Using a virus to teach the immune system to kill cancer

Hutch News

Using a virus to teach the immune system to kill cancer

‘Exciting’ results from early trial spurs further development of novel vaccine for sarcoma

June 2, 2017
High magnification micrograph of a monophasic synovial sarcoma

Microscopic image of a synovial sarcoma tumor in the lung. In a recent Phase 1 trial, patients with advanced synovial sarcoma and other soft-tissue sarcomas received injections of an experimental vaccine designed to teach their immune systems to fight their cancers.

Image by Nephron / Wikimedia Commons

They’re just strings of genetic material encased in protein. But for all their lack of frills, viruses have an incredible talent for infecting host cells. Although this finely honed ability has resulted in countless deadly pandemics throughout history, it also makes viruses a useful tool with the potential to save lives.

Today at the annual meeting of the American Society for Clinical Oncology, a team of scientists reported the results of an early-stage clinical trial of a cancer vaccine that uses an engineered virus to teach patients’ immune systems to recognize and kill tumor cells.

As a Phase 1 trial, the study was designed to evaluate the vaccine’s safety, home in on dosage and build a foundation for future trials. But signs of the experimental vaccine’s effects on the growth of advanced sarcoma tumors — and patient survival — were hopeful, the investigators reported.

“The results, so far, are exciting and show that the vaccine works, generates an immune response and stabilizes tumors, and [it] will definitely lead to additional studies,” said study leader Dr. Neeta Somaiah of MD Anderson Cancer Center, who presented the main trial results at the meeting, which is being held through Tuesday in Chicago. “Hopefully, if we design the studies right, we will have this as a treatment option in the near future.” 

At the meeting, Somaiah reported that in 16 of 25 participants with advanced soft-tissue sarcoma, tumors were stable after the patients received injections of the experimental vaccine, dubbed CMB305. Of these, about three-quarters had no disease progression by three months and 83 percent  of them were still alive after one year. 

Photo of Dr. Seth Pollack

Dr. Seth Pollack is a sarcoma immunotherapy researcher at Fred Hutch.

Photo by Robert Hood / Fred Hutch News Service

These results “compare favorably” to published data on several FDA-approved therapies for these cancers, said Dr. Seth Pollack, one of the senior investigators on the trial and a physician-scientist at Fred Hutchinson Cancer Research Center who specializes in sarcoma. For example, according to published trials, the tumors of about half of soft-tissue sarcoma patients who receive the chemotherapy trabectedin progress four months after therapy; for the chemotherapy eribulin, half have progressed less than three months out.

The findings from the CMB305 trial are especially noteworthy in light of how easy the drug was on most patients in the trial compared to chemotherapy, a typical treatment for sarcomas. Only one trial participant had a serious side effect (severe pain at the tumor site); the rest reported relatively minor side effects such as soreness at the injection site that lasted one day.

For most patients with these sarcomas, Pollack said, the most difficult symptoms they face throughout their illness are side effects from chemotherapy or other standard treatments — so getting off chemo is a big boost to their well-being, even though they still have cancer.

With stable disease, patients “are basically able to do whatever they want to do while they’re on vaccine because it’s not any significant toxicity,” said Pollack, who helped design the trial and led detailed studies of participants’ immune responses. He will present the results of those immune studies in a poster at the annual meeting on Monday morning.

Somaiah recalled one woman on the trial who competed in a golf tournament while she was receiving the experimental treatment. (She won.)

Photo of Dr. Neeta Somaiah

Dr. Neeta Somaiah led the sarcoma vaccine trial.

Photo courtesy of Dr. Neeta Somaiah / MD Anderson Cancer Center

The anti-cancer immune response doesn’t appear overnight after vaccination. In a previous trial of an earlier version of the vaccine, one patient’s tumors only started shrinking a year after vaccination, Somaiah said. She said that if this approach is used on its own as a treatment, doctors will need to account for a longer time to response, and it shouldn’t be used in patients who need their tumors to decrease in size immediately.

A follow-up trial that will be designed as a registration trial for FDA approval of the experimental vaccine should open later this year once a few final design details are ironed out, Somaiah said.

Harnessing the power of viruses

Viruses reproduce by attaching to cells in their hosts, slipping their genetic material into the cells, and transforming them into little virus factories. An infected cell pumps out dozens or even thousands of new viruses.

But harnessed properly, this finely honed ability to deliver genetic instructions to a specific target can make viruses incredible tools for genetic engineering, and they’ve been used for this purpose for decades. Many different gene therapy approaches currently in development for a variety of diseases use viruses to teach patients’ cells to fight disease or to correct an inborn genetic deficiency.

The engineered virus in CMB305, which incorporates elements of multiple natural viruses, derives from discoveries made in the lab of Nobel Prize–winning scientist Dr. David Baltimore of CalTech. Baltimore and the Hutch’s Dr. Larry Corey are among the scientific co-founders of Seattle’s Immune Design, which owns CMB305 and sponsored this trial.

Neither Somaiah nor Pollack has a personal financial interest in Immune Design. Pollack receives funding from the company through Fred Hutch to carry out research on some of the company’s products.

While several groups of researchers have worked on potential virus-based cancer vaccines, the viral vector used in the CMB305 study is the first of its class to be used in human cancer vaccine trials.

Patients on the trial received four injections of the engineered virus over three months, plus a series of injections of an immune-boosting formulation for a year.

Thanks to its significant re-engineering, the virus component of CMB305 doesn’t behave in the destructive way of natural viruses and doesn’t make patients sick. It also doesn’t insert itself into the genes of the patient’s cells, a property that notoriously triggered cancer-causing mutations in some patients who received first-generation gene therapies in the late 1990s and early 2000s.

Instead, CMB305’s virus carries the genetic instructions for producing a specific cancer marker to the sentinels of the immune system, called dendritic cells. Once infected by the engineered virus, the dendritic cells read the instructions and display the cancer marker like a red flag, putting the immune system’s assassins — killer T cells — on alert to seek out and destroy cells that bear that marker. The vaccine’s immune-boosting components are designed to help maximize and maintain the response.

The cancer marker that patients’ killer T cells are alerted to by the vaccine is called NY-ESO-1, and it’s especially common among patients with the main two subtypes of sarcoma studied in this trial — myxoid/round cell liposarcoma and synovial sarcoma. Because the marker is not found in healthy cells in adults (except for cells in the testes, which are naturally shielded from immune attack), it’s the focus of many developing cancer immunotherapies.

Zooming in on vaccine effects

Pollack and his teammates delved into the fine details of patients’ immune responses before and after vaccination. In the Monday poster, Pollack presents data on 62 patients enrolled in this trial or in an earlier trial that used only the virus component of the vaccine without the additional immune-boosters included in CMB305.

In patients on both trials, Pollack and his collaborators found multiple signs of escalating immune responses to NY-ESO-1 after the experimental therapy was administered. Patients’ immune systems also started recognizing and responding to other cancer markers besides NY-ESO-1 after vaccination, too. These data suggested that the vaccine was working as designed.

But across the board, Pollack’s team observed the biggest boost in signs of anti-cancer immunity among patients vaccinated with the newer version of the vaccine, CMB305.

“My feeling is that [the additional component in the CMB305 vaccine] does help because we definitely saw a better immune monitoring response,” Pollack said.

Somaiah said that the immune monitoring data Pollack and collaborators gathered from these trials is critical for designing future trials of the vaccine and homing in on the patients who are most likely to benefit from it.

“The biomarkers are key because they tell you what is happening in the body, why we are seeing responses and why not,” she said. The biomarker data “is a critical companion to the clinical outcomes. Without that, you can design another 500-patient study, but if you don’t design it based on what you’ve learned it may not be successful.”  

Susan Keown, a staff writer at Fred Hutchinson Cancer Research Center, has written about health and research topics for a variety of research institutions, including the National Institutes of Health and the Centers for Disease Control and Prevention. Reach her at skeown@fredhutch.org or on Twitter @sejkeown.

Are you interested in reprinting or republishing this story? Be our guest! We want to help connect people with the information they need. We just ask that you link back to the original article, preserve the author’s byline and refrain from making edits that alter the original context. Questions? Email us at communications@fredhutch.org

For information about participating in a cancer clinical trial, please contact Fred Hutch’s clinical care partner, Seattle Cancer Care Alliance, or email intake@seattlecca.org. Another good resource about clinical trials is the National Cancer Institute’s Contact Center, which can be reached at 1.800.4.CANCER. The phone line is staffed from 8 a.m. to 8 p.m. ET Monday through Friday.


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