Intralesional Oncolytic Viruses Harness in situ Immunization for Cutaneous Melanoma

Robert L. Ferris, MD, PhD

Robert L. Ferris, MD, PhD

Cutaneous melanoma is a potentially aggressive disease in which survival is optimized when detected early, and when completely resectable. For advanced, recurrent disease, immune checkpoint—based therapies targeting PD-1, CTLA-4, and other agents are effective. In addition, intralesional therapies, such as oncolytic virus therapies, may be more suitable when surgeons are involved in immunotherapy in the preoperative setting. The ability to activate pattern recognition receptors, such as toll-like receptors (TLRs), carry other genetic “cargo” to modify immunity, and induce lymphocyte infiltration into cancer is an appealing strategy accomplished by intralesional oncolytic viruses. Thus, the concept of combining these novel therapeutics in the preoperative setting to enhance in situ immunization and antitumor activity systemically, as well as to increase R0 complete resection (clear margins), may be a useful approach to lead to cure.

In this regard, the results of a randomized trial presented at the 2019 American Society of Clinical Oncology Annual Meeting showed that neoadjuvant talimogene laherparepvec (T-VEC; Imlygic) led to a significant improvement in the 1-year recurrence-free survival rate in patients with resectable, advanced melanoma compared with surgery alone.¹The results presented at the meeting involved 150 patients with high-risk, resectable, stage IIIB-IVM1A melanoma. The patients were randomized to immediate surgery or intralesional T-VEC followed by surgery at week 13. At 1 year, 33.5% of patients who received pre-operative T-VEC plus surgery remained recurrence free compared with 21.9% of patients who had surgery only (HR, 0.73; 80% CI, 0.56-0.93; P= .048).

“Neoadjuvant T-VEC resulted in a higher pathologic complete response (pCR) rate in resectable melanoma than that observed by the overall clinical response rate and may account for the higher R0 resection rate in the T-VEC arm than the surgery-alone arm,” reported Reinhard Dummer, MD, of the University Hospital of Zurich in Switzerland, and colleagues. The findings constituted a follow-up to previously reported data, which showed a pCR rate of 21% with T-VEC plus surgery and an objective response rate of 14.7%.²Other neoadjuvant immunotherapy studies have analyzed delay in time to surgery as a primary endpoint, raising the issue of what risk (receipt of standard of care surgery) neoadjuvant trials present for patients and surgeons.

Additionally, the complete/R0 rate was higher in the T-VEC arm, suggesting a benefit for making the resection easier. However, the fact that a higher proportion in the T-VEC arm did not go on to surgery suggests that the neoadjuvant window may have identified a subgroup who would not have benefitted from surgery. In all, in the field of neoadjuvant therapy, the use of immune checkpoint inhibitors, inflamma- tory agonists like TLR stimulation, or oncolytic viruses—with clinical benefit in other stages of disease—needs to be tested. That we lack good biomarkers clinically, the pre/post biopsy comparison afforded by neoadjuvant trials may enable a better understanding of novel therapeutics, specifically, why T-VEC has not shown greater benefit outside of melanoma.

References

1. Dummer R, Gyorki DE, Hyngstrom JR, et al. One-year (yr) recurrence-free survival (RFS) from a randomized, open label phase II study of neoadjuvant (neo) talimogene laherparepvec (T-VEC) plus surgery (surgx) versus surgx for resectable stage IIIB-IVM1a melanoma (MEL).J Clin Oncol. 2019;37(suppl 15; abstr 9520). doi: 10.1200/JCO.2019.37.15_suppl.9520.
2. Andtbacka RHI, Dummer R, Gyorki DE, et al. Interim analysis of a randomized, open-label phase 2 study of talimogene laherparepvec (T-VEC) neoadjuvant treatment (neotx) plus surgery (surgx) vs surgx for resectable stage IIIB-IVM1a melanoma (MEL).J Clin Oncol. 2018;36(suppl 15; abstr 9508). doi: 10.1200/JCO.2018.36.15_suppl.9508.