Intratumoral Plasmid Interleukin-12 Bolsters Pembrolizumab Response

Best Practices in Immunotherapy – June/July 2017 Vol 8

In patients with stage III/IV melanoma, intratumoral injections of plasmid interleukin-12 (IL-12) via electroporation enhanced response to immune checkpoint blockade.

According to data presented at the 2017 ASCO-SITC Clinical Immuno-Oncology Symposium, the combined strategy yielded responses in nearly half of the patients treated in the phase 2 study and appears to render immunologically “cold” tumors active.

“We think we are inducing a systemic immunologic effect with this treatment,” said Alain P. Algazi, MD, a melanoma specialist at the University of California, San Francisco. “The tumor microenvironment appeared to be immunologically enhanced, which, in some patients, led to regression of all metastatic lesions.”

As Dr Algazi reported, the expression of PD-L1 in the tumor microenvironment and the proportion of PD-1hiCTLA-4hi on CD8+ tumor-infiltrating lymphocytes (TILs) are presumed measures of immune activity.

“A low frequency of these markers seems to indicate a ‘cold’ tumor that will not respond well to immune checkpoint inhibition,” said Dr Algazi, who noted that delivery of cytokines may boost immunologic response in melanoma, but this approach is limited by toxicity.

To facilitate the uptake of the plasmid IL-12 into the tumor, Dr Algazi and colleagues developed a platform that applies electric current (ie, electroporation) during injection, which has been shown to increase TILs in both treated and untreated lesions. The investigators hypothesized that nonresponse could be “rescued” by combining this delivery method with anti–PD-1 therapy.

“IL-12 is a potent, well-characterized proinflammatory cytokine,” said Dr Algazi. “If we just inject protein it disappears quickly, but if we use plasmid and electroporation, the cytokine stays in the tumor for a week at a time. We thought this might potentiate response to anti–PD-1 antibodies, so we conducted a combination study.”

Study Design and Results

The phase 2 study enrolled 22 patients with stage III/IV melanoma who were predicted to respond poorly to anti–PD-1 therapy through evidence of their apparently immunologically inactive tumors. As measured by flow cytometry, patients had less than 22% PD-1hiCTLA-4+ cells, a value associated with nonresponse to anti–PD-1 agents. In addition, Dr Algazi noted, some patients were naive to anti–PD-1 agents, and others had previously been treated with immunotherapy.

Patients in the study received pembrolizumab (200 mg every 3 weeks) and intratumoral plasmid IL-12 delivered via electroporation 3 times every 6 weeks. Researchers collected and analyzed pretreatment and posttreatment blood and tumor specimens for immune phenotyping, gene expression, T-cell receptor diversity, and changes in the tumor microenvironment by immunohistochemistry.

Significant Immunologic Changes Observed

As Dr Algazi reported, when combined with pembrolizumab, intratumoral delivery of plasmid IL-12 via electroporation produced impressive results.

“This strategy stimulated a safe but powerful systemic immune response,” he observed. “Remarkably, although predicted to be an unresponsive population, the objective response rate was 40%, including 4 complete and 2 partial responses.”

“If we include a patient who progressed but ultimately had a very dramatic response,” Dr Algazi added, “the response rate was 48%.”

In addition, responses to plasmid IL-12 were durable, and some patients had regression of all lesions. One patient, who had previously progressed on ipilimumab, nivolumab, and pembrolizumab, “went from being incapacitated to going back to work as an electrician,” said Dr Algazi.

Moreover, in patients with objective responses, analysis of the tumor microenvironment revealed significant immunologic changes compared with nonresponders. For example, said Dr Algazi, responders showed increased immune cell infiltration into the tumor, typically associated with increases in the CD8+ to PD-L1+ cell ratio.

“We think we are increasing the number of effector cells relative to the number of regulatory cells,” he explained. “In a sense, you can bring in immune cells in many patients, but the difference in responders versus nonresponders is the nature of those cells.”

Investigators observed increased clonality of T cells and an increased number of TILs in responders versus nonresponders, and log-fold changes in markers of activated T cells were also significantly higher (P <.05). These changes were seen in lesions that were directly injected and in nontreated lesions as well.

“The excellent safety profile and striking 40% clinical response rate is encouraging, as treated patients were predicted to be nonresponsive to pembrolizumab,” Dr Algazi concluded. “Furthermore, the differentiation of immune-directed mechanism suggests that the combination can effectively alter the tumor microenvironment to benefit patients otherwise unlikely to respond to anti–PD-1 monotherapy.”

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Last modified: November 5, 2020

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