate was 51%; small tumor size, tumor location, and small number of lesions predicted pCR

Combination of T-VEC with ICIs: the theoretical synergism in activity (based on the cancer immunity cycle) and minimal increase in toxicity (above on ICIs) make the combination therapy an attractive prospect for neoadjuvant approaches for resectable advanced regional disease (lesser toxicity when compared with ipilimumab plus nivolumab [IPI-NIVO]); it can be used after failure of standard monotherapy with ICIs as a second-line strategy to overcome PD-1 resistance

Different therapies: response rates in patients with unresectable stage 3 and 4 disease — ipilimumab monotherapy 6% to 15%, pembrolizumab ≈30%, T-VEC 26%, IPI-NIVO 52% (with 55% grade 3 or 4 adverse events), T-VEC plus ipilimumab 39%, T-VEC plus pembrolizumab 56%, and HF10 (an HSV) plus ipilimumab 49% (has good toxicity profile compared with IPI-NIVO)

The MASTERKEY 265 study (Chesney et al [2023]): in patients with disseminated melanoma with injectable sites of disease, T-VEC plus pembrolizumab had an acceptable safety profile and a good response rate in the phase 1b study; however, in the phase 3 study, T-VEC plus pembrolizumab did not significantly improve progression-free survival (PFS) or OS (incorrect patient population selection in speaker’s opinion)

Neoadjuvant T-VEC: it can treat micrometastatic disease; Dummer et al (2021) — 12 wk of neoadjuvant T-VEC plus surgery led to a 21% pCR rate and improved 2-yr recurrence-free survival (RFS) and OS (vs surgery); increased cluster of differentiation 8 (CD8)-positive T-cell density within the tumor was associated with a favorable RFS outcome; the change in CD8-cell density was also important

Neoadjuvant daromun: the L19 antibody in the antibody cytokine fusion compound binds to fibronectin in the extracellular matrix of the tumor enabling it to remain in the tumor and deliver IL-2 and TNF; the PIVOTAL study (Hauschild et al [2024]) — neoadjuvant OI with daromun for patients with stages 3 and 4 resectable melanoma resulted in pCR of 21% (similar to T-VEC) and improved RFS; thus, as the tumor gets destroyed, the inflammatory signals disseminate and have a systemic adjuvant effect, ie, prevents distant disease

Neoadjuvant T-VEC plus ICIs: Zijlker et al (2023) — in patients with stages 3 (B-D) and 4 resectable melanoma, 12 wk of neoadjuvant T-VEC plus ICI resulted in clinical complete or near-complete response in 48% of patients and pCR in 51% of patients; in patients exposed to adjuvant ICIs for earlier stage disease, a 47% pCR was observed; the combination had an acceptable toxicity profile

Anti-PD-1 resistant melanoma: synergy between OI and ICIs has been observed; research on different agents, ie, TLR9, PV-10 (a chemical dye), and coxsackievirus in combination with ipilimumab or pembrolizumab, is ongoing; monotherapy and combination therapy with these agents have shown better overall responses when compared with single-agent ipilimumab; TLR9 agonist plus ipilimumab — in the ILLUMINATE-204 study (a phase 2 study), a novel TLR9 agonist plus ipilimumab resulted in a good response (OS) in patients with anti–PD-1 refractory melanoma (Haymaker et al [2021]); however, in the phase 3 study (ILLUMINATE-301), the TLR9 agonist plus ipilimumab did not significantly improve outcomes in patients with anti-PD-1 refractory melanoma

Clinical practice scenarios for T-VEC: T-VEC monotherapy can be considered for patients with intransit disease, with distant skin, soft tissue, and nodal metastasis (stage 4M1a disease limited to the sites), and with advanced age and comorbidites (having minimal visceral disease but with more injectable disease); T-VEC can be used off-label in combination with ICIs at second-line setting for stage 4 melanoma and for neoadjuvant clinical trials

Vusolimogene oderparepvec (RP1): RP1 is a genetically altered HSV with gene insertions similar to T-VEC plus an immunogenic glycoprotein; the phase 1 and 2 data from IGNYTE study suggests reasonable good overall response rates with RP1 in patients with anti-PD-1 resistant melanoma (Wong et al [2024]); a phase 3 RCT (IGNYTE-3) is ongoing

Readings

Andtbacka RHI, Collichio F, Harrington KJ, et al. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma. J Immunother Cancer. 2019;7(1):145. Published 2019 Jun 6. doi:10.1186/s40425-019-0623-z; Chesney JA, Ribas A, Long GV, et al. Randomized, double-blind, placebo-controlled, global phase III trial of talimogene laherparepvec combined with pembrolizumab for advanced melanoma. J Clin Oncol. 2023;41(3):528-540. doi:10.1200/JCO.22.00343; Dummer R, Gyorki DE, Hyngstrom J, et al. Neoadjuvant talimogene laherparepvec plus surgery versus surgery alone for resectable stage IIIB-IVM1a melanoma: a randomized, open-label, phase 2 trial. Nat Med. 2021;27(10):1789-1796. doi:10.1038/s41591-021-01510-7; Hauschild A, Hassel JC, Ziemer M, et al. Phase 3 study (PIVOTAL) of neoadjuvant intralesional daromun vs. immediate surgery in fully resectable melanoma with regional skin and/or nodal metastases. J Clin Oncol. 2024;42(17_suppl):LBA9501-LBA9501. doi:https://doi.org/10.1200/jco.2024.42.17_suppl.lba9501; Haymaker C, Johnson DH, Murthy R, et al. Tilsotolimod with ipilimumab drives tumor responses in Anti-PD-1 refractory melanoma. Cancer Discov. 2021;11(8):1996-2013. doi:10.1158/2159-8290.CD-20-1546; Kalsi S, Galenkamp AL, Singh R, et al. Talimogene laherparepvec (T-VEC) and emerging intralesional immunotherapies for metastatic melanoma: a review. Curr Oncol Rep. 2024;26(12):1651-1663. doi:10.1007/s11912-024-01611-9; Remon J, Hendriks LEL. Targeted therapies for unresectable stage III non-small cell lung cancer. Mediastinum. 2021;5:22. Published 2021 Sep 25. doi:10.21037/med-21-8; Stahlie EHA, Franke V, Zuur CL, et al. T-VEC for stage IIIB-IVM1a melanoma achieves high rates of complete and durable responses and is associated with tumor load: a clinical prediction model. Cancer Immunol Immunother. 2021;70(8):2291-2300. doi:10.1007/s00262-020-02839-7; Wong MKK, Sacco JJ, Robert C, et al. Efficacy and safety of RP1 combined with nivolumab in patients with anti–PD-1–failed melanoma from the IGNYTE clinical trial. J Clin Oncol. 2024;42(16_suppl):9517-9517. doi:https://doi.org/10.1200/jco.2024.42.16_suppl.9517; Zijlker LP, Houdt van, Emma HA, et al. Neoadjuvant T-VEC plus nivolumab combination therapy for resectable early metastatic (stage IIIB/C/D-IV M1a) melanoma with injectable disease: NIVEC trial. J Clin Oncol. 2023;41(16_suppl):9546-9546. doi:https://doi.org/10.1200/jco.2023.41.16_suppl.9546.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Ross is on the advisory board for Merck. Members of the planning committee reported nothing relevant to disclose. Dr. Ross's lecture includes information related to the off-label or investigational use of talimogene laherparepvec in combination with immune checkpoint inhibitors.

Acknowledgements

Dr. Ross was recorded at the Melanoma and Cutaneous Oncology Symposium, held January 25-26, 2025, in Coronado, CA, and presented by Scripps. For information on upcoming CME activities from this presenter, please visit scripps.org. Audio Digest thanks the speakers and Scripps for their cooperation in the production of this program.

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