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article imageMaking smarter T cells to fight cancer Special

By Les Horvitz     Jun 29, 2015 in Science
Boston - The war against cancer was never supposed to last this long or be this grueling. To fight some of the most intractable kinds of cancer scientists are trying to come up with new therapies and new approaches to old therapies.
One of these efforts focuses on T cells, white blood cells which, together with B cells and natural killer cells, play a crucial role in directing and regulating the body’s immune defenses. There are several different types of T cells. Some types are designed to hunt for and destroy cancerous cells. Because they have antibody-like receptors on their surfaces, T cells are customized to recognize specific antigens or tumor markers. An antigen (or a fragment of an antigen) can signal the presence of a potentially dangerous substance which might be there because of an external invader — a virus, for instance — or because the body turns against itself (a self-antigen) which is what often occurs in cancer. Once the antigen is identified by the T cells, the body mobilizes, alerts other cells that there’s a problem, and produces antibodies to neutralize the threat.
T cells, however, don’t always recognize or find their targets. In the 1990s, scientists discovered a molecule on T cells which acted like “an off switch" or “a brake pedal,” preventing the T cells from doing their job and attacking the affected cell.
That got scientists thinking about whether they could engineer T cells to hone in on their targets more effectively while ignoring cells that were perfectly normal. Could they make “smarter, stronger T cells’?
One researcher who has committed herself to building just such a smarter T cell is Yvonne Chen, an assistant professor of Chemical and Biomolecular Engineering at the UCLA. Chen recently described her research on T cells at the Synthetic Biology: Engineering, Evolution & Design (SEED) conference in Boston.
The three-day gathering brought together representatives of pharmaceutical companies, biotech start-ups, postdocs and graduate students, all of whom shared an interest in synthetic biology, a genetic technology that’s one part biology and one part engineering.
Trying to harness the potential in T cells dates back to the 1990s when physicians began to use adoptive T cell therapy or T cell transfer (ACT) to treat leukemia and Epstein-Barr, a viral disorder.
In this therapy, T cells are harvested from a cancer patient, engineered to target the malignant tumor, and put back into the patient. In many cases, the therapy seemed to work and the disease went into remission. A number of pharmaceutical companies specializing in adoptive T cell therapy sprang up in response to the excitement. One start-up saw its stock price rise sixfold in a matter of months. But, as often happens with "cancer cures," T cell therapy didn’t live up to the hype. In one case, the reintroduced T cells never reached the tumor but went into the patient’s lungs instead, resulting in his death four days later. In other cases, the T cells caused adverse, sometimes fatal, side effects. Altogether, four patients treated with adoptive therapy died because the T cells didn’t do what they were supposed to. There were other problems, too: some of the customized T cells failed to recognize telltale antigens that should have signaled the presence of a malignant tumor, a phenomenon known as "antigen escape." Antigen escape may explain why some patients initially go into remission after treatment and then relapse. The T cells effectively eliminated those cancerous cells they could identify while leaving behind others they failed to spot which were then free to proliferate unimpeded. In addition, because many normal cells have some of the same antigens that cancer cells do, the T cells would get confused and target them as well, producing unwelcome side effects.
Rather than giving up on T cell therapy altogether, Chen and her colleagues have been focusing on a particular type of T cell called CARs (for chimeric antigen receptors) in the hope that they can create T cells “with stronger anti-tumor functions and greater robustness against evasive mechanisms employed by cancer cells.”
Creating a smart T cell is a painstaking process, Chen admits, and it’s still “a trial-and-error exercise.” But if these engineered cells can be trained to scout out malignant tumors that have so far eluded the best efforts of modern medicine to find and destroy them the effort will have been well worth it.
Ideally, a smart T cell should be able to recognize different kinds of antigens, increasing the chances that it will recognize tumor markers that unmodified T cells might overlook. A smart T cell should also distinguish between antigens on cancerous cells and identical antigens on normal cells. In addition, it should be able to root out cancers in places where they might be hiding out, undetected. Chen’s group believes that it has a solution. Using an approach that one researcher in Chen’s group calls "thinking inside the box," T cells would act like heat-seeking missiles that deliver a payload. Only the payload in this case would consist of specially engineered molecules that once inside the tumor cell would kill it. These deadly molecules are called SUMO killers (short for synthetic zymogene). If the T cell identifies the target as a normal cell, it will abort the mission and the sumo killer won’t be delivered.
The UCLA researchers have to deal with another problem: T cells don’t have a long life expectancy, meaning they can die before they can even get to the tumors. So Chen’s group has to figure out some way to extend the survival of these cells, but they have to be careful; if engineered T cells grow too robustly and live too long they can run amok and turn into cancerous cells themselves, which would mean that the cure won’t be worse than the disease, it will be the disease.
So far the results have been promising: In small clinical trials, engineered T cells have shown significant promise in patients with advanced lymphoblastic leukemia and lymphoma. Many of the patients in these trials, once considered untreatable, are now cancer free. If the CAR T-cells can sustain their effect over time they may be able to prevent remission, but the therapy is so new that scientists, physicians and patients will have to wait to find out. Many patients, for obvious reasons, are praying that it’s sooner than later.
More about Cancer, Synthetic biology, Yvonne Chen
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