Unlike systemic IL-2, which has a morbid adverse-event profile, intralesional IL-2 typically produces flulike symptoms alone.36 Local adverse events such as injection-site pain and erythema have also been reported.12,13,18,23,36,37 The number of study patients in published reports has been small: 7 participants treated in 1 documented case series and 23, 39, and 48 study patients in 3 phase 2 studies.18,39,58,59 Response rates consistently exceed 80%.36,58,59

Boyd et al36 reported improved overall 5-yearsurvival rates in study patients with CR (51% of 39 patients) and study patients with PR (21% of 39 patients). The reported 5-year survival rates were 80% and 33%, respectively.36 Complete responders had a significant overall survival benefit when compared with partial responders (P = .012).36 Despite demonstrating a high response rate with minimal rates of morbidity, IL-2 has not demonstrated a significant bystander effect, despite its immune-mediated mechanism.36 Studies so far conducted have used an onerous administration scheme requiring multiple injections each week; furthermore, because IL-2 is a costly drug to purchase, it is not broadly pursued in research.36

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Rose Bengal

Rose bengal (10%) is an investigational agent for use as an intralesional therapy. The 10% rose bengal solution is a water-soluble stain used to diagnose liver and eye cancers and ocular damage, as well as in food coloring in Japan and as an insecticide, with medical reports being published as early as the 1920s.37,60 Because of the wide variety of its application, experience with the drug is extensive, and its safety profile has been well established.12,13,23,37 As an xanthine dye, the hypothesized mechanism of action of 10% rose bengal is that it creates reactive oxygen by reacting with visible and ultraviolet light, thereby mediating phototoxic reactions. It is selectively absorbed by lysosomes of cancer cells, inducing autolysis,61,62 and 10% rose bengal is currently under investigation for melanoma and liver tumors (NCT00986661, NCT02557321, NCT02288897).12,13,23,37 Responses have been reported in study patients refractory to previous systemic ipilimumab, anti–programmed death ligand 1, and vemurafenib, and therapeutic responses have been seen in study patients progressing after a median of 6 treatments.12,23

A bystander effect has been observed in 10% rose bengal.23,62 Use of 10% rose bengal leads to increased tumor-specific, interferon-γ secretion in a mouse model, induces an increase in circulating, cytotoxic CD3+/CD8+ T cells, and recruits dendritic cells to drain lymph nodes.12,62 Injection into the non–tumor-bearing flanks of mice had no effect on distant lesions.62 Rather, the agent must be injected into a tumor lesion to induce a bystander effect. The rate of morbidity is generally considered to be low, although most patients report some local adverse events, most

commonly pain (≤ 80%).60 Local blistering (40%) has been correlated with a better outcome.60 Other reported adverse events include vesicles, edema, skin discoloration, inflammation, headache, and pruritus around the treatment site.60

The first phase 1 trial of 10% rose bengal included 11 study patients.37 Treatment with 0.5 mL/cc per lesion induced an ORR in more than one-half of participants (both CR and PR, 27%).37 The effect was dose-dependent, as target lesions receiving less than 0.2 mL 10% rose bengal had a significantly lower response rate than lesions receiving a higher dose (25% vs 69%).37 A bystander effect was seen in 27% of the study patients and correlated with the response of the injected lesion.37 In another phase 1 trial, Thompson et al23 enrolled 20 patients, injecting a single dose of 10% rose bengal in up to 20 lesions per participant. Response rates were comparable with those seen the first phase 1 study.23,37 ORR was achieved in 40% of study patients, including a 20% complete response rate, and a bystander effect was reported in 15% of study patients.23

Thompson et al23 injected up to 20 lesions per study patient at day 0 and repeated the injection if needed after 8, 12, and 16 weeks. A total of 80 study patients were included, the majority of whom responded after fewer than 2 injections, resulting in an ORR of 51%, of which the CR rate was 26%.23 A bystander effect was seen in 40% of 35 evaluable study patients and was correlated with the response of injected lesions (CR rate, 31%; PR rate, 9%).23 Both visceral and cutaneous lesions were susceptible to this effect.23 Overall responses were correlated with initial treatment of all discernible disease, with a CR rate seen in 50% of study patients for whom all baseline disease was treated; CR was not seen in study patients with stage 4 melanoma.23

Based on these results, expanded access of this trial became available (NCT02288897). As of publication, more than 100 patients with melanoma have been enrolled in this trial. In the phase 3 trial, patients with stage 2C/3B disease will be randomized 2:1 to either 10% rose bengal or systemic chemotherapy, allowing crossover, with progression-free survival as the study’s primary end point.