For years, researchers have longingly eyed the human immune system as a potentially powerful weapon against cancer. Yet while the prospect of getting the body’s antibodies and immune cells to seek and destroy cancer — the same way they do bacteria and viruses — seems like a home run in theory, it hasn’t proven to be very reliable.
The reason has to do with the very nature of cancer itself: cancer cells aren’t invaders, but healthy cells gone rogue. So, targeting tumors often means having to target innocent, healthy tissue as well. That’s why cancer vaccines and immune-based treatments have had such mixed success.
But last weekend, at the annual meeting of the American Society of Clinical Oncology (ASCO), researchers reported on a promising advance: Dr. Kimberly Blackwell, director of the breast cancer program at the Duke Cancer Institute, said that she and her colleagues had successfully treated 991 women with advanced and metastatic breast cancer with an innovative “smart bomb” of a therapy, an antibody designed to bind only to tumor cells and then deliver its killer payload, an uberpowerful toxin, to destroy them. The idea is eloquently simple, yet, says Blackwell, it was a dozen years in the making.
The key was finding a way to ferry the toxin straight to breast cancer cells while bypassing healthy tissues along the way. The answer was an antibody that recognizes a protein called HER2 on certain breast cancers. Once attached to the HER2 on the cancer, the antibody and its partner toxin enter the cell where the antibody is broken down, releasing the toxin to destroy the cell from the inside out.
In the study, this new drug, called T-DM1, delayed worsening of disease by three months in women who received it, compared with those taking two other commonly used drugs. For women who got T-DM1, their disease did not progress for 9.6 months, compared with 6.4 months for the other group. The data also hinted that T-DM1 could extend women’s lives, but the study wasn’t long enough to determine survival.
(VIDEO: Beating Cancer from the Inside Out)
Because the drug was so targeted, it also spared patients many of the worst side effects of chemotherapy, including hair loss, nausea and vomiting.
“This is important proof of principle that the time has come for this type of therapy,” says Dr. Michael Link, president of ASCO and professor of pediatrics at Stanford University School of Medicine. “Historically, people have talked about using antibodies as a way of targeting cancer cells specifically. We know people’s immune systems do this quite well. The question has been how to jury-rig the system for anti-tumor purposes.”
Previous attempts at co-opting the body’s own immune system in the war against cancer have included using antibodies simply to locate tumors and then send up molecular flares to alert the immune system’s killer cells to their presence — much the way antibodies do for invaders of the bacterial or viral variety. But because cancer cells retain the legacy of their healthy states, antibodies turned out not to be very effective at raising the alarm against them.
What Blackwell and her team did was to attach a payload of toxin to their antibody, which was in this case trastuzumab (the T in T-DM1), also known as Herceptin, a Genetech drug designed to treat HER2-positive breast tumors. Herceptin attaches only to tumors that have the HER2 protein — the type of tumor that all the women in the study had. The other part of the drug, DM1, is a toxin and linker molecule that smuggles the DM1 past healthy cells, so that it was only active once inside the cancer cell. That explains the drug’s good side-effect profile. “This is an amazing change in the way we are going to be able to take care of patients once this drug becomes available,” says Blackwell.
Indeed, there are dozens of other smart drugs in development, including those that harness the immune system in different ways. At ASCO, researchers also presented data on a new treatment by Bristol-Meyers Squibb that a blocks a protein called PD-1 found on T-cells, crucial soldier cells of the immune system. Many cancer cells produce a molecule called PD-L1, which binds to PD-1 and inactivates the killer T-cells, thus making the tumor “invisible” to the body’s immune system. Bristol’s drug is an antibody that takes down that molecular shield by preventing PD-1 from binding to PD-L1. In studies, the drug shrank melanoma, kidney and some lung tumors that had resisted treatment with other drugs. And because this drug also appears to be very targeted, researchers expect it to cause fewer side effects than other drugs.
Blackwell is eager to continue her studies with such immune-based approaches as well. She says that even existing immune-based treatments aren’t taking full advantage of what the immune system can do: for example, drugs like trastuzumab, which stimulates the immune system to some extent, can be made much more powerful as a ferry for chemotherapy agents. “We are able to improve survival by giving an antibody to stimulate the immune system against cancer, but at the same time we’re also giving toxic chemotherapy that hurts the immune system — it doesn’t make sense,” she says. “I think that’s one potential reason why we saw such tremendous benefit in the [T-DM1] study — we allowed trastuzumab to work better because we spared the immune system.”
The idea, she says, is to move toward immune-aided cancer treatments that allow the immune system to fight cancer without being weakened by chemotherapy. “I’m convinced that my patients’ immune systems are fighting cancer as much as anything we can give them to battle the cancer,” says Blackwell.
If that’s the case, then researchers’ priority will shift toward identifying as many cancer-specific proteins as possible, and then developing antibodies that can home in on those proteins with targeted toxins. Ultimately, says Blackwell, it may even be possible to fight cancer with just these carefully crafted molecular smart bombs, and without relying on standard chemotherapy at all.
For now, the strategy behind drugs like T-DM1 is somewhat limited: this new drug benefits patients only with HER2-positive breast cancers, which leaves out up to 80% of breast cancers. But scientists are continuing to identify the various proteins and molecules that wily cancer cells use to evade the body’s immune system, and experts expect to see a flood of new treatments coming down the pike. “I think the implications of this are quite exciting in terms of the possibilities we will have for using the technology in other tumors,” says Link. “This is a technology whose time has clearly come.”