Seek and destroy: A new drug trains the immune system to recognize and kill myeloma cells

A promising new drug may actually teach the immune system to kill myeloma cells. On a recent mPatient Myeloma Radio podcast, a leading researcher explained how the drug works and who is eligible to participate in a clinical trial. Myeloma Crowd founder Jenny Ahlstrom interviewed Dr. Sarah Holstein for the podcast Sept. 19 . Dr. Holstein is Assistant Professor of Oncology at Roswell Park Cancer Institute in Buffalo, N.Y. Dr. Holstein said her interest in myeloma began when she was a resident and met myeloma patients, who had few treatment options at the time. “I was really amazed by how much damage myeloma could do to a person,” she said. “So I saw people in kidney failure and with broken bones, and I was a little bit dismayed about the relative lack of treatment options. “ When Dr. Holstein did a hematology-oncology fellowship just a few years later, she was pleasantly surprised to learn that several new drugs had been approved and patients were doing much better. She saw as many myeloma patients as she could, and started a myeloma research project. “Given my background in pharmacology for my graduate degree, I thought that this really seemed like a clinical field where there was a lot of room for pharmacology to improve things,” Dr. Holstein said. “And as I was finishing up my fellowship, it seemed clear to me that the most rewarding thing for me to do would be to continue to pursue both clinical treatment of myeloma and also basic research because I really think that seeing patients every day with myeloma reminds me how important the basic research is to improve their lives.” Dr. Holstein’s work in myeloma includes a clinical trial for ALT-803, a drug that the National Cancer Institute is calling the most promising among twelve immunotherapy drugs. Dr. Holstein’s study of ALT-803 will be the first one conducted in myeloma patients. ALT-803 is a modified, more active version of IL-15, a substance that is a normal part of the immune system. IL-15 is thought to protect a normal immune system against cancer cells. “The idea is if we could really ramp up the activity of the IL-15, we could really increase the activity of our own immune cells to recognize and kill the myeloma cells,” Dr. Holstein explained. When mice were infected with myeloma cells and then given a dose of ALT-803, that single dose killed off about 90 percent of the myeloma cells after four days. “That’s a very impressive cell killing,” Dr. Holstein said. When the mice were given two doses spaced a week apart, more than 80 percent of the mice were still alive 190 days later. Infected mice that didn’t get the drug had all died after 28 days. Next, the surviving mice were reinjected with cancer cells, but they didn’t receive any additional drug. The mice were able to fight off the cancer cells and were still alive six months later. “So why this is so exciting is that it means that this drug has changed the immune system and essentially given the immune system a memory,” Dr. Holstein said. “Even in the absence of giving more drug, this immune system has now learned to recognize the myeloma cells as bad and to kill them. So we’re really, really excited to try to see if this drug is effective in patients with myeloma.” The ALT-803 clinical trial will be conducted at Roswell Park and a few other sites across the country, Dr. Holstein said. A traditional Phase 1 study will allow researchers to figure out the correct dose, and a Phase 2 portion will treat more patients with the dose determined in the Phase 1 portion. “In addition to looking at the usual things like what the response rate is and how long our patients live before they progress, the study is also doing a number of blood samples where they’re going to look to see how effective this drug is in changing the immune system,” Dr. Holstein said. Any patient who has active myeloma and has had at least two prior treatments is eligible to participate in the Phase 1 trial, Dr. Holstein said. “I think they do count induction transplant as one treatment or it can be just two separate treatments,” she said. “And so that’s also another nice thing about the study. Sometimes with our relapsed refractory trials, we restrict the trials to patients who have been very heavily pre-treated — four, five, six prior treatments. Here, you can have had a relatively few number of treatments and still have access to this drug.” Dr. Holstein says the trial will be conducted in four or five sites across the country. Researchers at Roswell Park plan to enroll at least two patients within the first year, although the number of patients in the Phase 1 portion will depend on how many dose levels are needed. The Phase 2 portion at Roswell Park will enroll about 19 patients. Although this is the first trial to test ALT-803 in myeloma patients, the drug has been tested in patients with a variety of hematological cancers who have relapsed after an allogeneic transplant. Dr. Holstein said that side effects appear to be mild. “What we know is there is a bit of a reaction when you first get the drug,” she said. “But that unlike some other drugs … the experience with ALT-803 so far is that it’s a much less severe reaction. What I’ve been told so far is that it’s very tolerable and that once you get past the initial 24 hours, that patients are not really reporting side effects. But again, it’s still very, very early in clinical development at this point.” Will the extraordinary results in mice translate to humans? Dr. Holstein says she will keep her fingers crossed. “I think it’s one of the few approaches that I’ve seen so far which might truly be changing our immune system and allowing long-lasting activity, and it might potentially mean that we don’t need to keep re-dosing this drug which I think would be really exciting,” she said.