Approaching a cancer vaccine

“This is a very exciting time for the field of cancer vaccines,” said Vinod Balachandran, an oncology and surgeon scientist at the Memorial Sloan-Kettering Cancer Center. “We have made great strides in understanding how the immune system recognizes cancer. There are dozens of cancer vaccine candidates being studied by researchers around the world.”

The immune system plays an important role in controlling cancer. Many experts believe that cancer is always trying to germinate in our body, but it is only crushed by the immune system before it becomes detectable, a process known as immune surveillance. ..

“Our body probably always rejects cancer,” says Jay Belsovsky, head of the vaccine department at the National Cancer Institute. “It’s the escape from that immune surveillance that turns into cancer that we need to detect and treat. Tumors do that by learning how to take advantage of mechanisms that regulate the immune system.”

New approaches include the development of both preventative and therapeutic vaccines. The latter is designed to distinguish tumor cells from normal cells with the aim of inducing an immune response against the tumor cells. Researchers are also collecting a collection of immunotherapeutic drugs that enhance the effectiveness of vaccines.

“They look like normal cells.”

Cancer cells originate from our own cells and resemble them. Therefore, the immune system often tolerates them, says Belzovsky. He is also a senior researcher and head of the Molecular Immunogenetics and Vaccine Research section of NCI. “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 find ways in which cancer is different from normal cells, recognize them as foreign bodies, and reject them.”

Tomorrow’s cancer treatment is personalized

It is important to understand how therapeutic cancer vaccines differ from prophylactic vaccines and how immunotherapeutic agents differ from both types of vaccines.

Most people are familiar with traditional vaccines that protect against flu and childhood diseases such as measles, chickenpox, and whooping cough. Two vaccines have been approved to prevent infection with viruses that increase the risk of cancer: human papillomavirus (cervical and vaginal cancer, anal cancer, penis cancer) and hepatitis B virus (liver cancer).

However, scientists are also developing preventative vaccines in hopes of preventing people with precancerous lesions such as colon polyps from becoming cancerous.

Immune system targets

Olivera Finn, a prominent professor of immunology at the University of Pittsburgh, and her colleagues first identified tumor-specific antigens (proteins or other molecules found only in cancer cells, not normal cells). Immune system. (The term “antigen” refers to toxins or other foreign substances in the body that can elicit an immune response.)

The discovered tumor-specific antigen, fin MUC1, is present in several types of cancer, including the colon, breast, prostate, lungs, and pancreas.Ann MUC1-based vaccine She and her team developed a strong response from the immune system in clinical trials in patients with precancerous colorectal polyps, preventing the vaccine from growing new polyps and causing existing polyps to become cancerous. Made me believe that it would help prevent it.

The vaccine reduced polyp recurrence rates by 38 percent in their clinical trials, Finn says.

“We and the other groups are focusing on precancerous lesions and strengthening the immune system to prevent the progression from precancerous to malignant,” Finn said, her group said. In non-invasive ductal carcinoma in situ (an early stage of cancer that is localized to the duct and has not yet infiltrated), see if the vaccine can prevent the spread of the cancer.

Therapeutic vaccines, unlike preventive vaccines, treat people who already have cancer by attacking existing cancer cells or preventing their recurrence. They encourage the immune system to find and destroy cancer cells that have specific tumor-specific antigens that healthy cells do not have. Vaccines deliver specific molecules that behave like these antigens, stimulating the immune system to create new “killer” T cells. The same cells that also target the virus.

“Therapeutic vaccines introduce substances that stimulate the production of new immune cells that can fight tumors,” says Keith Natson, a cancer vaccine researcher at the Mayo Clinic in Florida. “We inject antigens (miniature pieces, fragments of protein) that stimulate the production of T cells that can attack tumors.”

(So ​​far, the only therapeutic vaccine on the market is Sipuleucel-T, which was approved for prostate cancer in 2010. There is no significant benefit. In clinical trials, the overall survival time is about 4 It was extended for a month, but that was enough. Berzofsky says, for the Food and Drug Administration to approve it.)

In some cases, therapeutic cancer vaccines are individualized. That is, it is created for only one person from a sample of that patient’s tumor. The goal known as a tumor antigen vaccine is to achieve the same results as other therapeutic vaccines. New antigens result from mutations specific to human cancer cells.

“Targeting neoantigens is really new,” says Patrick Ott, clinical director of the Dana-Farber Cancer Institute’s Center for Melanoma Disease, which is testing them in melanoma patients and other cancers. .. For example, in a recent small study Four of the six vaccinated patients had no tumor recurrence after 25 months.. The tumors in the other two patients grew, but completely regressed after taking additional immunotherapeutic agents.

“They responded amazingly,” says Otto. “Maybe because they had the vaccine, their immune system was prepared to work with the drug.”

Barachandran is a German company that is researching a new antigen vaccine for patients with pancreatic cancer, one of the most deadly cancers, and has partnered with Pfizer to successfully produce a coronavirus mRNA vaccine. We are working with BioNTech scientists. They use the same mRNA technology to produce individual vaccines, treating 19 pancreatic cancer patients since 2019. Preliminary results show that half of patients have a strong immune response to the vaccine and have a longer recurrence-free survival than half. The immune system did not respond.

Genetic experiments struggle to treat cancer

“The big advantage of the new antigen vaccine is that it can generate a strong immune response because it is tailored to the individual tumor and looks heterogeneous to the patient’s immune system,” says Berzofsky. “Also, advances in mRNA technology (the same technology that quickly provided an effective covid-19 vaccine) mean that tumor antigen vaccines can be produced quickly, removing major obstacles in the past.”

Many cancers also share a common antigen. In other words, individual vaccines are not always needed. HER2, a molecule found in about 25% of breast cancers, is one example. Berzofsky’s lab is testing several cancer treatment vaccines, including those that target HER2.

“this is “Driver” antigen, This means that cancer cannot be achieved without it, “says Berzofsky. “It keeps telling the cell: it divides and proliferates, so chasing it with a vaccine is very effective,” he says, with early clinical trials promising. There is a drug, Herceptin, that can be used to treat patients with HER2-positive breast cancer, but “patients need to come back to receive an IV drip every few weeks,” says Berzofsky. “If the patient has a vaccine that makes her HER2 antibody, she doesn’t have to come back for the drug.”

“It may be revolutionary”

Knutson and Amy Degnim, breast surgeons at the Mayo Clinic, Minnesota, have also designed a HER2 vaccine and recently completed a small clinical trial in 22 patients with invasive breast cancer. The Vaccine based on 4 fragments of HER2 protein, Induced both antibodies and T cells in all patients, says Degnim. The vaccine was given 6 times at monthly intervals.

More than two years later, only two patients had relapsed. One developed another tumor in the same breast and the second patient experienced recurrence in the lymph nodes. Four doses, says Degnim.

They are studying the same vaccine in patients with carcinoma in situ and hope to prevent its progression.

They are also developing another vaccine that wants to completely prevent breast cancer in women who are at high risk for breast cancer. However, initially, for safety reasons, it will only be tested in women who already have breast cancer.

“Once these safety trials are complete (not yet started), we need to carefully consider who should be enrolled in the efficacy trial,” Degnim said. But if that works, she says, “it could be really revolutionary.”

One of the early challenges scientists faced when they began researching cancer vaccines was that tumors often cause harmful effects on the immune system and often suppress it. Immunotherapeutic drugs counter these effects and play a role by unblocking the immune system.One example is “Checkpoint inhibitor” drug It works by preventing the tumor from sending an “off” signal to the immune system and allowing T cells to function.

“These drugs release the immune system adopted by the cancer’s immunosuppressive function,” says Joshua Brody, director of the lymphoma immunotherapy program at the Tissue Cancer Institute in Mount Sinai. Uses checkpoint inhibitors.

Development of checkpoint inhibitors — Discoverer won the 2018 Nobel Prize in Physiology or Medicine — Was a breakthrough in therapeutic cancer vaccine research, Finn says.

“Therapeutic vaccines failed at first because they couldn’t stimulate the immune system. [cancer] It depends on the treatment and the tumor, “she says. “Tumors knew how to evade the immune system, but now they know different ways in which the immune system of cancer patients is suppressed, and they understand what the immunosuppressive environment looks like. increase.”

Scientists are also trying vaccines in combination with other drugs, including cytokines. that is It is a substance normally secreted by the immune system, but in this case it is produced in the laboratory. Cytokines are injected to increase the effectiveness of the vaccine.

“These various applications work synergistically,” said Jeffrey Schlom, co-director of NCI’s Center for Immuno-Oncology.

Some cancer patients can skip treatment, two studies show

Research is growing, but experts warn that widespread use of cancer vaccines is still years away. Nevertheless, they predict that their use will become standard practice.

“We are setting the stage,” says Finn. “In the future, I think there will be times when doctors will be able to identify the risks of certain cancers and provide vaccines to prevent them.”

Schlom agrees. “It’s happening when we speak: more trials, more progress,” he says. “The best way I think about it, in terms of immunotherapy, hasn’t come yet. It’s only a matter of time. I’ve stepped into the door and now I’m opening it.”