Experimental Cancer Treatment That Terminates Rogue Cells Could Arrive in 2017

CAR T-cell therapy, a cutting-edge immunotherapy technique, is engineered to target cancer at a cellular level.

If there were such a thing as a cancer silver bullet, it would be something that only targets those cells in your body that have gone rogue, while leaving the rest of you unharmed.

This prospect more or less sums up the hopes for CAR T-cell therapy (also known as CAR-T), an experimental cancer immunotherapy that basically sends out cells that are bioengineered to target and terminate cancer - and only those cells.

There are more than 100 CAR-T clinical trials currently underway worldwide, and the U.S. Food and Drug Administration is expected to approve the first CAR T-cell therapy, from the biotech company Kite Pharma, in 2017. Researchers have seen promising results so far, but there have also been tragic outcomes, with five patients dying while undergoing treatment during clinical trials this past year.

'Biological Assassin'

When it works, CAR-T turns the body's immune system against the cancer through the introduction of a custom-made "biological assassin," according to Ezra Cohen, associate director of translation science at University of California, San Diego (UCSD) Moores Cancer Center.

"You're essentially taking a regular cell and engineering it to attack a very specific target," Cohen explained. "And you're equipping that cell with everything that it needs to get activated to essentially release its payload or its poisons to kill that target cell."

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The acronym "CAR" stands for chimeric antigen receptor. These are proteins that are engineered into T cells to hunt down cancer. The receptors are an artificial combination (chimera) of the corrupted cells and the activation sequence that takes effect when a specific protein found in a cancer cell is encountered. The result is a made-to-order seek-and-destroy T cell.

Not all patients will receive their own custom cancer homing missile, however. A number of factors go into determining eligibility. For now, CAR-T is primarily reserved for patients for whom standard, front-line treatments have not worked.

"Right now, it's not the primary treatment for the treatment of disease," noted Jeffrey Sosman, an oncologist at Northwestern Memorial Hospital. "It's a secondary treatment when patients have failed the first line of treatment. That may change over time, but that's just the way it is for now."

If an effective traditional therapy is available to a patient, forgoing the established course to try an experimental method instead could be unethical.

Patients need to be physically healthy enough to tolerate some of the potential health effects that come with CAR-T treatment. Side effects can range from debilitating to lethal in the worst circumstances, and may include high fever, low blood pressure, swelling, confusion, pulmonary edema and cardiac failure, among other things. These are all within the bounds of what is known as cytokine-release syndrome, a potentially life-threatening condition commonly seen in some immunotherapy treatments.

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There's one other major requirement - the biggest hurdle, in fact.

"You need a good target, and that's probably the biggest obstacle to this kind of therapy," Cohen said. "We found a good target in leukemias and lymphomas. In solid tumors, it's been a bit more evasive."

The target protein has to be exclusively associated with the type of cancer cell that the treatment is designed to kill. If it occurs in other types of cells, the results could be disastrous. Even successful immunotherapy treatments can destroy healthy cells, and researchers concede that achieving pinpoint accuracy remains a major challenge. Unfortunately, there have already been cases in which CAR-T patients have died.

Last month, two patients died in a CAR-T clinical trial being conducted by Juno Therapeutics, while three patients died in the same trial earlier in the year, according to MIT Technology Review. Kite Pharma had also reported a death during one of its own trials in 2015, but determined that it was not cause by the treatment.

Does It Work?

Cohen points to early successes following a UCSD study that provided CAR-T treatment to patients who had already tried traditional cancer therapies and saw little or no improvement.

"One of them is an 11-year-old child who didn't have really any other treatments available, and now appears to be cancer-free," he said. "Another is a man with a family, who again had lymphoma. The cancer failed all conventional therapies and now appears to be in remission."

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"There's no question that the most effective and clearly major breakthrough has been in lymphoid malignancies, and that includes acute lymphoblastic leukemia and non-Hodgkin's lymphoma," said Sosman.

What these have in common is a protein called CD19. The T cell will target and destroy cells with that protein. Because other tumor cells have their own unique antigen, T cells need to be reprogrammed to specific cancers.

"And that's been the difficulty so far: finding the right protein or antigen to be recognized [by the T cells] that isn't seen in normal cells," Sosman explained.

While the type of tumor matters, size isn't an issue. Even patients with very large tumors have responded to CAR-T, Sosman added.

Future Outlook

For situations where CAR-T has been shown to work, the immunotherapy technique could well prove to be an effective option before patients have exhausted every possible conventional treatment.

The next push in the field of immunotherapy for cancer is personalization, according to Cohen. No two cancers are alike; the same goes for our immune systems. Future treatments will match the uniqueness of each cancer case with the distinctiveness of each individual's immune system.

This future is not necessarily far off. Scientists already have the ability to genetically sequence cancer and identify how an individual's immune system responds to that cancer in order to devise effective treatments for the patient. And while it's unlikely that the advent of CAR-T will soon push traditional treatments from the front line to the back bench of the medical establishment, its potential impact could be profound.

"If one uses their imagination - and honestly it's not that far-fetched - you can begin to think how immunotherapy is going to replace surgery in many settings, replace radiation therapy, and, I think, for many patients, replace chemotherapy," Cohen said. "But at the same time, I see many settings where we learn to combine immunotherapy with all those things."

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Top photo: This electron micrograph shows an immunotherapy treatment in action. Two T cells (red) attack a cancer cell (white). Credit: R.E. Serda/National Cancer Institute and Duncan Comprehensive Cancer Center at Baylor College of Medicine