We’ve come to the point in modern medicine where a single compound to treat a complex disease like cancer has become increasingly less of an option. However, on the positive side, the number of successful combination therapies continues to grow. For instance, results from a new clinical trial by investigators at the Hollings Cancer Center, part of the Medical University of South Carolina, show that a novel immunotherapy combination is surprisingly effective at controlling the lung cancer progression. Findings from the new study were published recently in The Lancet Oncology through an article entitled “ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial.”

“People don't talk about 'curing' patients with metastatic lung cancer. We now get to flirt with the idea for certain patients using immunotherapy,” remarked lead study investigator John Wrangle, M.D., an oncologist at the Hollings Cancer Center. “And at the very least we have a significant proportion of patients enjoying prolonged survival even if we can't call them 'cured.'”

Patients with metastatic non-small cell lung cancer will always progress after chemotherapy, so most patients go on to be treated with immunotherapy, a type of therapy that uses the body's immune system to fight cancer. One class of immunotherapeutic drugs are known as checkpoint inhibitors, as they target checkpoints in immune-system regulation to allow the body's natural defenses, such as white blood cells, to more effectively target the cancer. Checkpoint therapies work by cutting the brake cables on the white blood cells that are inherently able to kill tumor cells.

“Tumor cells often produce suppressive factors which essentially turn the brakes on tumor-killing white blood cells,” explained senior study investigator Mark Rubinstein, Ph.D., assistant professor at the Medical University of South Carolina. “What's unique about the therapy that we're testing is that in addition to cutting the brake cables on white blood cells, we're providing fuel to them so that they can more effectively kill cancer cells.”

The new therapy used in the study is a combination of a checkpoint drug, nivolumab, with a new and powerful immune stimulation drug called ALT-803.

“What's unique about our trial is that it's two completely different types of drugs that have never been combined in humans before, and the trial demonstrated that these drugs could be safely administered, and also, there's evidence that it may help patients where checkpoint therapy is not good enough alone,” noted Dr. Rubinstein.

Patients who have stopped responding to checkpoint therapies may be helped significantly by adding ALT-803. Preclinical studies have shown that ALT-803 activates the immune system to mobilize lymphocytes against tumor cells and could potentially serve as a key component in combination treatments. Of the 21 patients treated, nine previously either had stable disease or responded to single-agent immunotherapy before becoming resistant to this treatment. Of these nine patients, 100 percent either had stable disease or had a partial response to the treatment used in this study.

“We can reassert control, at least in terms of stable disease, in essentially everybody we've treated so far,” Dr. Wrangle said. “Whereas for decades the modalities of therapy were surgery, radiation, and chemotherapy, the last decade has brought targeted therapy, and more recently, immunotherapy. It fundamentally alters the balance of power between your body and your cancer.”

The researchers were surprised and elated at the success demonstrated in their latest study. Dr. Wrangle said the landscape of oncology is “eyeball-deep in failed trials,” so he and Dr. Rubinstein are hopeful this will provide more treatment options for patients. “The number of trials that work is minuscule, so was I surprised? I was ecstatic that it was working,” he said.

The investigators noted that there's still plenty of work to do before the new combination of drugs can be used outside of a clinical trial. “We have a lot to figure out about how to use this therapy, and we need to treat a few hundred patients in order to get a better sense of how to refine the synergy of these two classes of drugs. That's just going to take time,” Dr. Wrangle concluded.








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