Conventional wisdom about the best way to treat cancer has changed in our lifetime. For a while, the answer seemed to be chemotherapy, specifically the more chemotherapy the better. That’s what brought us bone marrow transplantation, a way to maximize chemotherapy dose by rescuing the “poisoned” bone marrow. There were many ways that chemotherapy could kill a cancer cell, most commonly by directly injuring DNA. But we soon learned that chemotherapy wasn’t going to do the job except in uncommon cancers like testis cancer.
Next came the biological agents. These were usually monoclonal antibodies targeting a specific marker on the surface of cancer cells, like Her 2 in breast cancer (Herceptin) or CD20 in lymphoma (Rituxan), or other molecules important for tumor survival, like Avastin (which attacked the blood supply). These antibodies either alone or in combination with chemotherapy killed the cancer cell. Sometimes this approach was effective, but it was limited by requiring a marker that was either preferentially expressed on the tumor cell or critical to tumor cell growth. And making these antibodies was very complicated.
About the same time as biological agents were developed, other “precision” therapies were added to the therapeutic armamentarium. These were generally small oral molecules that targeted cells that possessed a specific mutation (like EGFR). The mutated genes gave the cancer cell some growth advantage. But as I pointed out in my personalized medicine post, sometimes this approach was a home run but often it was much less spectacular. There were lots of mutations but not all of them had equal importance, and the number of mutations successfully targeted was fairly small.
More recently, we have entered the era of immunotherapy for cancer. For years we hoped that the immune system could be stimulated to attack cancer cells. We have known that the immune system is important in controlling cancer; patients who are immunosuppressed have a much higher incidence of cancer. Nonspecific immune stimulation, tried over several decades, yielded little. There was even an attempt to harvest immune cells from the blood and “educate and activate” them in the lab before reinfusing them. This treatment, called Provenge (Sipuleucel-T) was tested in prostate cancer. The results were confusing and controversial; the treatment didn’t cause the tumors to shrink but appeared to prolong the life of treated patients. There was extensive debate about whether the results were real, as there were many flaws in the trial. Despite what was (at the time) an exorbitant cost, Medicare and the commercial health plans paid for the treatment. But the treatment was really complicated to deliver and the real world results were not all that impressive, and so Provenge largely disappeared from the therapeutic armamentarium.
But immunotherapy was far from dead. Recently, the use of antibodies directed against PD-1/PDL1 have been shown to be very effective in treating a host of malignancies by releasing the normal “brakes” that keep the immune system in check. This has been most dramatic in the treatment of lung cancer where survival (as well as quality of life) has been substantially improved with quite acceptable toxicity. This approach also works in a number of other malignancies, but curiously not in all. And it is (for the most part) not curative.
Like everything that has come before, the ability to CURE advanced malignancy has eluded us. Cancer cells are smart. But what if we were able to molecularly attack the root cause of cancer? What if we could just replace the gene that is causing all the trouble?
The most straightforward disease candidates for this “gene replacement” approach are those in which a single gene defect is completely responsible for the condition and by replacing the dysfunctional (or absent) gene the condition disappears. A classic example is sickle cell disease, a hereditary form of hemolytic anemia caused by the inheritance (in the most typical cases) of two copies of a mutated beta-globin gene. The mutated beta-globin protein is unstable, and under low oxygen conditions polymerizes with other beta-globin molecules causing the red blood cell to become misshapen and rigid (to assume a sickle shape). These abnormal blood cells occlude small blood vessels causing tissue injury with the resultant symptoms and signs of sickle cell disease. The most clinically obvious symptom is recurrent painful crises (vaso-occlusive crises) that are so severe that the episodes can require hospitalization and narcotic analgesia. But the occlusive crises can occur anywhere: the lungs (acute chest syndrome), the brain (stroke), even the placenta (fetal loss).
The understanding of the pathophysiology of sickle cell disease dates back 75 years. In 1949, Linus Pauling, a chemist at the University of California, published a critical paper that reported that sickle hemoglobin and normal hemoglobin had different electrical charges. He theorized that a mutation in the hemoglobin gene resulted in an abnormal protein that was responsible for the disease. Watson and Crick didn’t publish their seminal work on the double helix until 1953; this hypothesis by Pauling was incredible (and correct). Pauling subsequently won two Nobel prizes (chemistry and peace), neither for his work in sickle cell disease; he was clearly a genius.
Over the subsequent 75 years there has been extensive research which has led to a deep understanding of this complex disease. Among the findings was that the severity of sickling was related to the concentration of sickle hemoglobin. Patients who co-inherited another abnormality of hemoglobin production called hereditary persistence of fetal hemoglobin (HPFH) had minor disease. Under normal circumstances, the fetus uses an embryonic form of beta globin which gets switched off at or shortly after birth in favor of adult beta globin. In HPFH, this switch off doesn’t occur which results in continued production of the fetal hemoglobin. This “dilutes” the sickle hemoglobin resulting in a form of sickle cell anemia that is much less severe.
Knowledge of the molecular mechanisms involved in sickle cell anemia unfortunately did not translate into clinical improvements for the patient. Sickle cell disease is horrible for the patient. The painful crises are debilitating, leading to frequent hospitalizations requiring narcotic analgesia (which can in turn lead to addiction). The effects on other organs are profound, with sickle cell patients rarely living beyond their 40’s. Many of the therapeutic advances to date involve trying to find ways to reduce the sickle hemoglobin concentration, including aggressive RBC transfusions and the use of drugs like hydroxyurea. The impact of these modalities is modest, making sickle cell disease one of the most frustrating diseases to live with for patients and to manage for physicians. And yet, there was the curious observation that for unclear reasons not all patients with sickle cell disease were equally affected.
The only curative treatment for sickle cell disease was bone marrow transplant. This was discovered quite by accident in 1982 when a child with sickle cell disease and acute myelogenous leukemia underwent an allogeneic BMT and was cured of both diseases. But finding a compatible sibling donor was not easy, and the risk of death from the BMT was very real. So BMTs are not used very commonly in sickle cell disease.
As the science progressed, it became possible to isolate bone marrow stem cells and use a virus to introduce a new gene into them. After extensive laboratory and animal studies, this was successfully applied to introduce a normal beta globin gene into the bone marrow stem cells of mice. Could this be done in humans?
This, as it turned out, was not a trivial exercise. In order to isolate the stem cells, insert the gene, and reinfuse the altered stem cell into patients, a bone marrow transplant was required. Because the stem cells could come from the patients themselves (an autotransplant), there weren’t the risks associated with using a matched allogeneic donor, which included graft versus host disease and many other potentially fatal complications. But it was still a bone marrow transplant. Plus there were other challenges.
Given the heterogeneity of sickle cell disease, the investigators wanted patients who were “sick enough” but not “too sick”. As sickle cell disease progresses and organs get damaged, the real benefit of a gene therapy transplant might be limited by the accumulated organ dysfunction. But subjecting a minimally symptomatic patient seemed unwise since there were still very real risks. For example, it was discovered in the trials that the “conditioning regimen” or chemotherapy used to prepare the host to receive the transplant could cause leukemia. And the early trials actually had patients die of leukemia. But it finally got done.
The result: bone marrow transplant of gene modified stem cells could result in prolonged production of normal hemoglobin. This meant normalization of the blood counts and elimination of symptoms of the disease. Gene therapy worked. The FDA approved gene therapy for the treatment of sickle cell disease in 2023. Hooray.
Not so fast. As I noted above, this is really complicated. And it comes at a cost, somewhere between $2 and $5 million dollars per patient. It is clearly not for everyone. Some patients have really mild disease. And some patients have severe end organ damage from a lifetime of sickling. Some people won’t accept the risk of a BMT. Even if we restrict the number eligible, the price tag could entirely blow up health care budgets. Many eligible patients are children and they are on Medicaid, and Medicaid funding of health care is always contentious. Because sickle cell disease is predominantly in African Americans, patients are either in the southern US or large urban centers like New York City and Chicago; the burden of illness is not uniform across the US, meaning some states could be disproportionately impacted. So who should get this gene therapy?
As if the economic challenges of sickle cell gene therapy weren’t enough, there is another big challenge. We do not know how long the gene therapy will last. Is it really curative or will those new corrected genes just poop out? And are there other late effects of the BMT? For example, sterility is very common after a BMT. How about heart disease? We won’t know the answers to these questions for several years. Some have interpreted this cautious approach to the implementation of transplant for sickle cell disease as an example of racism in American medicine. I personally find this suggestion without merit. We have let our enthusiasm cloud our judgment in the past; as an example I refer the reader to the disaster of bone marrow transplant in the treatment of advanced breast cancer which definitely killed more women than it helped (https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003139.pub3/full). The road to hell is lined with good intentions.
I reviewed gene therapy in sickle cell disease because it should have been easy compared to gene therapy in cancer. Next week, we will turn our attention to the challenge of gene therapy in cancer.