More Positive News on Treating Blood Cancers Through the Immune System Instead of Chemotherapies
A good weekend for news on progress against blood cancers. The news is coming out now because the weekend and first part of this week are the dates for the annual meeting of ASH (the American Society of Hematology), the major national group of researchers and doctors focused on blood diseases, including cancers arising in the blood system.
One new approach rejects chemotherapy in favor of taking steps to activate the immune system in ways that will let it destroy the cancer. The work has been ongoing for for some time, and another success was formally released this weekend. It’s a story of using a modified version of the HIV virus to invade and then destroy B cells. The B cells are targeted because they are the aberrant cells in various blood cancers.
The results create hope and excitement. The most recent instance involves the first use of this method to treat a child. Here, that child is Emma, a 7 year old. For her, science had run out of answers, and hope was dwindling. Today, she is in complete remission. It’s too early to say the remission will remain, but for now, she is a kid with a future. The story is told well in this NYT article by Denise Grady. The first person treated with this therapy was treated over two years ago, and remains in remission, as described last year by Ms. Grady.
How does it work? Conceptually, it’s simple – train T cells to recognize, enter and destroy B cells through use of a modified strain of HIV, and make sure they stay around. But of course, hitting a hole in one also is conceptually simple. The longer, real world version is described in this excerpt from the story last year after a year of success with the first patient, Mr. Ludwig. Note the length of the journey – 30 years (or more), depending on where one starts counting, and that the "war on HIV" produced these collateral benefits. It’s hard to overstate the value of learning the real inner workings of our many types of cells.
"Hitting a Genetic Jackpot
To make T-cells search out and destroy cancer, researchers must equip them to do several tasks: recognize the cancer, attack it, multiply, and live on inside the patient. A number of research groups have been trying to do this, but the T-cells they engineered could not accomplish all the tasks. As a result, the cells’ ability to fight tumors has generally been temporary.
The University of Pennsylvania team seems to have hit all the targets at once. Inside the patients, the T-cells modified by the researchers multiplied to 1,000 to 10,000 times the number infused, wiped out the cancer and then gradually diminished, leaving a population of “memory” cells that can quickly proliferate again if needed.
The researchers said they were not sure which parts of their strategy made it work — special cell-culturing techniques, the use of H.I.V.-1 to carry new genes into the T-cells, or the particular pieces of DNA that they selected to reprogram the T-cells.
The concept of doctoring T-cells genetically was first developed in the 1980s by Dr. Zelig Eshhar at the Weizmann Institute of Science in Rehovot, Israel. It involves adding gene sequences from different sources to enable the T-cells to produce what researchers call chimeric antigen receptors, or CARs — protein complexes that transform the cells into, in Dr. June’s words, “serial killers.”
Mr. Ludwig’s disease, chronic lymphocytic leukemia is a cancer of B-cells, the part of the immune system that normally produces antibodies to fight infection. All B-cells, whether healthy or leukemic, have on their surfaces a protein called CD19. To treat patients with the disease, the researchers hoped to reprogram their T-cells to find CD19 and attack B-cells carrying it.
But which gene sequences should be used to reprogram the T-cells, from which sources? And how do you insert them?
Various research groups have used different methods. Viruses are often used as carriers (or vectors) to insert DNA into other cells because that kind of genetic sabotage is exactly what viruses normally specialize in doing. To modify their patients’ T-cells, Dr. June and his colleagues tried a daring approach: they used a disabled form of H.I.V.-1. They are the first ever to use H.I.V.-1 as the vector in gene therapy for cancer patients (the virus has been used in other diseases).
The AIDS virus is a natural for this kind of treatment, Dr. June said, because it evolved to invade T-cells. The idea of putting any form of the AIDS virus into people sounds a bit frightening, he acknowledged, but the virus used by his team was “gutted” and was no longer harmful. Other researchers had altered and disabled the virus by adding DNA from humans, mice and cows, and from a virus that infects woodchucks and another that infects cows. Each bit was chosen for a particular trait, all pieced together into a vector that Dr. June called a “Rube Goldberg-like solution” and “truly a zoo.”
“It incorporates the ability of H.I.V. to infect cells but not to reproduce itself,” he said.
To administer the treatment, the researchers collected as many of the patients’ T-cells as they could by passing their blood through a machine that removed the cells and returned the other blood components back into the patients’ veins. The T-cells were exposed to the vector, which transformed them genetically, and then were frozen. Meanwhile, the patients were given chemotherapy to deplete any remaining T-cells, because the native T-cells might impede the growth of the altered ones. Finally, the T-cells were infused back into the patients.
Then, Dr. June said, “The patient becomes a bioreactor” as the T-cells proliferate, pouring out chemicals called cytokines that cause fever, chills, fatigue and other flulike symptoms.
The treatment wiped out all of the patients’ B-cells, both healthy ones and leukemic ones, and will continue to do for as long as the new T-cells persist in the body, which could be forever (and ideally should be, to keep the leukemia at bay). The lack of B-cells means that the patients may be left vulnerable to infection, and they will need periodic infusions of a substance called intravenous immune globulin to protect them.
So far, the lack of B-cells has not caused problems for Mr. Ludwig. He receives the infusions every few months. He had been receiving them even before the experimental treatment because the leukemia had already knocked out his healthy B-cells."