A Hopeful Headline
In a new study published in the New England Journal of Medicine, researchers cured cancer using modified HIV viruses to turn the patient's own white blood cells into “cancer cell serial killers”. This gene therapy technique was tested in three patients afflicted with B-cell neoplasms, a form of leukemia. , (Perhaps start a new sentence and discuss one patient who one who had been continually diagnosed with the disease since 1996 and the other patients with advanced or chronic or …?. Over the course of six weeks, the disease disappeared from two of the patients entirely and was reduced by 70% in the third. The most serious side effects observed were similar to an intense fever, and one year later the disease remains in remission.
Researchers are hopeful that, based on these initial results, they have developed a powerful new treatment which may help those diagnosed with B-cell neoplasms and other forms of cancer.
The Science of Leukemia
Leukemia is a type of cancer which primarily afflicts the bone marrow and blood cells. Up to 250,000 people worldwide are diagnosed with it every year, and 210,000 die from it. It is the eleventh most common form of cancer, but the most common variety diagnosed in children. Depending on the type it causes tumors in the bone marrow and/or uncontrolled multiplication of certain blood cells.
Leukemia can treated by many avenues, but is notoriously difficult to eradicate completely. In later stages, cancerous cells may multiply so wildly that they crowd out healthy, functioning blood cells, or infiltrate internal organs and grow into tumors. Tumors can also develop in the bone marrow itself.
Treatments almost always include chemotherapy targeted at the type of leukemia the patient has, as well as radiation therapy if malignant tumors are present. Another common procedure is the bone marrow transplant, also called hematopoietic stem cell transplantation (HSCT). Hematopoietic stem cells exist in bone marrow and have the ability to divide and transform into any type of blood cell. In a healthy person the bone marrow continually replenishes blood cells that wear out with fresh-grown replacements. In advanced cases of leukemia, unhealthy cells can accumulate in the marrow, continually producing diseased cancer cells no matter how many times they are cleansed from the blood stream. An HSCT procedure removes healthy stem-cell containing bone marrow from a compatible donor and transfers it to the patient, replacing the cancerous marrow.
HSCT is a powerful tool, but is fraught with potential complications. Bone marrow produces blood cells of all types, including white blood cells whose job it is to attack anything they encounter that is foreign or unfamiliar. When white blood cells from a donor find themselves in a new body, they can sometimes confuse it with dangerous foreign material and attack. When this happens, it is called graft versus host disease, and it is extremely dangerous.
The graft versus host phenomenon and its underlying medical causes have been known since early immunology experiments with mice in the 1940's. In the 1980's, researchers began to observe a similar effect with positive ramifications for the patient, which was christened the graft versus tumor or graft versus leukemia effect. Like in graft versus host disease, donor white cells recognize parts of the host as foreign and attack. In this case, however, they specifically single out and attack leukemia cells, slowing the progress of the cancer. Unfortunately, the strength of the graft versus tumor effect is generally linked with the severity of the graft versus host disease, requiring a balancing act on the part of attending oncologists to keep the patient alive while combating the cancer as aggressively as possible.
There has been a lot of interest among researchers to develop treatments which take advantage of the graft versus tumor effect without the drawback of graft versus host disease. A number of projects have attempted to manufacture white blood cells, which would target only cancer cells while leaving healthy ones alone.
A new avenue
Reprogramming a cell requires the use of an advanced and controversial technique known as gene therapy. Gene therapy allows researchers to edit the DNA of target cells directly, rewriting the code of life in order to treat a disease. Since cancer is often the result of dangerous mutations in a cell's DNA, gene therapy is ale to rewrite the cancer cells' genes to turn of their malignancy, rendering them dormant or harmless.
Unfortunately it can be difficult to find all the malignant cells and edit their DNA, and a single surviving cancer cell may eventually multiply and reestablish the disease. In addition, the genetics of cancer are vastly complex and poorly understood, making it hard to know how exactly what changes to make to cure the patient. Even if a particular sequence could be singled out as the culprit, cancer is an individual disease that manifests in varying, often unique ways in different patients. A gene therapy regimen may have to be individualized in order to maximize its effectiveness, a slow and very expensive prospect.
Dr. June and his collaborators chose a different approach. Instead of finding and rewriting the cancer cells, they chose to use gene therapy principles to reprogram the host's own white blood cells, which are already specialized at hunting down contaminants and attacking them. These modified cells would be told how to recognize dangerous cancer cells, which normally hide from white blood cells because they look so similar to the rest of the body.
The result would hopefully be what the study's authors call “cancer cell serial killers”. If it worked, it would be the most advanced form of immunotherapy ever administered, skirting many of the dangers of chemotherapy and HSCT by using the patient's own reprogrammed immune cells to fight off the cancer.
How to build a cure for cancer
The researchers chose a kind of white blood cell called T-cells to be their tool. T-cells are the body's assassins, pillars in its defense against infection and contamination that specialize in binding and killing enemy cells. They are the rank and file, seeking out foreign bodies and going where they are directed by the rest of the immune system, but for this project the researchers taught them a few new tricks.
Before the reprogrammed cells can get to work, researchers need a way to deliver their instructions to the interior of the cell and edit the DNA. This is a complex task requiring precision at the molecular level, a technique far beyond the capability of researchers to accomplish directly. To do it they again co-opted machinery that evolved in nature for a very different purpose. In this case they took a virus, usually known for causing disease, and re-purposed it to deliver their package to target white blood cells.
Many scientists do not consider viruses to be living things, in part because they are unable to reproduce alone. Instead they invade a host and hijack its reproductive capabilities to produce copies of themselves. A particular group of viruses, called retroviruses, actually do this by editing the host cell's DNA. If a virus could be altered to edit DNA in a particular, useful way, it would allow researchers to reprogram a target cell indirectly.
HIV, the virus responsible for AIDS, is perhaps the most famous and feared of the retroviruses. It specializes in infecting immune cells, particularly T-cells, killing them off as its first wave of attack while tricking them into producing millions of copies of the virus. In an ironic twist, the same qualities that make it so devastating to an infected immune system also make it the perfect tool to deliver the package of genetic material which turns a normal T-cell into a cancer killer.
Researchers of course removed the parts of the genome that lead to AIDS, leaving only the instructions needed for slipping into the cell and changing the host DNA. With AIDS this process tricks the host cell into producing copies of HIV, but the researchers edited those instructions as well. By piggybacking HIV's normally deadly lifecycle, the researchers now had a way to tell a white blood cell to do whatever they wanted.
Anti-cancer vigilantes
Being able to order someone around, of course, tends to be the easy part. Researchers still had to tell the T-cell what to do. They could tell it to ignore its usual restraints and attack the leukemia, but an indiscriminate killer could prove as dangerous to the patient as to the cancer. Researchers had to teach these T-cells to tell the difference between healthy cells and dangerous ones.
B-cell neoplasms involve the aggressive and out-of-control multiplication of B-cells, a type of white blood cell. B-cells produce antibodies, tiny pieces of protein which find and identify foreign contaminants. Antibodies and the B-cells that produce them are scouts for the rest of the immune system's army.
In another example of adapting natural tools for medicinal purposes, researchers used the ability of antibodies to recognize very specific targets as part of the treatment. Every type of cell in nature has different surface markers, they “look” different on a chemical level. Because those differences are microscopic it's hard to recognize them, though many white blood cells have evolved for that very purpose. Antibodies in particular are extremely good at noticing the subtle differences between a liver cell, a bacterial cell, and a B-cell because of their function as the immune system's scout.
Normally the body does not produce antibodies which could attack its own cells. When it does, the patient experiences what is known as an autoimmune disorder. Arthritis and Lupus are common autoimmune disorders, as is graft versus host disease. In the latter case donated white blood cells don't recognize the host's unfamiliar cell markers as “friendly”, and attack. This is why most cases of graft versus tumor treatment involve an associated graft versus host disease; antibodies that target canerous tumors also tend to target other, healthy parts of the patient's body.
Antibodies can be specific enough to attack the cancer and not the rest of the patient, if you know how to get them to tell the difference. In B-cell neoplasms, the researcher's approach was simply to teach antibodies to recognize B-cells. In yet another ironic twist, the very weapons employed by B-cells to defend the body are adapted as weapons used to attack them when they go rogue. Thanks to the modified HIV virus, they can then implant those antibodies in a T-cell's DNA, creating a dedicated killing machine whose sole target is cancerous B-cells.
Persistence is key
While the science that creates these cancer hunting T-cells is exciting, other groups have attempted to make them before. The problem so far has been that the T-cells work for a little while, but soon die off, allowing the cancer to quickly reassert itself. In healthy individuals those cells would be soon replaced by the bone marrow, but the diseased marrow of leukemia patients is unable to do this, and the modified T-cells are introduced from the outside in the first place. A method was needed to ensure that modified T-cells are around for the many months needed to clear the cancer completely.
The researchers working in this study tried out a particular gene known as CD137, which had been observed in other studies to enhance the lifespan and replication of T-cells. By including it with the DNA package delivered by the HIV derived viral vector, they hoped to increase the longevity of the treatment.
The clinical results were striking. In previous trials, modified T-cells without the enhanced longevity were administered to patients, but steadily declined in number and effectiveness over the following days. When the patients were examined three weeks after the initial infusion of T-cells in this study, the cells had multiplied a thousand fold.
Soon patients experienced a condition known as tumor lysis syndrome. Symptoms include muscle weakness, seizures, blood toxicity, and others. While the condition is serious and can be fatal, there was a bright side: tumor lysis syndrome occurs when the body is overloaded by debris from dying cancer cells. Patients lost as much as five pounds of cancerous tissue in those weeks as the T-cells purged them from their bodies.
“It was like the worse flu of their life,” said Dr. June. “But after that, it's over. They're well.”
Three months later, the cancer was in remission and levels of the synthetic T-cell remained high. Tumors could no longer be detected in two of the patients at all, and had shrunk by 70% in the third. No symptoms of the cancer or tumor lysis syndrome were apparent, though a few side effects of the treatment necessitated further medication. In hunting down the cancer cells, the T-cells indiscriminately wiped out all B-cells present in the body. While this side effect was expected, it does severely compromise the immune systems of the patients, exposing them to infections. In cases of terminal cancer, a patient surviving to worry about this complication is a step in the right direction.
As the patients were monitored following their dramatic recoveries, another benefit of the treatment became apparent. Some of the synthetic T-cells had made the transition to “memory” T-cells. Once a disease has been fought off, some T-cells become dormant as an insurance policy for future attacks. If the disease were to reappear, these memory T-cells would reactivate and multiply in order to fight it off. Researchers are hopeful that their presence will grant a lasting ability to fight off any reemergence of the patients' leukemia.
One year after treatment, the patients' physicians haven't detected any resurgence of the disease. Following the publication of their findings in the New England Journal of Medicine, the study's authors are sure to expand the trial to include more patients, and other groups are looking to adapt the technique to other types of cancer. The reaction by experts in the field has been very optimistic and positive, with certain reservations with regards to the treatment's long term effects.
What's next
Physicians and researchers are not the only people likely to show great interest in the treatment. Patients suffering from B-cell neoplasms, as well as any form of cancer that might benefit from this experimental treatment, will be asking their doctors about it in the months to come. Since it is still in phase I clinical trial, the total number of patients that can benefit from it is limited and patients will be carefully screened to see if they meet the criteria for the trial. The treatment is also very complex and expensive, and it will take a great deal of time for clinics around the country to gain the expertise and equipment required to administer it.
There is also the question of long-term effectiveness and side effects, which won't be answered until the patients can be observed over a longer time period. The lack of B-cells in treated patients is sure to expose them to further health complications, and the T-cells themselves may exhibit unpredictable behaviors over longer time frames.
All of these observations, as well as an expansion of the number of test patients benefiting from the treatment, will form the rest of its phase I clinical trials. It is impossible to know how long this phase will last, though several years of continued testing and observation is a certainty. Upon entering phase II, the scope and availability of the treatment will expand, but its a long and expensive road to get there.
Whatever the results of this long process, at least three patients have received the treatment and are thankful for the extra time it affords them. Before Bill Ludwig was inducted into the study one year ago, he was told that the leukemia would kill him within weeks. "I'm more closer to the people I love and I appreciate them more... I'm getting emotional... the grass is greener and flowers smell wonderful," he said of his recovery.
Another patient , himself a former scientist, released an anonymous statement. “I am still trying to grasp the enormity of what I am a part of – and of what the results will mean to countless others with CLL or other forms of cancer. When I was a young scientist, like many I’m sure, I dreamed that I might make a discovery that would make a difference to mankind – I never imagined I would be part of the experiment.”
The Bottom Line
The study done by Dr. Carl June and his collaborators at the University of Pennsylvania took patients' own immune systems and programmed it with a modified HIV virus to recognize and destroy cancer cells. It avoids the destructive side effects of marrow transplantation while harnessing their strengths. The side effects of the treatment are manageable but potentially serious over the long term, though not nearly so serious as the cancer if left untreated. By programming the cells to multiply and persist in the patients' bodies, the study has advanced the fledgling science of immunotherapy, raising hopes that it may someday replace the toxic chemotherapy that currently dominates cancer treatment.
Much progress been made over the decades in combating cancer, yet many seeming miracle treatments have turned out to have serious negative ramifications, or limitations not anticipated during their development. With that in mind, this study will still give great hope to patients fighting cancer, their families who suffer with them, and to the doctors who deal with the tragedy of cancer every day.
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