November 2015, Vol. 2, No. 6

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Intralesional Oncolytic Immunotherapies Show Benefit in Melanoma

American Society of Gene and Cell Therapy

For patients with advanced melanoma, checkpoint inhibitors are not the only means of modulating the immune system to treat disease. According to research presented at the American Society of Gene and Cell Therapy (ASGCT) Annual Meeting, intralesional oncolytic therapy is also providing profound benefit in several phase 2 and phase 3 clinical trials.

“Oncolytic immunotherapies represent a new and important strategy in the treatment of cancer,” said Robert Andtbacka, MD, Associate Professor of Surgical Oncology at the University of Utah, Salt Lake City, who has been directly involved in many of these studies. “They are extremely well tolerated and can be used in combination on the immune system with a number of therapies.”

Ten years ago, Andtbacka reminded the audience, treatment options for metastatic melanoma were slim to none. Today there are a number of promising new agents, including BRAF inhibitors, but these drugs are not a magic bullet.

“Many targeted therapies don’t work to the extent that we want and fail to give us a durable response,” he said. “So, in melanoma we are trying to use immune therapies to target the host, not a specific mutation.”

According to Andtbacka, oncolytic immunotherapies work through 2 mechanisms of action—a lytic effect and activation of the whole immune system, not just the lesions directly treated. Melanoma, it seems, is perfectly suited for intralesional therapies because of in-transit cutaneous lesions and accessible lymph nodes, which are characteristic of the disease.

A dozen or so types of intralesional agents are in development: antibodies, cytokines, glycolipids, microspheres, plasmids, small molecules, radiosensitizers, vaccines, viruses, xenoantigen cell lines, and combinations. Most are in early stages, but data from some phase 2 and phase 3 trials have become available.

Promising Compounds in Development

At the meeting, Andtbacka focused on talimogene laherparepvec (T-VEC), coxsackievirus A21, plasmid IL-12 electroporation, and PV-10 (rose bengal).

T-VEC is a modified herpes simplex type 1 virus. When injected into dermal, subcutaneous, and intralymphatic lesions, it enters the tumor cell, which leads to virus replication and a mechanism of action not entirely understood. Lysis of the cell occurs, which then leads to exposure of tumor-specific antigen to the immune system, activation of the immune system, and, finally, immune activation against the tumor at distant sites, Andtbacka believes.

“We are also moving forward with direct injection into lung and liver metastases,” he reported.

In the phase 3 OPTiM trial, 436 patients had lesions injected with either T-VEC or granulocyte-macrophage colony-stimulating factor. The primary end point was durable response (≥6 months), and this was achieved by 16.3% versus 2.1%, respectively, a 14.2% difference (P <.0001) (J Clin Oncol. 2014;32[suppl]. Abstract 9008a).

“This durable response rate is an unusual end point and very stringent,” he noted. “For comparison, if we had used this in trials of BRAF inhibitors, the end point would not have been achieved.”

Among the injected lesions, 64% responded, of which 47% were complete responses to T-VEC. Responses were also seen in 34% of noninjected (nonvisceral) lesions. Two-thirds of patients had responses lasting at least 1 year, and the treatment was well tolerated.

T-VEC also reduced the development of visceral metastases, boding well for the use of this agent earlier in disease.

T-VEC received approval from the FDA on October 27, 2015.

A phase 1b study has also evaluated T-VEC in combination with ipilimumab in previously untreated stage III/IV patients, showing responses in 56% of patients and complete responses in 33% (J Clin Oncol. 2014;32[suppl]. Abstract 9029). Toxicity was not increased with the combination versus what is seen with single agents.

“This study shows we can use these agents in combination, which is ultimately what we need to think about,” he said. “There are a number of treatments moving forward in combination.”

Other Intralesional Immunotherapies

PV-10 is a fluorescent compound that accumulates in the lysosome of cancer cells and leads to acute autophagy, lysis of cells, and exposure of antigenic tumor fragments to antigen-presenting cells. A phase 2 study in which 80 patients were injected found that 51% of target lesions responded, as did 33% of nontarget lesions. Median progression-free survival was 11.4 months in responders and 4.1 months in nonresponders (Ann Surg Oncol. 2014;22:2135-2142).

“We found this effective, more so in patients with earlier disease, and we did see responses at distant sites, including lung and liver,” Andtbacka said.

Researchers are also exploring a technique called intratumoral electroporation, which delivers a small current directly into a tumor to enhance cell permeability. Plasmid IL-12 is then injected into the exposed membranes of the cell.

In a phase 2 study in which 85 lesions were treated, 53% of injected lesions responded (31% stabilized), as did 59% of uninjected lesions (J Clin Oncol. 2014;32[suppl]. Abstract 9025). A randomized clinical trial is under way.

Finally, coxsackievirus A21 gains access to cells by binding to the ICAM-1 protein that the cancer cell expresses. In a process resembling that of T-VEC, the virus replicates, tumor cells are lysed, and the immune system is activated.

In a phase 2 study (CALM), patients received multiple injections of coxsackievirus A21 over 48 weeks. More than 40% of patients were progression free at 6 months, meeting the study’s primary end point. Responses were observed not only in patients with localized disease but also with visceral metastases. There were no grade 3/4 toxicities.

According to Andtbacka, these are likely immune-mediated responses—not just working by direct lytic effect on the tumor—and testing these therapies in combination is the next important step.

“We want to prevent patients without visceral metastases from ever getting them,” he concluded. “And we need to increase the durability of response while limiting toxicity.”

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