The body’s immune system is often likened to an army, and vaccines to training exercises that build up defenses against pathogens. By exposing the immune system to inactive forms of a virus or bacteria, a vaccine trains antibodies to fight off a real pathogen in the event of an invasion. However, while vaccines prepare antibodies to identify an attacker, they often don’t give specific instructions on exactly how to bring it down. Some antibodies may successfully hit a pathogen’s weak spot, while others may miss the mark entirely. That’s part of the reason why it normally takes several weeks or months for some vaccines to build up an effective immune response.
Now researchers at the Scripps Research Institute have developed preprogrammed chemicals that bind to antibodies and tell them how to recognize part of a pathogen, known as its epitope. In experiments, the team found that such chemicals prompted a therapeutic immune response that inhibited the growth of two types of tumors in mice. The researchers published their findings in the latest issue of the Proceedings of the National Academies of Science.
“We used a chemistry-based approach that wouldn’t induce antibodies that might be wasted,” says Carlos Barbas, a professor of molecular biology and lead investigator on the paper. “[This approach] could focus an immune response on functional epitopes of the pathogen, be it cancer or a virus.”
The group’s chemical-based vaccine may address a number of problems with some current vaccines, both in the clinic and in the lab. Today, there are only two FDA-approved, licensed cancer vaccines: one that targets Hepatitis B associated with liver cancer, the other for human papillomavirus (HPV), which leads to cervical cancer. For both vaccines, patients must go in for multiple immunizations to build up an effective defense over time. There are no licensed therapeutic vaccines that directly treat existing cancers, and researchers have found it difficult to train antibodies to attack cancer cells, since they arise from the body and are not generally regarded by the immune system as foreign.
In the past few years, however, researchers have identified cell-surface markers unique to cancer cells. There are molecules called adjuvants that attach to such markers and trick the immune system into recognizing and attacking tumors. Adjuvants are used in clinics today, but some come with unwanted side effects–for example, soreness, fever, and arthritis. Scientists are now looking for ways to genetically engineer monoclonal antibodies–antibodies created from a single cell line–to recognize tumor markers and attack cancer. But these methods are expensive, and Barbas says that a chemical-based approach may provide a cheaper and faster alternative.
Barbas and his team developed a two-stage chemical strategy that first puts the body’s antibodies on alert, and then gives them instructions on which targets to destroy. In the first stage, Barbas designed a chemical that, once injected, enables antibodies to form covalent bonds. Normally, antibodies cannot form such bonds. The second stage involves injecting a small adapter molecule with two parts: one that bonds covalently with antibodies, and the other that binds with a specific epitope, or cancer marker. When injected, this adapter molecule links with antibodies and then seeks out and attaches to a target’s specific epitope. The method is essentially like handing antibodies a beeper and putting them on standby. They wait around for a “call,” in the form of the adapter molecule, which, once connected, instantly leads them directly to a target’s weak spot, where the antibody can attack and deactivate the pathogen.
In their experiments, Barbas and his colleagues implanted tumors for colon cancer and melanoma into the flanks of mice and watched the tumors grow over time. They then injected mice with a chemical that “primed” antibodies, before injecting them again with adapter molecules that bind both with antibodies and with integrins–surface proteins found on each type of tumor. The researchers measured the volume of tumors up to a month after injection, then removed the tumors and weighed them. They found that those treated with the two-stage vaccine were significantly smaller than those removed from animals that had been injected with just the adapter molecules, or with a commonly used adjuvant vaccine. “The molecules we used can also bind human receptors as well,” says Barbas. “This could potentially translate directly into humans.”
Barbas says that it may be possible to tailor the new vaccine approach to other cancers and diseases. Researchers would have to first identify specific molecular markers for each disease, and then design adapter molecules that lead antibodies to bind to those markers.
“The challenges are just coming up with these targeting molecules,” says Barbas. “Certainly, a lot exist in the literature that can be used, but the fascinating ones we want to go after don’t exist yet. Recently, there’s an epitope in flu that was found that’s highly conserved, and we would like to design a small molecule that binds to that epitope and binds to an antibody. We’d also like to do the same thing with HIV.”
Howard Kaufman, director of the Mount Sinai Melanoma and Sarcoma Program, studies cancer’s immunosuppressive mechanisms, particularly in melanoma, and is beginning phase I clinical trials to test a melanoma vaccine. Kaufman says that Barbas’s vaccine technique represents a new way to treat cancer and other diseases. “It’s appealing as an approach,” says Kaufman. “It’s a way to get instant immunization as opposed to waiting for kinetics to develop T cell responses.”
Kaufman also stresses that more work needs to be done to figure out if the technique would work in humans. “It’s not clear if this is towards long-term protection, and it would be interesting to try and challenge mice who have rejected tumors with [another] tumor later, to see if they’re still protected,” he says. “That would be more relevant to the human situation.”
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