In his review in this issue of ONCOLOGY, Dr. Agarwala lays out the rationale for intratumoral therapy in melanoma. As he notes, melanoma has some unique features that make it favorable for an intratumoral approach—chiefly, the importance of the immune system in controlling and treating melanoma, and the propensity of melanoma to form cutaneous and subcutaneous tumors with easy access for treatment. Dr. Agarwala points out that there are two main types of intralesional therapy: direct lytic and immune-activating. The principal direct lytic agent is PV-10 (rose bengal), which is a dye that is selectively taken up by melanoma cells. Other direct lytic approaches include laser light and hyfrecation, as well as surgical resection and radiation therapy. Immune approaches are more interesting due to their potential synergy with checkpoint inhibitors and novel immunotherapies. For treatments in this class, the active immune molecule can be delivered virally (eg, the modified herpes virus used in talimogene laherparepvec [T-VEC]) or nonvirally (eg, electroporation-delivered interleukin-12 [IL-12]).
Viral vectors are further along in development, and, as noted by Dr. Agarwala, these are now in clinical use in stage III and IV melanoma. However, nonviral therapies have also shown interesting single-agent results and are now being tested in combination therapies.
Perhaps the greatest attraction and chief benefit of intratumoral therapies is their ability to synergize with systemic checkpoint therapies and accelerate the development of a lymphoid infiltrate and perhaps secondary lymphoid structures in vivo, which in turn can result in systemic mobilization of a T-cell response: the local injection–global effect model. While data are still preliminary at this point, there are hints that this model may in fact be valid, as noted in the review. The model may be valid for both viral and nonviral immunotherapy approaches.
Currently, a phase II clinical trial (ClinicalTrials.gov identifier: NCT02493361) at the University of California, San Francisco (UCSF) is assessing the potential synergy between intratumoral IL-12 (given on days 1, 5, and 8 every 6 weeks) and concurrent administration of pembrolizumab (200 mg every 6 weeks). One 69-year-old female patient in the UCSF trial, with stage IV melanoma and an accessible lesion of the left inner arm, after 2 cycles of IL-12 and 4 cycles of pembrolizumab experienced a positron emission tomography (PET)/computed tomography (CT)–confirmed complete response of the target lesion, and had no other sites of disease by the fifth cycle of treatment. Another female patient in the same trial (72 years old), with a treatable melanoma of the left forearm, after 4 cycles of IL-12 and 10 cycles of pembrolizumab experienced > 98% shrinkage in lesion size from baseline, based on Response Evaluation Criteria in Solid Tumors (RECIST). The most remarkable case in this cohort, however, is that of a 62-year-old male patient with at least stage III melanoma of multiple primary sites who experienced a complete clinical resolution of all treated subcutaneous lesions after only 1 cycle of IL-12 and 2 cycles of pembrolizumab. Radiographic evaluation of any distant metastases and confirmation of response are pending, but these results are expected to be good. Furthermore, another three patients have experienced interval tumor reduction, with one patient exhibiting locoregional shrinkage of distant untreated melanoma nodules.
A retrospective analysis of patients who were treated at the same site in a phase II study of single-agent intratumoral IL-12 with electroporation has generated promising findings that suggest potential immune-priming effects of IL-12 therapy on anti–programmed death 1 (PD-1) monoclonal antibody treatment. The investigators evaluated a total of 34 patients from a study of single-agent IL-12. Those patients had stage III/IV melanoma at enrollment and were included in the analysis if there were documented clinical follow-up histories and if they had received treatment with systemic anti–PD-1/programmed death ligand 1 (PD-L1) therapy after cessation of IL-12 treatment. Of the patients analyzed, some completed IL-12 therapy with complete or partial responses or stable disease, while 18 of them were dropped from the study because of clinical or RECIST-based disease progression. Within this cohort of 34 evaluable patients, 14 went on to receive systemic PD-1/PD-L1 inhibitor therapy, either as a single agent or as part of a combination therapy, with or without any intervening therapies. Five of these patients experienced a complete response and four experienced a partial response (9/14, for a best overall response of 64%). The remaining five patients experienced stable disease or had progression of disease. Interestingly, a separate group of eight patients received systemic anti–PD-1/PD-L1 without any interim antineoplastic therapies; four of those (50%) demonstrated a complete response and two (25%) demonstrated a partial response.
In light of these findings, we suggest that therapy with intratumoral IL-12 injection and electroporation, either before or concurrent with anti–PD-1/PD-L1 therapy, has the potential to augment the clinical oncologist’s arsenal in the fight against melanoma.
Financial Disclosure: Dr. Daud owns intellectual property licensed to OncoSec, and owns stock in OncoSec; he receives research funding from Bristol-Myers Squibb, Incyte, Merck, and Pfizer. Dr. Chen has no significant financial interest in or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Agarwala SS. The role of intralesional therapies in melanoma. Oncology (Williston Park). 2016;30:436-41, 443.
2. Algazi A, Tsai K, Takamura KT, et al. Intratumoral electroporation of plasmid IL-12 can prime responses to anti-PD1/PD-L1 blockade in patients with stage III/IV-M1a melanoma. American Association for Cancer Research; 2016 Annual Meeting; 2016 Apr 16–20; New Orleans, LA. Abstr CT134.