Velimogene aliplasmid is an intralesional agent that advanced to phase 3 clinical trial testing based on results seen in phase 1/2 trials; however, both phase 3 trials conducted with velimogene aliplasmid failed to reach their primary end point (NCT00395070).24,25 Velimogene aliplasmid is classified as a gene therapy because it contains plasmid DNA encoding for HLA-B7.25 It recruits macrophages and T cells, which attack injected and noninjected lesions alike, bringing about immune responses against the alloantigen. Most of the initial studies were limited to study participants negative for HLA-B7; however, after no correlation between HLA status and response rate was found, other studies did not incorporate HLA status as an inclusion criterion.16 Reported adverse events include paresthesias, asthenia, myalgias, fatigue, injection-site pain, rigors, and flulike symptoms.16
Velimogene aliplasmid was first investigated in 4 small phase 1 trials with up to 17 study participants and reported response rates reaching 50%.20-23 The study of this drug advanced to 4 phase 2 trials that reported ORRs ranging from 10% to 28%.16,25,27 The most frequently reported schemes used 2 mg velimogene aliplasmid per lesion with 1to 2-week intervals.16,27 The largest study was a dose-escalation/efficacy trial conducted by Bedikian et al,16 who enrolled 133 patients and assigned them to groups that received 0.5 to 2 mg velimogene aliplasmid for 6 weeks with 1-week intervals. A total of 127 participants were treated with the highest dose; efficacy data were also available for all enrollees.16 Complete response (CR) was reached in 3% and partial response (PR) in 9%.16
In the first phase 3 study, Richards et al24 randomized 202 patients to either systemic dacarbazine/velimogene aliplasmid on days 3 and 10 out of 28 to the chemotherapeutic cycle (n = 98) or dacarbazine alone (n = 104). Response rates were 13.2% and 11.6%, respectively.24 Adding velimogene aliplasmid did not cause any significant difference in median time to progression (1.9 vs 1.6 months) or survival (10.8 vs 9.2 months).24 The second phase 3 trial was stopped early when no difference was shown in ORR at more than 24 weeks and in overall survival rate for the 390 study participants, who were randomized 2:1 to either velimogene aliplasmid or physician’s choice of chemotherapy (dacarbazine or temozolomide; NCT00395070). No new trials are planned for velimogene aliplasmid.
Bacille-Calmette-Guerin (BCG) has been historically used in intralesional therapy, but it has a severe adverse-event profile. The aim of using BCG for intralesional therapy against metastatic melanoma is to stimulate an immune reaction to eliminate the tumor using the patient’s own immune system.28 BCG is a live, attenuated strain of Mycobacterium bovis, which is an antigen that can trigger an immune reaction. In animal models, BCG produces a nonspecific immune response.28 In humans, it has been used for intralesional therapy in patients who have already demonstrated an immune reaction to BCG to stimulate an immune response against the injected lesion.28 Adverse events include fevers, chills, diaphoresis, arthralgias, malaise, and angioedema in patients positive for tuberculin and those with lymphadenopathy, pneumonitis, BCG granulomas, and granulomatous hepatitis.21,28-30 Toxicity is caused by the patient having an immune response to BCG; thus, patients who have no immunity against BCG cannot demonstrate adverse events.
Seigler et al29 recruited 160 patients with locally recurrent melanoma who were treated with intralesional BCG using a 4-stage approach. In the first stage, participants who were immune sensitive to BCG were selected; in the second stage, a delayed hypersensitivity reaction to BCG was stimulated in participants with booster therapy; in the third stage, adoptive immunity was achieved by harvesting participant lymphocytes, which were exposed to tumor cell samples and reinjected into the participants; and, in the fourth stage, to further increase antitumor responsiveness, the participants were injected with a vaccine of tumor cells and BCG.29 Of the 70 study patients evaluated in stage 1, 44% (31) were sensitive to BCG, and, as those study patients progressed through the 4 stages, they demonstrated increased rates of antitumor immune responsiveness.29 Of the 62 participants examined for cell-mediated, tumor-specific immunity, 69% (n = 43) had a prolonged response, with 60% mean tumor lysis.29 Of the 19 study patients who never developed immunity against melanoma, all of them progressed and died of complications from diffuse, distant metastatic disease.29 Although results from early clinical trials correlated well with the rationale for BCG intralesional therapy, the adverse-event profile of BCG is a limitation to its broad implementation.21,28-30 And, although BCG uses M bovis to stimulate an immune, antitumor response, it also produces complications associated with that same immune response, leading to adverse events and disseminated intravascular coagulation at a rate of 12%.45 Because of these inflammatory reactions and the concomitant high risk of morbidity, BCG treatment requires that patients be closely observed. Prophylactic treatment should be provided, such as antihistamines and isoniazid, because of the morbidity of these adverse events.30 In addition, to minimize the morbidity of these reactions when they do occur, signs or symptoms of these complications should be treated with hydration, antituberculosis therapy, steroids, antihistamines, and supportive care.30