Trials Testing PEGylated Interleukins Against Advanced Melanoma Under Way at UH Seidman Cancer Center

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Novel agents thought to preserve interleukin’s ability to boost T cell growth and fight cancer, without harmful side effects associated with high-dose interleukin

Innovations in Cancer | Fall 2021

Melanoma specialists at University Hospitals Seidman Cancer Center are optimistic about a novel approach to the disease that they’re evaluating in new clinical trials. The trials involve PEGylated interleukin agents, which are designed to increase the efficacy of the current checkpoint inhibitors and reduce the serious side effects associated with high-dose interleukin-2 (IL-2) therapy, while preserving interleukin’s ability to promote growth and infiltration of CD8+-T-cells to fight the tumor.

Ankit Mangla, MDAnkit Mangla, MD

“High dose IL-2 is a toxic therapy and requires inpatient admission and close monitoring,” says UH Seidman melanoma specialist Ankit Mangla, MD, who is leading the new trials here. “As a result, it is administered only at very few centers in the country where resources and experience in administering high dose IL-2 therapy are available. With the PEGylated interleukins, the hope is that we can bring the benefit of interleukins in the outpatient setting. With PEGylated interleukin, we are noticing less grade 3/4 side effects in the Phase 1 and 2 trials, especially the capillary leak syndrome, which was one of the most dreaded complications from the high dose IL-2 therapy. The results are encouraging in the sense that the PEGylated interleukins are safe while maintaining their clinical efficacy.”

One PEGylated interleukin under investigation here, bempegaldesleukin (BEMPEG), Dr. Mangla says, is a first-in-class, CD-122-based IL-2 pathway agonist, which is designed to preferentially bind with CD-122 rich CD8+ T-cells. The introduction of the Polyethylene-glycol component (PEG) increases its half-life. The Phase 1/2 PIVOT-02 study, recently reported in the Journal of Clinical Oncology, evaluated BEMPEG plus nivolumab as a first-line therapy for metastatic melanoma. It concluded that the combination was tolerated, with relatively low rates of treatment-related and immune-mediated adverse events. The combination had encouraging anti-tumor activity in first-line metastatic melanoma, including an extended median progression-free survival.

“So far, BEMPEG has proven to be a safe drug with low incidence of capillary leak syndrome, which was more common with the high dose IL-2 therapy,” Dr. Mangla says. “The risk of capillary leak syndrome has been reported to be less than 1%.”

He says he’s hoping for similar encouraging results in the trial of BEMPEG under way at UH Seidman Cancer Center. That Phase 3 trial is randomizing patients with Stage 3 melanoma to nivolumab or nivolumab + BEMPEG, testing the idea that the combining the agents has a synergistic effect and can help prevent relapse.

“When we use checkpoint inhibitors alone, we are not actually ’stimulating’ the immune system, per se,” he explains. “The checkpoint inhibitor blocks the inhibiting signals on cancer cells through the pathways of PD1 and CTLA4 that cause exhaustion of T cells and prevent the T cells from fully attacking the cancer cells, essentially giving the T cells room to do their job. But these agents don’t ‘grow’ the immune system by themselves -- we are not supplying any growth factor to the immune system. The idea of giving interleukin along with the checkpoint inhibitor is that you are not only exposing the cancer cell to the T cell, but you’re also providing a growth factor for that T cell. That’s the synergism that is expected, that both drugs will help the immune system find the cancer cell, but also help the immune system to grow itself. The hope is that and decrease the relapse rate of patients diagnosed with Stage 3 melanoma.”

Another trial of a PEGylated interleukin under way at UH Seidman Cancer Center is evaluating DF6002, a fusion protein that comprises of human IL-12 fused to the Fc fragment. This Phase 1 trial is enrolling patients with Stage 4 melanoma who have either progressed or have not responded to first-line treatment with checkpoint inhibitors and will test DF6002 alone or in combination with nivolumab.

Although this trial is still enrolling patients, Dr. Mangla says he’s already seeing some positive results with the patients he has enrolled.

“We have a patient on the Dragonfly trial who has undergone six cycles,” he says. “He has shown a tremendous reduction in the tumor burden which is quite encouraging. In the adjuvant BEMPEG trial, we have to wait for final results because there really is no tumor to measure. We are trying to reduce the number of relapses. What remains to be seen is the tolerability of the combination. When the final results come out, the expectation that I have is that the recurrence-free survival will increase with the combination compared to single agent. But we need to see what kind of side effect profile that will have.”

In the meantime, Dr. Mangla says he’s pleased to be able to offer options to these patients with difficult-to-treat cancers and to be able to do his part to push the science forward.

“At this point, there’s frankly no good treatment in second line for patients with Stage 4 disease who progress after exhausting the option of checkpoint inhibitors and BRAF/MEK inhibitors, for those who have BRAF mutation,” he says. “We also need to do better for patients with Stage 3 melanoma. Current treatment of one-year therapy reduces the chances of relapse by approximately 50%. We need to do better. We hope these new PEGylated interleukins might be part of a better solution.”

To reach Dr. Mangla, email Ankit.Mangla@UHhospitals.org.

Contributing Expert:

Ankit Mangla, MD

Hematology/Oncology

UH Seidman Cancer Center

Assistant Professor of Medicine

Case Western Reserve University School of Medicine

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