Dov Michaeli
First posted 10/02/11 on The Doctor Weighs In
Yes, you read it right: the dreaded AIDS virus provided a breakthrough in the search for cancer treatment. In a brilliant Jiu Jitsu maneuver University of Pennsylvania scientists (Dr. Carl June and his group) turned the strength of the virus into an advantage to the patient.
Here is the background to their feat.
There are 2 types of lymphocytes (white blood cells): T cells and B cells. T cells are the “generals,” directing the attacks on non-self interlopers, like bacteria, viruses and virus-infected cells, and importantly –cancer cells.
But generals need warriors to carry out the attack, and this function is left to the foot soldiers, the B cells, which are basically factories of antibodies. The T cells get “educated” as to the nature of the attackers through contact with them. They do it by recognizing specific molecules (receptors) on the surface of the cancer cell. Then they select the B cells that are most likely to make antibodies that would attach those receptors.
All this has been known for over 50 years, and attempts to “educate” T cell to initiate an attack on tumor cells started about 20 years ago. But despite the best minds and the most sophisticated approaches, they fell short. At best, the T cells mounted a feeble attack that fizzled out in a couple of months. Then came the brilliant, and I might add, gutsy, experiment.
Aren’t AIDS viruses attacking T cells? Of course, so why not use these bad viruses to serve as vectors, or carriers, of genes that will arm the infected T cells with the right membrane proteins that will recognize the tumor cells of CLL (Chronic Lymphocytic Leukemia), which are…B cells. Yes, CLL is a malignancy of B cells, and directing the T cells to attack those malignant B cells is just what is needed. What about the non-malignant B cells? Let’s worry about that later.
To make a long story short, it worked! T cells were obtained from the patients’ blood, infected with modified AIDS virus that had been
engineered to carry genes that will endow the T cells with the proteins that will help it home in on the B cells (think of smart missiles). And (sigh of relief) the virus was deprived of the genes that allow it to proliferate inside the cell thus rendering it, well, impotent.
The three patients that were treated became sort of a bioreactor: the cells started dividing at a rapid rate, each cell making 1000 progenies in 3 weeks. Those cells mounted a furious attack on the B cells, malignant and non-malignant alike, and eliminated them completely; no sign of disease by blood test, CT scans of lymph nodes, and histopathology of the bone marrow. The picture below is an electron microscope picture that caught a T cell (the small one) in the act of attacking a tumor cell. Don’t let the size fool you: the T cell is a professional killer, using a variety of proteins and other molecules that deliver a knockout punch to the larger tumor cell.
What about the elimination of the normal B cells? The patients became deficient of gamma globulins, the protein of which antibodies are made. Fortunately, we know how to treat this problem: intravenous infusion of immunoglobulins (IVIG) every three months, obtained from blood donors like you.
One serious complication: cytokine storm. The T cells attack was so effective that massive amounts of tumor (and non-tumor) B cells were
destroyed in a very short time, and this is too much of a good thing. When cells lyse (break down) they release a bunch of proteins that cause some bad things, like fever, low blood pressure, even kidney failure. Two patients, each receiving an infusion of about a billion cells, experienced within 10 days life-threatening fever, low blood pressure and kidney problems. They were transferred to the ICU, and for two weeks their lives were hanging by a thread. But they survived and are still cancer-free, 10 months after the treatment.
The third patient merited a separate report in the August 25 New England Journal of Medicine. For some technical reasons the investigators could not coax the T cells they had obtained from the patient to divide to the 1 billion cells-level they needed to infuse into the patient. They got only 15 million cells. They were on the verge of ditching this experiment, but then decided to administer this puny number of cells anyway. Lo and behold, the cells proceeded to divide at the same furious rate, and 20 days later the cytokine storm set in. But unlike the first patients who thought the “storm”signified failure and were psychologically getting ready to depart this world, this one knew that it meant that the T cell army is on the attack destroying the enemy, and that he will survive. And he did!
Oh, yes, more great news. The T cells that proliferated inside the patients didn’t just expend all the ammunition on killing B cells. A proportion of them became “memory cells”, a reservoir of cells in the bone marrow that keep dividing and replenishing the older cells that are ready to call it quits and die off. I can’t think of a better gift than the one that gives on giving. As we said, it is already 10 months out, the T cells are still going strong and the patients are cancer-free.
A Victory Dance?
Not yet. More CLL patients will have to be treated before pharmaceutical companies get convinced that there is gold in them thar T cells. And they will then have to embark on the grueling process of making the invention clinically useful, in other words- scale it up to mass production.
And don’t forget, this was geared to CLL. Other cancers, like pancreatic and ovarian, are very difficult to treat, and a lot of spade work will have to be done to identify proteins on their membranes before T cells can be “educated” to attack them. And what if these proteins, or antigens, are shared with normal tissues? In the case of normal B cells being obliterated it’s really no big deal – just administer immunoglobulins with IVIG every so often. But what if the pancreatic cancer genes are shared by the liver? Or by some other vital organ? As you can appreciate- it ain’t over ‘til it’s over.
But let’s not lose sight: this work is a veritable breakthrough. The work ahead is arduous, the problems are tough – but the principle was proven in a spectacular way.
Dov Michaeli MD, PhD is a cancer researcher who writes at The Doctor Weighs In.
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