Decloaking cancer

Metastatic melanoma cells

New therapies unmask tumors that hide from immune system

By Jennifer Brown

At first it felt like a hamstring pull, but the pain didn’t go away. Then a lump appeared. Trent Phillips’ surgeon in Cedar Falls ordered an MRI, and when the results came back, he had bad news. He told Phillips, a graphic designer from Jesup, Iowa, that the lump might be a sarcoma.

Sarcomas are rare tumors that form in bones and soft tissue, including muscle and tendons. While treatments for many cancers have improved markedly over the past few decades, sarcoma remains stubbornly resistant to new therapies. Almost no progress has been made to increase survival rates for sarcoma in the last 30 years.

Trent Phillips participates in a clinical trial using cancer immunotherapy to treat sarcoma.

Phillips’ surgeon referred him to Mohammed “Mo” Milhem, MD, a medical oncologist and national expert in sarcoma and melanoma at Holden Comprehensive Cancer Center at the University of Iowa. Milhem immediately had a plan. He wanted to enroll Phillips as the first patient in a brand new clinical trial only available at the UI sarcoma clinic.

The foundation of the treatment would be the standard of care for sarcoma—radiation of the tumor site followed by surgery to remove the primary tumor. But the trial would also include immunotherapy—a new way of treating cancer that is taking the world of cancer therapy by storm.

Immunotherapies direct a patient’s immune system to seek out and destroy cancer. This seemingly simple idea of using the body’s natural defense mechanisms to fight cancer has been around for more than a century, but only recently has an understanding of how cancer and the immune system interact advanced sufficiently for the concept to achieve clinical success. In just five years, several of these new therapies have proven so successful they are now regarded as a first-line treatment for some cancers alongside the traditional approaches of surgery, radiation, and chemotherapy. And the pipeline looks robust, with many more immunotherapies currently being tested in hundreds of clinical trials.

“I have been doing this research for 25 years and this is the most exciting time by far that I’ve seen,” says George Weiner, MD, cancer immunologist and director of Holden Comprehensive Cancer Center at the UI. “It seems like we are always saying, ‘We’re on the cusp.’ In this case, we’re not just on the cusp, but we are two steps in.

“These treatments work,” Weiner adds. “They are not working in everybody, so we still have a lot to learn, but this is a revolution in cancer therapy and there’s no question that the way we practice cancer medicine is going to be very different in 10 years because this isn’t just a theory—this works.”

Immunotherapy comes of age

Early attempts at immunotherapy focused on simply boosting the immune response without being able to precisely and effectively target the cancer. There were hints that the research was on the right track—a small number of patients in immunotherapy studies did well—but overall, clinical trials were disappointing and the approach was widely dismissed as a “failed hypothesis,” Weiner says.

The problem is that many cancer cells deploy stealthy molecular disguises to evade detection by the immune system. It’s as if cancers have donned invisibility cloaks that allow them to hide in plain sight.

Decades of research have gradually improved understanding of how cancers are able to hide from the immune system, and the effort has finally started to pay off. The new generation of immunotherapies works by revealing cancer to the immune system.

Checkpoint-Inhibitor[2]“We have discovered that the key is not only to stimulate the immune system, but to also remove the negative regulators of the immune system. It is a completely different paradigm of thought,” Milhem says.

Among the most successful of these new therapies are drugs that prevent tumors from co-opting the “secret handshakes” of healthy cells. These cellular handshakes essentially put the brakes on the immune response, causing the immune system to back off.

The drug that eliminated the metastatic melanoma in the brain and liver of former President Jimmy Carter targets one of these “handshakes” normally used by the immune system’s T-cells to distinguish friend from foe. T-cells express checkpoint proteins on their surface. When a T-cell encounters a normal, healthy cell with a complementary checkpoint ligand on its surface, this handshake interaction prevents the T-cell from attacking the normal cell. However, many cancers also express these ligand proteins and fool T-cells into accepting the tumor as normal. Immunotherapies called checkpoint inhibitors block this false interaction, releasing the “brake” and allowing the immune system to attack the cancer cells.

In 2011, ipilimumab (Yervoy), an antibody that blocks the interaction of the checkpoint protein CTLA-4, was the first checkpoint inhibitor approved by the Food and Drug Administration (FDA) for treating cancer (advanced melanoma). Two more checkpoint inhibitors targeting a different checkpoint protein (PD-1) were approved in 2014: nivolumab (Opdivo) for melanoma, lung, and kidney cancer; and pembrolizumab (Keytruda)—the drug that helped President Carter—for melanoma and lung cancer. In 2016, atezolizumab (Tecentiq), which targets PD-L1, was approved for bladder cancer.

Despite much excitement over the potential of immunotherapy to benefit many patients across a wide and increasing range of cancer types, researchers are keenly aware that many challenges remain. Single checkpoint inhibitors only work for about 20 to 40 percent of melanoma patients, for example. The impetus now is to determine how to help patients for whom these therapies don’t work. Options include testing combinations of immunotherapies, testing approved immunotherapies in conjunction with other cancer treatments, and manipulating other aspects of the immune system to effect an improved anti-cancer response.

New treatment goes viral

Although checkpoint inhibitors have led the way, they are by no means the only form of immunotherapy making the breakthrough into clinical practice.

In fall 2015, the FDA approved the first oncolytic virus—a modified herpes virus that infects and destroys cancer cells and also provokes a cancer-directed immune response—for clinical use in patients with melanoma. The green light for talimogene laherparepvec, or T-Vec (Imlygic), followed results from a large, phase 3 clinical trial that showed the treatment improved durable response rates in patients with advanced melanoma.

Holden Comprehensive Cancer Center at the UI was one of the leaders in recruiting participants among the 52 sites that participated in the T-Vec trial. Milhem was principal investigator of the UI site and a co-author on the study that reported the trial’s success, which was published in the Journal of Clinical Oncology in May 2015.


T-Vec orchestrates a two-pronged attack. It also forces infected cells to produce granulocyte monocyte colony stimulating factor (GM-CSF), which acts like a homing beacon for immune cells. When the infected cancer cells burst open, the cellular destruction draws the attention of the immune system. The GM-CSF also acts as a red flag, calling the immune system and priming it to attack and destroy the cancer cells. By presenting the immune system with pieces of the cancer, this approach teaches T-cells to recognize the patient’s particular cancer, including metastatic cells that may be encountered elsewhere in the body.

Patients in the trial who had stage 3 and early stage 4 melanomas lived almost twice as long (41 months on average) when injected with T-Vec compared to earlier-stage melanoma patients using the control therapy (21.5 months on average).

“We had success in the patients we treated,” Milhem says. “Some are still living without the cancer right now (it has been five years since the trial was done). So it is a very potent drug.”

But surprisingly, a failure of the T-Vec approach encouraged Milhem to consider a broader application for the therapy. A patient on the trial had a large melanoma tumor inside the pelvis that was not responding well to the T-Vec, so Milhem decided to radiate the tumor while continuing with the injections, hoping the combination therapy would help amplify the anti-tumor immune response. It worked. The patient’s tumor responded dramatically to the combination of radiation and T-Vec injection. And Milhem started wondering if this one-two punch would work against sarcoma.

“I saw something in the melanoma that I thought could be translated into sarcoma where we already are using radiation as a frontline therapy, and we could add this injection into the protocol,” he says. “This therapy is designed to present the cancer to the body. This may be the first time I have a drug that can do that for sarcoma and allow the immune system to recognize it and potentially prevent tumors from spreading.”

Attacking sarcoma

Treatment options remain extremely limited for the roughly 14,000 cases of sarcoma diagnosed each year in the U.S. The current approach is to surgically remove the tumor, ideally sparing the limb and avoiding amputation. If this is done successfully before the cancer spreads, outcomes are generally good. However, approximately half of patients are not diagnosed until the sarcoma is already in an advanced stage. Even with an ideal surgical removal of the primary tumor, patients with metastatic disease have only a 50 to 60 percent survival rate.

Mo Milhem

Milhem reasoned that combining T-Vec injections with pre-surgical radiation could potentially recruit the immune system to recognize and attack sarcoma cells. If the T-Vec works as intended, this approach could not only increase cell killing at the primary tumor site, but it might also teach the immune system to recognize and attack sarcoma cells that have spread to distant sites in the body—in essence creating an “internal vaccine” against the sarcoma.

As the first of eight patients so far recruited to the trial, Trent Phillips’ therapy consisted of 25 radiation treatments and 13 injections of T-Vec over five weeks, which killed 70 percent of the tumor. Surgery removed the rest of the tumor and tests revealed no signs of cancer.

If sarcoma does recur following treatment, it’s usually two to five years after surgery. So the ultimate answer of whether the T-Vec injections reduce the risk of metastatic disease, which makes sarcoma so deadly, won’t be known for several years. That’s too long for Milhem and his partner in the sarcoma clinic, orthopedic surgeon Benjamin Miller (’03 MD), to idly wait. They have enlisted basic scientists to examine sarcoma samples collected at multiple times before, during, and after treatment, looking for biological markers to indicate if the therapy has affected tumor biology or to help identify which patients are or are not responding to the treatment.

Although their approach of moving ideas to clinical trial as quickly as possible bypasses some of the traditional step-by-step approach of doing research, Miller and Milhem argue that for patients with few good options, a more rapid route to clinical trials is necessary. They also insist that despite its speed, their approach is built on a rigorous foundation: ideas that make sense biologically and therapeutically and, most important, therapies that can be given to patients without altering the underlying standard of care.

“We have interventions that we know are safe and we know have been effective in other circumstances. By doing it this way, we are able to offer these treatments years sooner than we could with the normal, accepted way of doing research, potentially intervening in patients’ lives right now instead of waiting 10 years,” Miller says.

Fast-forward to clinical trials

By Jennifer Brown

Bringing a clinical trial to life is not a trivial proposition, but Mohammed “Mo” Milhem, MD, and Benjamin Miller, MD, co- leaders of the University of Iowa Sarcoma Multidisciplinary Oncology Group, point to several features of Holden Comprehensive Cancer Center at the UI that create an ideal environment to rapidly transform an idea on paper into a clinical trial recruiting patients.

“If there’s a new idea that makes sense or a compelling new treatment option, we have the flexibility to do something different. This is where Iowa is superior to other places,” Miller says.

Benjamin Miller

“Our sarcoma trial is a model for our approach: Get together, discuss the idea, figure out the protocol, understand how all the providers will work together, obtain approval from the ethics and scientific committees, identify appropriate patients, and get them here,” Miller adds. “It gives us a blueprint and highlights exactly how we distinguish ourselves and what we can offer to a group of patients who really need better treatment.”

From first discussing Milhem’s idea to recruiting patients to the trial took only one year. Eight patients are currently enrolled, with the goal of recruiting a total of 24 patients to this phase 1 trial.

Recruiting patients is one of the team’s biggest challenges. The rarity of sarcoma and Iowa’s small population mean that on average fewer than 40 cases are diagnosed each year in the state, so Miller and Milhem actively engage regional and national providers who may have patients with sarcoma. Their goal of increasing access to clinical trials reflects one of the priorities of the National Cancer Moonshot Initiative led by Vice President Joe Biden, which aims to double the rate of progress against cancer.

At Holden Comprehensive Cancer Center there are approximately 20 immunotherapy clinical trials underway. In addition to testing combinations of available immunotherapies, researchers also are testing chimeric antigen receptor (CAR) T-cells, another promising new approach that reengineers a patient’s T-cells to target cancer.

Milhem is leading another unique trial for melanoma patients who are not responding to an anti-PD-1 checkpoint inhibitor. The phase 1 trial, being conducted with Checkmate Pharmaceuticals, revisits an immune-boosting molecule discovered at the UI two decades ago. The difference now is that the powerful immune stimulator—a CpG oligonucleotide—is used in conjunction with a checkpoint inhibitor designed to remove the brakes from the immune system. The hope is that this combination will significantly increase the response rate to the treatment, allowing more patients to benefit from immunotherapy.

George Weiner

“New lines of research are opening up that we haven’t thought of before,” says George Weiner, MD, director of the cancer center and president of the Association of American Cancer Institutes, which comprises 95 leading cancer research centers in the U.S. “As exciting as this is, however, it is still not to the point where it helps the majority of cancer patients, and that’s why research and support for that research remains so incredibly important. The more research funding we have, the faster the progress will be.”

For information on clinical trials at Holden Comprehensive Cancer Center, contact Mary Schall, 319-356-3516,