Scientists have worked for years to harness the power of the immune system. New approaches make researchers optimistic about success.
“It’s a very exciting time for the field of cancer vaccines,” says Vinod Balachandran, an oncologist and surgeon-scientist at the Memorial Sloan Kettering Cancer Center. “We have made so much progress in understanding how the immune system recognizes cancers. There are dozens of cancer vaccine candidates under study by researchers around the world.”
The immune system plays a critical role in controlling cancer. Many experts believe that cancers are constantly trying to sprout within us, only to be squelched by the immune system before they become detectable, a process known as immunosurveillance.
“Our bodies are probably rejecting cancers all the time,” says Jay Berzofsky, chief of the National Cancer Institute’s vaccine branch. “The ones we detect and that turn into cancer we need to treat are the ones that have escaped from that immunosurveillance. The tumors do it by learning how to exploit the mechanisms that regulate the immune system.”
The new approaches include developing both preventive and therapeutic vaccines, the latter designed to discern tumor cells from normal cells with the goal of provoking an immune response against them. Researchers also are assembling a collection of immunotherapy drugs that would boost the vaccines’ efficacy.
‘They look like normal cells’
Cancer cells arise from our own cells and resemble them; thus, the immune system often tolerates them, says Berzofsky, also senior investigator and head of NCI’s molecular immunogenetics and vaccine research section. “They hide their differences, so they look like normal cells,” he says. “The idea of a cancer vaccine is to activate the immune system to pick out ways that the cancer is different from normal cells, recognize them as foreign and reject them.”
Cancer treatment of tomorrow is personalized
It’s important to understand how therapeutic cancer vaccines differ from preventive ones, and how immunotherapy drugs differ from both types of vaccines.
Most people are familiar with traditional vaccines that protect against influenza and such childhood diseases as measles, chickenpox and whooping cough. Two vaccines are approved to prevent infection with viruses that raise the risk of cancer: human papillomavirus (cervical and vaginal cancer, anal cancer, penile cancer) and hepatitis B virus (liver cancer).
But scientists also are developing preventive vaccines for people with premalignant lesions such as colon polyps, hoping to keep them from turning cancerous.
Target for the immune system
Olivera Finn, distinguished professor of immunology at the University of Pittsburgh, and her colleagues were the first to identify a tumor-specific antigen — a protein or other molecule found only on cancer cells and not on normal cells — that could serve as a target for the immune system. (The term “antigen” refers to a toxin or other foreign substance in the body capable of inducing an immune response.)
The tumor-specific antigen Finn found, MUC1, is present in several types of cancers, including colon, breast, prostate, lung and pancreatic. An MUC1-based vaccine she and her team developed showed a strong response from the immune system in clinical trials in patients with premalignant colon polyps, leading them to believe the vaccine could help prevent the growth of new polyps and keep existing ones from turning cancerous.
The vaccine reduced polyp recurrence rates by 38 percent in their clinical trial, Finn says.
“We and other groups are paying attention to premalignant lesions and focusing on trying to boost the immune system to stop the progression from premalignant to malignancy,” Finn says, adding that her group is about to begin a trial of the same vaccine in patients with ductal carcinoma in situ — an early stage of cancer that is confined to breast milk ducts and not yet invasive — to see whether the vaccine can stop it from spreading.
Therapeutic vaccines, unlike preventive ones, treat people who already have cancer by attacking existing cancer cells or preventing a recurrence. They prompt the immune system to find and destroy cancer cells that have certain tumor-specific antigens that healthy cells do not have. The vaccine delivers certain molecules that behave like these antigens to stimulate the immune system into making new “killer” T cells, the same cells that also target viruses.
“Therapeutic vaccines introduce substances that stimulate the production of new immune cells that can fight the tumor,” says Keith Knutson, a cancer vaccine researcher at the Mayo Clinic in Florida. “We inject an antigen — a miniature piece of a protein, a fragment — that stimulates the production of T cells capable of attacking the tumor.”
(There is only one therapeutic vaccine on the market so far, Sipuleucel-T, licensed in 2010 for prostate cancer. It doesn’t provide a huge benefit — a clinical trial showed it increased overall survival by about four months — but that was enough for the Food and Drug Administration to approve it, Berzofsky says.)
In some cases, experimental therapeutic cancer vaccines are personalized, that is, created for just one person from samples of that patient’s tumor. Known as neoantigen vaccines, the goal is to achieve the same result as other therapeutic vaccines. Neoantigens arise from mutations unique to a person’s cancer cells.
“Targeting neoantigens is really something quite novel,” says Patrick Ott, clinical director of the Melanoma Disease Center at the Dana-Farber Cancer Institute, who has been testing them in melanoma patients and in other cancers. In one recent small study, for example, four of six patients vaccinated had no recurrence of their tumors after 25 months. The other two patients’ tumors grew, but then regressed completely after they took additional immunotherapy drugs.
“They had amazing responses,” Ott says. “Maybe having had the vaccine primed their immune system to work with” the drugs.
Balachandran is studying neoantigen vaccines in patients with one of the deadliest cancers, pancreatic cancer, working with scientists at BioNTech, the German company that partnered with Pfizer to produce the successful mRNA vaccine for the coronavirus. They are using the same mRNA technology to make individualized vaccines and have treated 19 patients with pancreatic cancer since 2019. Preliminary results showed half of the patients produced a strong immune response to the vaccine and experienced a longer recurrence-free survival time compared with the half whose immune systems did not respond.
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“The big advantage of neoantigen vaccines is that they can produce a strong immune response because they are tailored to the individual tumor and look foreign to the patient’s immune system,” Berzofsky says. “Also, advances in mRNA technology — the same technology that quickly gave us effective covid-19 vaccines — means that neoantigen vaccines can be made rapidly, removing a major past obstacle.”
Many cancers also share common antigens, meaning a personalized vaccine isn’t always necessary. HER2, a molecule found in about 25 percent of breast cancers is one example. Berzofsky’s lab is testing therapeutic vaccines for several cancers, including one that targets HER2.
“It’s a ‘driver’ antigen, which means the cancer can’t do without it,” Berzofsky says. “It keeps telling the cell: divide and multiply, so going after it with a vaccine would be very effective.” Early clinical trials have been promising, he says. There is a drug, Herceptin, available to treat HER2-positive breast cancer patients, but “the patient has to come back to get an IV drip every few weeks,” Berzofsky says. “If we had a vaccine that caused a patient to make her own HER2 antibodies, she wouldn’t need to come back for the drug.”
‘It could be revolutionary’
Knutson and Amy Degnim, a breast surgeon at the Mayo Clinic in Minnesota, also designed a HER2 vaccine and recently completed a small clinical trial in 22 patients with invasive breast cancer. The vaccine, based on four fragments of the HER2 protein, provoked both antibodies and T cells in all the patients, Degnim says. The vaccine was given in six doses, each one a month apart.
After a little more than two years, only two patients had recurrences: one developed another tumor in the same breast, the second patient experienced a recurrence in the lymph nodes, “but that patient did not complete the full vaccination course,” having received only four doses, Degnim says.
They are studying the same vaccine in patients with ductal carcinoma in situ, hoping to keep it from progressing.
They are also developing another vaccine they hope will completely prevent breast cancer in women at high risk for the disease. Initially, however, it will be tested — for safety reasons — only in women who already have breast cancer.
“Once we have those safety studies done — they haven’t started yet — then we need to give careful thought as to who should be enrolled” in efficacy studies, Degnim says. But if it works, “it could be revolutionary, really,” she says.
One of the early challenges facing scientists when they began researching cancer vaccines was that tumors often induce damaging effects on the immune system, suppressing it. Immunotherapy drugs counter these effects by unblocking the immune system so it can do its job. One example is “checkpoint inhibitor” drugs that work by preventing tumors from sending an “off” signal to the immune system, thus allowing T cells to work.
“The drugs free an immune system that has been co-opted by the immunosuppressive features of the cancer,” says Joshua Brody, director of the Lymphoma Immunotherapy Program at the Tisch Cancer Institute at Mount Sinai, who is studying several therapeutic vaccines delivered in combination with checkpoint inhibitors.
The development of checkpoint inhibitors — which won its discoverers the 2018 Nobel Prize in physiology or medicine — was a breakthrough for therapeutic cancer vaccine research, Finn says.
“Therapeutic vaccines initially failed because they could not stimulate the immune system, which was suppressed, both by [cancer] treatments and by the tumors,” she says. “The tumors had figured out how to evade the immune system. But now we know the many different ways the immune system of a cancer patient is suppressed, and we understand what the immunosuppressive environment looks like.”
Scientists are also trying vaccines in combination with other agents, including cytokines, which are substances normally secreted by the immune system, but in this case produced in the lab. The cytokine is injected to enhance the efficacy of the vaccine.
“These different applications work synergistically,” says Jeffrey Schlom, co-director of NCI’S Center for Immuno-oncology.
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Although the research is growing, experts warn that widespread use of cancer vaccines is still years away. Nevertheless, they predict their use will become standard practice.
“We are setting the stage,” Finn says. “I believe there will be a time in the future when a doctor will be able to identify your risk for certain cancers and give you a vaccine to prevent them.”
Schlom agrees. “It’s happening as we speak: more trials, more progress,” he says. “The way I think about it, in terms of immunotherapy, the best is yet to come. It’s just a matter of time. We’ve got our foot in the door, and now we are opening the door.”
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