Treatment of anti–PD-1 refractory melanoma remains a challenge. Intratumoral injection of ONCOS-102, a chimeric oncolytic adenovirus expressing GMCSF, into anti–PD-1–resistant melanoma with administration of pembrolizumab was safe and effective. Response to therapy was associated with increased lymphocyte infiltration and expression of cytotoxicity and costimulatory genes.

See related article by Shoushtari et al., p. 100

In this issue of Clinical Cancer Research, Shoushtari and colleagues report the safety and efficacy of intratumoral injection of ONCOS-102 with administration of pembrolizumab for the treatment of anti–PD-1 refractory advanced melanoma (1). In this open-label, multicenter, pilot study, 21 patients were treated following two different injection schedules (Part 1: three-dose priming on days 1, 4, and 8 followed by eight doses of pembrolizumab every 3 weeks; Part 2: four-dose priming on days 1, 4, 8, and 15 followed by eight doses of ONCOS-102 plus pembrolizumab every 3 weeks) with an overall objective response rate (ORR) of 35%. Notably, for 15 patients in whom noninjected lesions were assessed, 8 (53%) had a reduction in size of at least one noninjected lesion, indicating successful priming of immune cells. The safety profile was favorable with no dose-limiting toxicities and the most common ONCOS-102 related adverse events reported were pyrexia (43%), chills (43%), and nausea (28%).

The use of intratumoral injection to stimulate the immune system has been well documented since the 1890s when William Coley, a surgeon in New York, began administering heat-killed bacteria, the so-called “Coley's Toxins,” to his patients with osteosarcoma (2). Since that time, the field of intratumoral immunotherapy has advanced significantly. Agents such as talimogene laherparepvec (T-VEC: an oncolytic virus), and vidutolimod (CMP-001: a VLP-encapsulated TLR9 agonist), have demonstrated efficacy and attained FDA approval for the treatment of advanced melanoma (3–5). Successes such as these have ignited research with numerous intratumoral agents being investigated in active clinical trials (6). However, it is unclear where ONCOS-102 and other investigational agents fit within the growing landscape of intratumoral therapies and the even larger armamentarium of immunotherapies. It is evident that various immunotherapies produce benefits in a highly overlapping patient population, and it is prudent to ask how ONCOS-102 compares with established intratumoral therapies.

A recent study by Gastman and colleagues has similarly evaluated the efficacy of T-VEC in the setting of anti–PD-1–resistant disease (7). This phase II, open-label, multicenter study enrolled 72 patients with advanced, anti–PD-1–resistant melanoma to receive T-VEC in combination with pembrolizumab. Patients were evaluated in four cohorts; cohorts 1 (primary resistance) and 2 (acquired resistance) had already received anti–PD-1 in a locally recurrent or metastatic setting, and patients in cohort 3 and 4 were disease free for < 6 months or ≥ 6 months, respectively after adjuvant anti–PD-1. The ORR was 0%, 6.7%, 40%, and 46.7% in cohorts 1–4, respectively, demonstrating the least activity in those with primary resistance and efficacy in those with adjuvant recurrences. While a direct comparison between these two distinct oncolytic viruses (ONCOS-102 and T-VEC) cannot be made, the promising results from Gastman and colleagues indicate similar outcomes between the two therapies. Future studies comparing the two therapies may determine whether ONCOS-102 has benefits that surpass T-VEC. In addition, the findings highlight the importance of patient specific factors and may guide patient selection as combination intratumoral immunotherapies are implemented. A more precise characterization of the anti–PD-1 resistance in patients receiving ONCOS-102 in future studies would be useful.

There are other limitations in terms of patient selection in the Shoushtari study. For instance, there were 3 patients with B2M somatic missense mutations who were included in the study. Given that these mutations are associated with dysfunctional antigen presentation, those patients were less likely to respond and could be considered poor candidates for ONCOS-102 and other immunotherapies. In addition, at least 20% of the patients included in the study had either acral or mucosal melanomas which are known to be less immunogenic with poorer responses to immune checkpoint blockade (ICB; ref. 8). The inclusion of these patients in the current pilot study may have resulted in an underestimate of the effectiveness of ONCOS-102 and follow-up studies should aim to differentiate outcomes between these distinct patient populations.

The clinical indications for use of intratumoral injection are currently being expanded. A recent study by Dummer and colleagues evaluated the efficacy of T-VEC in the neoadjuvant setting (9). The open-label, phase II trial randomized patients with advanced, resectable stage IIIB–IVM1a melanoma to receive T-VEC followed by surgery or surgery alone. The results showed a higher 2-year recurrence-free survival (29.5% vs. 16.5%) and 2-year overall survival (88.9% vs. 77.4%) in the patients who received T-VEC. The 5-year results from this trial were recently presented at the 2022 European Society for Medical Oncology Congress, showing persistent benefit in the T-VEC plus surgery arm at 5 years. Future study into the effectiveness of ONCOS-102 in the neoadjuvant setting would be worthwhile.

Numerous studies have shown that baseline infiltration of lymphocytes into the tumor microenvironment is associated with response to immunotherapy across multiple cancer types (10). Moreover, recent studies emphasize the role of T-cell phenotype in antitumor response to ICB (11). The findings reported in the ONCOS-102 study are consistent with that paradigm—tumor infiltration of both CD8+ and CD4+ lymphocytes were higher at baseline in patients with subsequent disease control compared with those with progressive disease. Furthermore, there were significant differences in the gene expression profiles obtained from whole transcriptomic analysis of tumor biopsies with increased expression of cytotoxicity genes, costimulatory genes, and checkpoint inhibitors among patients who achieved disease control versus those with progressive disease. Interestingly, these markers increased from baseline to week 3 in all patients, indicating early response to ONCOS-102 with T-cell activation, but remained elevated only in patients with disease control at week 9, while patients with disease progression had a decrease in expression below baseline. These results again raise the question about patient selection: should lymphocyte infiltration density be a selection criterion for administration of ONCOS-102? More importantly, are there other approaches that can be used in patients with sparse tumor lymphocyte infiltration?

While immunotherapy has revolutionized the treatment of melanoma, many patients have recurrent or progressive disease and new therapies are much needed. Overall, the early clinical findings reported by Shoushtari and colleagues are encouraging, with an ORR that is comparable to other intratumoral agents. Follow-up studies with larger cohorts can better delineate which patient populations are most likely to benefit from ONCOS-102 therapy. Furthermore, direct comparison with well-established agents such as T-VEC and, eventually, assessment of ONCOS-102 in the neoadjuvant setting are warranted. Additional clinical trials are merited to clarify where ONCOS-102 fits in the expanding immunotherapy tool kit.

G.M. Boland reports grants from Olink Proteomics, Teiko Bio, and Palleon Pharmaceuticals; grants and personal fees from InterVenn Biosciences; other support from Iovance, Nektar Therapeutics, and Novartis; and personal fees and other support from Merck and Ankyra Therapeutics outside the submitted work. No disclosures were reported by the other author.

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