Clinical Trials to Watch: Intralesional Therapies for Melanoma

To an outsider, the number of new treatment options for melanoma may seem to be moving at a breakneck pace. Checkpoint immunotherapy and BRAF/MEK inhibitors have greatly improved outcomes for many late-stage melanoma patients, with over 50% of patients on combination ipilimumab/nivolumab still alive after 5 years. Moreover, with these therapies being made available to earlier stage patients (fully resectable, Stage 3C), a greater number of patients stand to benefit.

While these therapies have proved transformative for some, still up-to-half of patients aren’t benefiting at all and some that initially respond will later go on to experience disease recurrence. These therapies can also cause serious side effects, some of which can continue even after the treatment is stopped. For these reasons, interest in locally administered therapies is growing. These treatments, called ‘intratumoral’ or ‘intralesional’ therapies are delivered directly to the tumor, often by needle injection and often more than once, and consist of a wide array of agents. Early data for several of these agents are quite promising and suggest that effective and long-lasting responses can be achieved, especially when combined with systemic therapies, most typically anti-PD-1 (such as FDA approved medications nivolumab and pembrolizumab).   

Why go the intratumoral route? 

One of the main reasons that patients do not respond to checkpoint inhibitors is that their tumors lack the necessary immune components to kill the tumor. Intratumoral (intra = in, tumoral = tumor) therapies aim to bridge this gap by modifying the tumor microenvironment by injecting the drug directly into the tumor. The drug will ‘boost’ the immune response, by attracting killer T cells and reducing the numbers of other, immunosuppressive cells in the tumor. Sometimes these therapies also kill the tumor cells directly. Moreover, because immune cells circulate throughout the body, often the anti-tumor effects can be seen in both injected and non-injected tumors, producing what doctors call a systemic effect.

Another major advantage of intratumoral therapies is that they typically have relatively minor side effects compared to systemic therapies, often limited to injection site reactions. While someone facing advanced, stage 3 or stage 4 melanoma might be willing to tolerate the serious, and potentially life-altering side effects of systemic therapies, this decision becomes much harder when these same therapies are being offered for patients with earlier-stage disease.

TVEC (Talimogene laherparepvec) and oncolytic viruses

TVEC is a genetically engineered herpes virus – termed an ‘oncolytic virus’ for its ability to specifically target and kill tumor cells. It was approved by the Food & Drug Administration (FDA) in 2015 to treat patients with Stage 3 or Stage 4 melanoma who have tumors that can be directly injected, but for whom surgery is not appropriate (what doctors call unresectable melanoma). TVEC works by directly killing tumors and by stimulating an anti-tumor immune response. Alone, TVEC can extend overall survival in patients who have not previously received systemic treatment, but data suggest that its effects may be even more promising when used in combination with systemic therapy. For example, a randomized phase II trial of TVEC + ipilimumab versus ipilimumab alone showed a 38.8% overall response rate with the combination compared to 18% for ipilimumab alone. Promising results were also seen in a Phase 1b trial testing combination TVEC and pembrolizumab in patients with advanced melanoma. Finally, patients with resectable, advanced melanoma treated with TVEC prior to surgery show improved recurrence free as well as overall survival. Additional clinical trials are underway testing anti-PD1 + TVEC versus anti-PD-1 alone, with results expected later this year. 

Besides TVEC, a number of other oncolytic virus-based therapies are being studied. RP1, 2, and 3 also use modified versions of the herpes viruses, but have been engineered to spread throughout the body more efficiently. RP1 is currently being tested alone and in combination with anti-PD1 in patients with advanced solid tumors, including melanoma in a Phase 1/2 trial (NCT03767348).

Researchers are also testing other viruses in order to optimize tumor killing and activate anti-tumor immunity. For instance, a poliovirus-based approach that has demonstrated early success in patients with glioblastoma is currently being tested as a monotherapy in melanoma patients (NCT03712358). A trial combining with approach with anti-PD-1 is also planned (NCT04125719).

Stimulating innate immunity

Another class of intratumoral agents aim to boost ‘innate immunity’ – that is the first responder cells of the immune system that kickstart T cell killing of tumors. These therapies mimic viruses, such that they activate the same warning signs that an invading virus would trigger. Ideally, this sets off a strong reaction within the body, able to turn an immunologically ‘cold’ tumor into an active one. One example of this approach is experimental agent IMO-2125, which targets Toll like receptor 9 (TLR9). IMO-2125 is currently being evaluated in combination with systemic ipilimumab in patients with metastatic melanoma as part of a Phase 3 trial (NCT0344553). Another experimental agent, CMP-001, is being tested in combination with pembrolizumab (NCT02680184). Several other experimental therapies based on this approach are also in development, as well as agents like E7766 that targets a different receptor called STING, which is also involved in the anti-viral immune response (NCT04144140). 

Cytokines

One of the best predictors of immunotherapy success, is the presence of T cells, also called tumor-infiltrating lymphocytes (TILS), in a tumor. A class of proteins called cytokines attract T cells to tumors in the body. In fact, the cytokine IL-2 (interleukin-2), in this case infused systemically, was one of the first approved immunotherapies for melanoma because it does exactly this – it boosts the number of T cells in tumors. Unfortunately, when administered systemically it can cause severe adverse reactions, and so researchers are now focusing on determining whether intratumoral IL-2 combined with checkpoint immunotherapy might work just as well without the toxicity. A Phase 1 trial will test experimental therapy hu14.18-IL2 in patients with advanced melanoma when given alone or in various combinations that include radiation, ipilimumab, and nivolumab (NCT03958383).

An additional approach is testing an experimental therapy called Daromun that combines IL-2 with another cytokine, TNF-alpha, that increases inflammation. In this Phase 3 trial, patients with Stage 3 melanoma will receive Daromun injected directly into their tumors prior to their surgical removal, with the goal of extending both recurrence free and overall survival (NCT03567889).

Several cytokine-based approaches beyond IL-2 are also being studied. One promising agent is tavokinogene telseplasmid (TAVO) in combination with the anti-PD1 therapy pembrolizumab. TAVO is DNA-based IL-12, which helps boost T cell immunity to tumors. In contrast to most intratumoral therapies, TAVO is delivered in a two-step process that consists of intratumoral injection of DNA encoding the IL-12 protein, followed by a short sequence of electrical pulses to the tumor, which helps it to enter the tumor and its surrounding cells. Initial data from a phase 2 trial (NCT03132675) of TAVO combined with pembrolizumab in melanoma patients whose tumors had advanced on anti-PD-1 therapy showed an impressive 22.2% best overall response rate.

Antibodies

Researchers are also interested in testing whether checkpoint immunotherapies could be injected directly into a tumor – dramatically reducing side effects without reducing the treatment’s efficacy. Specifically, a Phase 1/2 trial will test this theory by comparing traditionally administered ipilimumab/nivolumab to intratumoral ipilimumab plus intravenous nivolumab (NCT02857569).

Similarly, intratumoral delivery of APX005M is being tested in combination with pembrolizumab (NCT02706353, funded in part through an MRA award to Adi Diab of University of Texas MD Anderson Cancer Center). APX005M is an antibody that stimulates the CD40 receptor, which has been shown to boost anti-tumor immunity in melanoma and other cancers when delivered systemically. APX005M, however, is associated with high rates of serious side effects when delivered in this manner and so this study hopes to deliver this added boost to the immune system while minimizing serious side effects.

Other Small Molecules and Treatment Approaches 

A variety of other small molecules are being delivered intratumorally and tested in clinical trials. One example is PV-10, a solution of rose bengal disodium, a water-soluble xanthene dye typically used as a tool for examining the eye for damage. PV-10 is currently being tested in combination with pembrolizumab in patients who have not received prior checkpoint immunotherapy – what researchers call treatment naïve patients – as well as in patients who have already progressed on checkpoint immunotherapy – what researchers call checkpoint-refractory patients. In the checkpoint-refractory patients, the best overall response rate was 20% (NCT02557321). A phase 2 trial will test PV-10 + pembrolizumab versus pembrolizumab alone. 

While traditional chemotherapy agents are generally not effective when delivered systemically to patients with advanced melanoma, approaches that deliver chemotherapy agents such as cisplatin and vinblastine sulfate intratumorally are advancing in clinical trials. INT230-6 combines cisplatin and vinblastine sulfate with an agent that increases the ability of the drugs to enter tumor cells. This agent is expected to both improve drug dispersion throughout the tumor, leading to tumor death, and to boost anti-tumor immunity. INT230-6 is being tested alone as well as in combination with pembrolizumab in patients with several types of late-stage cancer, including melanoma (NCT03058289).

With these therapies and more, combinations of checkpoint immunotherapies with intratumoral therapies are progressing rapidly in the clinic and show great promise in increasing response rates by boosting anti-tumor immune responses in patients that might not typically respond to checkpoint therapy alone.