If Cheryl Reinhart hadn’t been in the habit of sleeping on her stomach, she’s pretty sure she never would have noticed the grapefruit-size lump growing in her abdomen. “Cancer is not something you have like a headache or [the pain] if you stub your toe,” she says. “Cancer never hurts. You don’t know you have it until it’s too late.”
Reinhart’s cancer didn’t hurt, but she did start to notice a strange discomfort as she lay with her stomach pressed against the mattress at night. She’d get up, move around a bit, and the feeling would seem to pass.
One night, she couldn’t ignore it any longer and got herself to the emergency room near her home in Buffalo, New York. When the doctor finally came to give her an answer, she knew immediately from the look on his face that it wasn’t good news. The way she remembers it, he told her to “get herself a box.” The diagnosis was advanced ovarian cancer. The doctor told Reinhart she had six months to live.
Reinhart didn’t accept that doctor’s gloomy advice or prognosis. Instead she found her way to Kunle Odunsi, a gynecologic oncologist and a co-leader of the Tumor Immunology and Immunotherapy Program at the Roswell Park Cancer Institute in Buffalo. Reinhart first received standard treatment: surgery to remove the stage 4 ovarian tumor, followed by chemo. She then opted to become one of the first people to try an experimental treatment aimed at fighting ovarian cancer by enlisting the immune system.
In thinking about cancer treatment vaccines, it’s useful to consider first why the immune system would not be able to find cancer without extra help. Cancer cells originate from the body’s own cells. The immune system has developed to recognize foreign invading organisms, including bacteria and viruses. To fight cancer cells effectively, the immune system needs to first recognize a cancer as foreign and mount an effective attack against it. Odunsi and researchers around the world have been working on various ways to activate or engineer the immune system to more effectively fight cancer cells without causing too much harm to the body’s other cells.
Cancer treatment vaccine approaches introduce specific antigens — a peptide (a short bit of protein), a DNA molecule, or an RNA molecule, for example — intended to elicit the production of immune responses against proteins associated with cancerous cells that have already arisen in the body. Treatment vaccines are not to be confused with preventive cancer vaccines, which strive to prevent a cancer from ever developing. Prevention vaccines protect against virally induced cancers, such as cervical cancer, which is caused by the human papillomavirus [HPV]. The HPV vaccine trains the immune system to fight the infection responsible for virtually all cervical cancers and some other cancers too. In addition, researchers across the country are seeking to develop prevention vaccines against cancers like lung, colon, and breast cancer that are not caused by viruses.
Odunsi and his colleagues at Roswell have been working for the past 15 years on various immune-boosting strategies, including a cancer treatment vaccine targeting a protein antigen called NY-ESO-1 that is on the surface of many types of cancer cells. The year before Reinhart showed up in his office, Odunsi reported in the medical literature on the potential of NY-ESO-1 as a useful target for battling many hard-to-treat ovarian cancers. What made NY-ESO-1 look so promising was that the antigen turns up in a variety of cancers, including 40 percent of epithelial ovarian cancers, and not in other adult tissues (except sperm-making germ cells in the male testis). In many cases, women with those NY-ESO-1-bearing tumors also showed evidence of an immune response. Although that natural response against NY-ESO-1 and the cancer wasn’t enough to improve survival, at least their immune systems saw those ovarian cancer cells and were trying, if unsuccessfully, to put up a fight.
In 2007 Odunsi reported the results of the first clinical trial of an NY-ESO-1 peptide vaccine in 18 women with ovarian cancer. Women in the study who received at least five injections with the experimental vaccine showed elevated levels of important immune cells, known as T cells, for up to a year after immunization. Since then, he and his colleagues have worked on a variety of other approaches to encourage the immune response against NY-ESO-1 and ovarian cancer. In one line of investigation, they’ve engineered and delivered modified poxviruses expressing the cancer-associated protein.
They’re also attempting to tackle the cancer by taking some of a patient’s own immune cells out of the body and “teaching” them to recognize and attack NY-ESO-1-bearing cancer cells before they are returned. In a clinical trial now recruiting patients using that approach, researchers isolate T cells from a patient’s bloodstream, modify them with new genetic material, and then return them in the billions in a single infusion. In every formulation, the hope is the same: to make a patient’s own cells better able to launch an attack and fight back against cancer.
Cancer vaccines and other immune-boosting strategies have experienced a revival in recent years. Science magazine named the broad area of cancer immunotherapy a breakthrough of the year in 2013. But the concept of cancer vaccines and the first evidence that the strategy might actually work is surprisingly old, dating back more than a century, to the late 1800s. As the story goes, a young doctor named William Coley discovered a case in which a man with an aggressive form of bone cancer mysteriously recovered after he developed a strep infection following surgery to remove the tumor. Coley decided to give it a try in another patient with a terminal case of neck cancer by purposely infecting the man with streptococcal bacteria. It worked: The tumor shrank.
Coley continued to experiment with the treatment, transitioning eventually from using live to heat-killed bacteria. The treatment, known as Coley’s toxin, was essentially the first cancer vaccine. The trouble was, back then, Coley knew next to nothing about how the immune system worked or the specifics of the cancers he was attempting to treat. Some work on immunotherapy treatments continued, but, for the most part, cancer treatments went off in other directions. Even today, proven success in cancer treatment vaccines has been modest and slow to emerge.
“The idea is old, but so far vaccines have not been very successful,” says Dmitriy Zamarin, a medical oncologist at New York’s Memorial Sloan Kettering Cancer Center, where Coley got his start. “Part of the problem is we didn’t know the right targets. We didn’t have quite the right formulation of vaccines to vaccinate against these targets. Now, with recent developments and a better understanding of how the immune system works, there’s a lot more potential for vaccines.”
That’s not to say there haven’t been successes. Two approved treatments that fit loosely under the umbrella of cancer treatment vaccines are on the market. The first came along in 2010 with the FDA approval of Provenge (sipuleucel-T), a vaccine to treat patients with advanced prostate cancer. A patient’s immune cells are sent to a lab, exposed to a specific protein from prostate cancer cells, and delivered back in three separate infusions.
While safe and effective, the impact of Provenge has been modest at best. Provenge doesn’t stop growth of the cancer, but it does extend survival. Patients receiving Provenge typically live about four months longer on average than they would otherwise. As the first cancer vaccine on the market, Provenge offered a modest benefit at a hefty price — $31,000 per infusion, for a total cost approaching $100,000 per patient. (In 2014, Dendreon Corp., the maker of Provenge, filed for bankruptcy after sales of the treatment fell far short of original expectations.)
The second FDA-approved cancer treatment vaccine, known as Imlygic (T-VEC), is not a vaccine exactly, at least not in the usual sense. The treatment involves injecting patients with a modified cold sore virus, which preferentially infects cancer cells, causing them to burst. By destroying infected cancer cells in that way, Imlygic makes it harder for those diseased cells to hide from a patient’s immune system. As Robert Andtbacka, at the University of Utah School of Medicine in Salt Lake City, explains, Imlygic is an oncolytic virus, meaning literally that it infects and causes cancer cells to burst. But, he says, “it leads in a way to auto-vaccination.” As proteins spill from the cancer, the body can build immunity against those that it recognizes as foreign.
The FDA approved Imlygic in 2015 as a first-of-its-kind treatment for patients with inoperable melanoma skin cancers. A clinical trial showed that 16 percent of patients who received injections of the virus directly into cancerous lesions on their skin saw their cancer shrink over a period of at least six months. However, Imlygic didn’t lead to an overall increase in patient survival. In part that could be because it didn’t do anything to combat melanoma that had already spread to other parts of the body, such as the brain, bone, or liver.
Andtbacka, who led the study that earned Imlygic the distinction of being the first oncolytic virus to show a therapeutic benefit, says the treatment has more promise when delivered to patients at an earlier stage of disease. In some instances, he says, patients who’ve received the treatment have seen their cancers completely disappear for a period of at least three years. There’s evidence that Imlygic revs up the immune system at both near and more distant sites. A clinical trial testing Imlygic, delivered as a first step for use in patients whose melanoma can subsequently be removed through surgery, is ongoing.
Melanoma has been a good test case for oncolytic viruses as a means to vaccinate the body against an existing or recurrent cancer. That’s in part because melanoma is easily accessible, right there at the surface of the skin. But many more oncolytic viruses are currently at some stage of clinical testing in other tumor types. A recent search for “oncolytic virus” at clinicaltrials.gov turns up 70 trials for patients with ovarian cancer, bladder cancer, brain cancer, and other solid tumors.
Andtbacka notes ongoing efforts to turn the common cold virus into a weapon against the fast-growing and incurable brain cancer known as glioblastoma. The virus is injected right through the skull and into the tumor in huge doses. As Frederick Lang, a neurosurgeon at MD Anderson Cancer Center in Houston, has described it, we’re “almost creating a vaccine inside the brain, specifically against the tumor.” Similar efforts are underway in Japan for the treatment of pancreatic cancer, another diagnosis that typically comes with an exceedingly grim prognosis. Researchers there are using ultrasound guidance to allow them to get right to the cancerous site.
“The way I look at this, the future for oncolytic viruses is fantastic,” Andtbacka says. “They will be part of the armamentarium, an additional arrow in our quiver, to treat patients with melanoma and other cancers. But no treatment works all the time. We need multiple options.”
In fact, a major reason for the renewed optimism about the promise of cancer vaccines has been the success not of vaccine or vaccine-like approaches themselves but of other treatment strategies that unleash the immune system. To fight against cancer, the immune system needs to recognize cancer as the foreign invader it is, but then also mount a sufficient anti-tumor immune response to destroy the tumor. One reason cancer cells are able to get a foothold in many cases is by shutting down the immune system. For T cells to fight against cancer, they must not only recognize tumor-specific antigens, but also have the ability to act.
New checkpoint inhibitor drugs for treating cancer work by blocking proteins that prevent killer T cells from doing their job. It’s a mechanism often described as releasing the “brakes” on the immune system. The first of these drugs, called Yervoy (ipilimumab), received approval for patients with late-stage melanoma in 2011. Its use has since been expanded to reduce the risk of recurrence in melanoma patients after surgery. Two other FDA-approved checkpoint inhibitors work in essentially the same way: They target another protein that acts as a brake on the immune system. Researchers suspect that the combination of checkpoint inhibitors and treatment vaccines of various types should have an even better chance of defending against cancer. Checkpoint inhibitors can release the brakes, while vaccines can ensure that T cells then know what to do once they take the wheel.
Zamarin, at Memorial Sloan Kettering, says advances in DNA sequencing are also breathing new life into cancer vaccines, as they are in so many other areas of medicine. While antigens like NY-ESO-1 are common to many tumors, it’s now clear that individual tumors also bear unique proteins based on the specific mutations they carry. The challenge is in identifying those unique proteins and devising personalized vaccines tailor-made to turn the immune system against those tumor “neoantigens” not previously recognized by the immune system.
Personalized tumor vaccines produced in this way have been a hot topic. Some say neoantigens could be just the paradigm shift needed for cancer vaccines to finally succeed. Others have warned that sequencing individual tumors and fashioning customized vaccines for every patient, even if it’s possible, might still be too costly, too time consuming, and otherwise impractical.
Catherine Wu, a pioneer of the neoantigen approach to cancer vaccines at the Dana-Farber Cancer Institute in Boston, is undaunted by such arguments. She says there is absolutely reason for renewed optimism that more powerful and effective cancer vaccines could be on the way. “We can go from those [unique] mutations to predicting what type of amino acid changes those could generate to a peptide that can bind and stimulate [an immune] response,” she says. “Suddenly, with sequencing and a week of analysis, boom, we can generate a list of predicted targets” specific to each individual cancer.
Evidence has also emerged in studies of mice and human patients that supports the notion that T cells can recognize those neoantigens and launch an attack against them. There is plenty of work ahead, but “for the first time, we have really good antigens,” Wu says. “Now at least that part is anchored. In the years to come, we can actually nail all the other aspects and get to what we hope for, which [are effective] cancer vaccines.”
Wu’s team already is conducting two small clinical trials testing the neoantigen approach in patients with melanoma and glioblastoma. They are customizing vaccines including 20 neoantigen targets, which are delivered to patients in five doses over a short time. The phase 1 study won’t be large enough to show whether the personalized vaccine approach helps patients, but it will provide an early indication as to whether the shots produce an immune response.
While neoantigens are promising on their own, Wu echoes the idea that the future is in combination therapies. She suggests that targeted treatments, which tend to work well, but only temporarily, might shrink tumors down to a more manageable size. Next, a vaccine could be delivered to mount a good “standing army of T cells that are tumor specific,” helped along by checkpoint inhibitors to unleash the immune system’s full potential. “Maybe all you need [then],” she says, “are [booster] vaccines on the back end to remind the body to keep going.”
Potential side effects of immunotherapies and combinations of immunotherapy treatments including vaccines are, of course, another big question. In some people, immunotherapies intended to fight cancer can lead to unpredictable and poorly understood immune reactions that damage other parts of the body. Andtbacka says oncolytic viruses seem to come with minimal side effects, and early indications suggest that combination treatments don’t increase their toxicity much. But there have been surprises, good and bad, in related arenas.
Last summer, for example, Seattle Children’s Hospital announced that 39 out of 42 children with relapsed or refractory acute lymphoblastic leukemia treated with experimental, genetically reprogrammed T cells (chimeric antigen receptor T-cells or CAR T-cells) achieved complete remission. Those kids, who entered the trial with less than a 20 percent chance of survival, showed no detectable leukemia cells after treatment.
And in a more recent phase 2 trial, CAR T-cell therapy produced a dramatic response in adult patients with refractory B-cell lymphoma. Of the 101 participants in the trial who received the treatment, nearly half had a complete response, a rate that is “sixfold higher compared with historical outcomes,” said co-lead author Sattva Neelapu, of MD Anderson Cancer Center in Houston, at the American Society of Hematology’s meeting last December.
But questions about the safety of CAR T- cells arose in July 2016, when the FDA put a CAR T-cell trial in adults on hold following the deaths of three patients from celebral edema caused by severe neurotoxicity. The trial resumed, based on evidence that the conventional chemotherapeutic drug given to patients as part of the treatment had caused the trouble, not the experimental T cells. However, after two more deaths, the company stopped development of the drug in March 2017.
“If it was easy, we would have cured cancer a long time ago,” says Igor Puzanov of Roswell Park Cancer Institute, who was not involved with that work. “We have to step back and think. The problem sometimes is that people go from extreme to extreme. They become overenthusiastic and then disappointed. We have to take a measured approach.”
A measured approach is something Cheryl Reinhart, now 61, can certainly relate to. She has participated in three phase 1 trials to test the safety of various NY-ESO-1 targeted treatments over the years. Any side effects she has experienced have been minor in comparison to the chemo — a little soreness, as might be expected with any shot to the arm, and some additional hours spent in the hospital.
She has been lucky, moving from one treatment to another and surviving for more than 12 years since the ER doctor told her to “get a box.” Her cancer has come back twice, but she has beaten the odds — few patients have lived so long following a diagnosis of advanced ovarian cancer. At the moment, she’s keeping her cancer under control by taking eight daily pills of Lynparza (olaparib), a drug approved by the FDA two years ago for women with “heavily pretreated ovarian cancer that is associated with defective BRCA genes,” which she carries.
She doesn’t know for certain if any of her experimental treatments have played a role in her good fortune over the years, as is the case for most people who’ve received cancer treatment vaccines. A long list of clinical trials for various NY-ESO-1-targeted treatments like those she’s received are still underway. Regardless of what those trials ultimately show, for her, she says, “it was so worth it. You’re giving yourself and other people hope.”