Cancerland

by David Scadden

  TGCA had been started by the National Cancer Institute to create a public catalog of cancer cell mutations organized around types of malignancies. Theoretically, these mutational landscapes, as they were called, could be useful in developing treatments for specific disease and, eventually, for the specific cancers found in patients. As the first pages in the atlas were being written, the big excitement in oncology was related to immune response. In June 2006, the Food and Drug Administration approved a vaccine against the human papillomavirus (HPV), which causes about 70 percent of all cervical cancers.

  It makes sense to mention, here, the double benefits of many vaccines. In addition to protecting individuals, vaccines also create what’s called “herd immunity” by depriving pathogens of the reservoir of hosts they need to thrive. With the measles vaccine, for example, herd immunity occurs when 95 percent of children are immunized and infection becomes so rare that even the five percent who are not inoculated are protected. Unfortunately, this effect decreases dramatically when the immunization rate drops below the 95 percent threshold. A case in point arose in France in 2008 when measles vaccination rates dropped to 89 percent. By 2011, France had 15,000 cases, which caused the deaths of six children. This occurred in part because parents who believed unscientific claims about vaccines opted to forgo or delay them for their children. As this scenario illustrates, when it comes to infectious disease we are all in the fight together, and the best outcomes arise when we recognize our responsibilities to our communities.

  The link between HPV and cervical cancer is one of the most well-established relationships in oncology. A vaccine against it took enormous effort but was finally available and represented an easy, cost-effective way to reduce the incidence of this cancer. While a relatively uncommon cause of death in this country because of PAP smears, it is a common cancer and the most common cause of cancer death in the developing world. A preventive vaccine could spare untold numbers of women a great deal of suffering, and save the health care system significant sums of money. Most effective if given before a person might be exposed to the virus via sexual activity, the vaccine would be recommended for preadolescent girls and would halve infection rates in teenager by 2012.

  Human nature being what it is, the HPV vaccine’s connection to sex, or more precisely the thought that young unmarried women might have sex, bothered people. In Texas, the state legislature prioritized sexual anxiety over health and voided Governor Rock Perry’s order making the vaccine one of many required by the state. Later, during the 2012 GOP presidential primary, candidates Rick Santorum and Michelle Bachmann added their voices to the HPV vaccine opposition. In Great Britain an antiabortion group opposed the vaccine with the argument that it “gives young people another green light to be promiscuous.” The specious quality of this claim was refuted by a scientific study, done by researchers at Emory University, who found no correlation between the vaccine and sexual activity. Nevertheless, as of 2017 the vaccine was required for children only in Virginia, Rhode Island, and Washington, D.C.

  A second oncological advance made on the basis of immunology was a prostate cancer therapy marketed under the brand name Provenge. This used patient’s cells to make an antitumor vaccine for prostate cancer. This is not a vaccine in the traditional sense of something used to prevent a disease, but rather a therapeutic vaccine. It could be categorized as an immunostimulant as it uses dendritic cells: cells that come from blood stem cells and whose job it is to activate T cells. They process proteins and serve them up in a digested format that turns on specific T cells, selectively those T cells with a predetermined appetite. The Provenge approach is to isolate dendritic cells from the patient’s blood, grow them and feed them a prostate cancer protein before sending them back into the blood to get the T cells going against the tumor. It is very patient specific and that makes it very expensive and complicated, but it is an FDA approved therapy.

  Modern immunotherapies like Provenge descended from William Coley’s toxins, which he developed after noticing that some of his cancer patients got better after they fought off an unrelated infection. The great hope for immunotherapies rested in the idea that they could work with the body, enhancing the natural response to malignancies. Patients, physicians, and the public were thrilled by reports on the early successes achieved in the development of immunotherapies, and research in this area attracted billions of dollars from the government, foundations, and investors attracted by the profits available in blockbuster drugs priced as high as $250,000 per patient, per year.

  More than a little irony attended the fact that much of the scientific community and enormous caches of national research funding focused on the human genome and, particularly, the cancer genome while major leaps forward in benefit were coming from immunology, an area that was often outside the limelight in cancer research. There is no question that genome science was a powerful force for good in rationally designing therapies, but durable tumor responses were a rarity apart from Gleevec. Immune-based treatments seemed to offer hope for more effective cancer control. One of the leaders in this science, Carl June of the University of Pennsylvania, imagined a range of therapies that would depend on immune cells that had been genetically modified to do a better job of dispatching malignancies. June wrote of a time when transfusions of these lab-improved cells would be as routine as whole blood transfusions became in the early twentieth century. The goal, he said, would be a therapy that would be “clinically effective, scalable, reproducibly manufactured, appropriately priced, and marketed.” When he outlined this ambition in 2007, it seemed like something beyond reach. Barring an unexpected new technology, the investment required to create the infrastructure for this type of medicine would compare with one of NASA’s historic missions. And even if we had the money, we would have to solve an untold number of extremely difficult biological problems to determine if the idea was plausible.

  Fortunately, science is generally done in the sort of step-by-step process that yields answers to questions and also points to the next challenge. This journey is inspired by the big goal, whether it’s curing cancer or reaching the moon. But success requires organization, teamwork, and, for individual scientists, a devotion to solving the discrete puzzle that sits before you. You must enjoy this pursuit, even when you know that you might reach a dead end. Indeed, much of what can happen when you tackle one small piece of the work required to advance a huge scientific project might be considered bad. First, you could fail to design your study in a way that addresses the question at hand. If you get the design right, you may run into problems with execution. Get over this hurdle and the accurate result from all your hard work may indicate that your theory about a gene or a chemical or a process in the body is all wrong. But say you succeed in moving from an idea to a promising result that fits into your team’s larger, long-term endeavor. There’s always a chance that the next step in the process will bring everything to a halt or some other group could beat you to the finish line. This is science. You think hard to come up with a big idea, work hard, and if you fail but have time left in your life, you start all over again.

  Carl June’s big idea called for exploiting elements of the immune system, including the fact that some cancer-fighting cells retain memories of the invaders they once dispatched and are primed to destroy them. This happens thanks to genetic mutations that occur as part of the normal process of developing the lymphocyte arm of the immune system: T and B cells in particular. Think of this as an example of gene mutations “gone good.” Cells with a particular mutation that allows them to connect with and be activated by a particular target expand and durably remain. In this way, they serve to provide a kind of memory for the immune system. Upon encountering an old enemy anew, the memory-equipped immune cells possess extra power to deal with it and the ability to multiply to get the job done. When cancer prevails, however, the response wasn’t vigorous enough.

  As June imagined it, the solution to an insufficient immune response would involve intervention
s that improved the cancer-killing cells’ ability to see, seek, and destroy while also multiplying and then creating something like a permanent rapid response team, ready to deploy when needed. The fix he would add to the immune cells was called chimerica antigen receptor. (“Chimeric” because, like the mythical chimera, it would be made from more than one animal source.)

  “Antigen receptors” are chemicals that are the product of the controlled mutations in T and B cells. They can recognize particular targets, another name for which is antigens. Those that recognize targets on cancer cells can sometimes be identified and cloned. Once in the hands of molecular engineers, the antigen receptor can be manipulated to create a more potent activator of T cells by fusing it with other parts of the T cell activation molecular machinery. That chimera is then placed into other T cells to arm them for targeting a particular tumor antigen. Those cells can be grown to large numbers outside the body so you create a large army of cells with one target in mind. These CAR T cells are especially good at killing cancer cells that bear the target antigen. They are good at killing any cell that bears the antigen. Therein lies a problem. If cancer cells are from us, from genetic events that involve our own genes, how can normal cells be shielded or not attacked? That problem forced the field to focus only on targets that were malignancies of cells that were somewhat dispensable. B cell cancers have targets that are on both normal and malignant B cells, but only on B cells. B cells make antibodies that can be replaced by injections (so-called gamma globulin, an injection of which you might have had as a traveler to protect you from hepatitis A). So the pioneers of CAR T therapy, led by Carl June, focused on B cell cancers.

  A lanky fellow with thinning hair and a pleasing, crooked smile, June is a determined scientist who was inclined to push forward on his ideas even though most major funders refused to support him financially and many colleagues doubted his ideas. This doesn’t mean he was overly egotistical. In fact, when he was once encouraged to explain how he was trying to “cure cancer,” he blanched at the thought and, in a stammering way, said, “Those words are hard to say.” He added, somewhat shyly, “I think sometimes it’s actually hard to think that you might actually succeed.”

  As a veteran of navy medicine, June was trained at Seattle’s Fred Hutchinson Cancer Research Center (often called simply the Hutch), which is the world leader in blood stem cell transplantation. He is also heir to a long history of U.S. military research into immunotherapies that, at first, were imagined as a response to injuries caused by radiation accidents or nuclear weapons. One of the very earliest of these, and an example of cell therapy, was the bone marrow transplant procedure developed at the Hutch by E. Donnall Thomas. Recipients of this therapy produced fresh new armies of T cells that would confront their leukemia. June encountered the procedure early in his career and decided, by 1983, that he would devote himself to the science of immunotherapy.

  In the late 1980s, I worked with June on an HIV study in an effort to help stem the AIDS epidemic. HIV is extremely good at getting into a particular kind of T cells that have a molecule on their surface called CD4. The virus uses the CD4 molecule as its doorway to the inside of the cell where it exerts its mischief. A colleague at MGH, Brian Seed, thought that it might be possible to use the viruses’ dependency on CD4 against it. What he did was create a chimeric molecule that had CD4 on it as a way to create a Velcro-like connection with HIV. He fused the CD4 to the activating machinery of T cells. By placing that into T cells that were professional cell killers (so called “cytotoxic” T cells) he could generate an army of T cells capable of killing HIV-infected cells. A visionary physician-entrepreneur, Steven Sherwin, acted on that to create a company with the ability to move it from a laboratory to patients. Carl June was one of those who championed moving it to patients. I was a part of the group of physicians who joined with him to do so.

  We treated patients with HIV who were also on medicines and we monitored if the new engineered T cells could persist in the body and attack HIV infected cells. I remember the first patient in whom we infused these cells at the MGH. Much trepidation on our part—my wonderful study nurse, Jocelyn Bresnahan, and I—at the bedside thawing the cells in a water bath and then infusing them like a blood transfusion. Our fears, kept private to not alarm the patient, were calmed by how smoothly all proceeded, how lively the patient was conversing throughout, and how nothing amiss was happening medically. The patient went home happy and well.

  The cells are preserved in a solution called DMSO that prevents water crystals from forming. It has a particular and strong odor. When we saw the patient the next day in follow-up, we encountered an unanticipated complication: the patient’s dog liked the scent of the DMSO. According to the patient, “he thought I was a pork chop.” Fortunately, all lick and no bite. It apparently made for an entertaining evening rather than any trouble and the scent was gone by morning.

  The cells targeting HIV were safe and stayed in the body for years. They appeared to have the activity we hoped for in killing HIV-infected cells, but we couldn’t tell for sure. When new medicines are used, whether they are drugs or antibodies or cells, the first step is to be sure they are safe. That is called a Phase I study. It involves doses that gradually increase in a step-wise manner as safety information is gathered. A Phase II study is when activity is tested, usually at a single-dose level. The Phase III is when safety and activity have been established and the medicine can be tested against a control group of patients receiving the standard of care for the condition. These are generally very large and expensive studies that are often required by the FDA prior to approval of the medicine for sale. Phase IV studies are conducted after a drug is approved, with the intent of collecting information that might reveal otherwise hidden side effects. Not all medicines are required to undergo Phase IV testing.

  The trial of modified T cells to attack HIV was somewhat different because of the complexity of making enough cells. It was small like a standard Phase II, but did include a comparison group who just received T cells, just not engineered T cells. The results were ambiguous so the funding for further testing dried up and the company died, despite its visionary leadership in engineering T cells. The idea and much of the technology resurfaced with CAR T cells targeting cancer.

  Ironically, engineering cells often depends on HIV, or at least its basic composition. Putting new genes into cells like a chimeric antigen receptor takes advantage of what viruses do for a living—getting their genes into cells by infecting them. HIV is particularly good at doing that and having its genes remain durably present in the cell and all its descendents. Just as Mayor Vellucci and the Cambridge City Council struggled to understand and accept early genetic engineering work at Harvard and MIT, the idea that the most-feared virus of our age—HIV—could be used to devise some sort of therapy would unsettle many people. By the middle of the last decade, microbiologists and virologists had figured out ways to create a version of HIV that lacked the genes that cause AIDS but would be an effective delivery vehicle for genes.

  “The disarmed AIDS virus acts like a Trojan horse,” noted S. Y. Chen, of the University of California–Los Angeles. It is also helpful to think about the modified virus as a burglar who could defeat the lock on a door but forgot his purpose once he got inside the house. It penetrated into immune cells but couldn’t deliver its virulent punch. It could, however, “infect” T cells with genes to produce chimeric antigen receptor and make them into superstars of the immune system.

  In 2010, Carl June’s team was working without much support. The National Cancer Institute, having seen failures in similar experiments, wouldn’t back June. He found just enough funding from a small foundation created by Penn alumni to keep going. His group took roughly one billion T cells from the bodies of three men with CLL and augmented them with the chimeric antigen receptor genes. They added microscopic beads bearing proteins to the cell culture, which pushed the cells to divide and increase in number at a faster rate. (Earlier experiments had de
termined that the signaling molecules that were on the beads could accelerate cell division without causing any changes that diminished the cells’ abilities to act against cancer or infection. These techniques had been used for years with consistent success).

  The patients in Carl June’s trial were at a stage of CLL sometimes referred to as “ultrahigh risk.” This phase is reached when tests show increased numbers of cells bearing a defect in the famous p53 gene, which is a tumor-suppressing gene and in whose absence cancer can occur. In this condition, people with CLL progress more rapidly, and most will not improve with chemotherapy. Life expectancy is shorter than that of people who have CLL without a p53 defect.

  The reality of late-stage CLL is much easier to discuss when you refer to genes and time spans and abstract complications. Turn to address actual human beings, who love life and are cherished by friends and family, and the conversations become exceedingly difficult. A recent study of patients at cancer care centers around the country found that of those with a terminal illness, nearly 40 percent had never discussed end-of-life options with their doctors. Only 5 percent could answer four elementary questions about the basics of their condition. Separate studies have found that people cling to the long-shot chance when they are told, for example, that they have a one-in-ten possibility of recovery.

  It is the “optimism bias” that keeps patients and families seeking and believing in the chance to have the “Lake Wobegon effect” where “all of the children are above average.” It comes with a tendency for people to believe they are special and will prevail where others do not. If they do not prove to be exceptional, those who care for them must work at persuading them that when it comes to cancer no one is at fault when they fail to beat the odds. Sometimes the belief turns to anger and suspicion when the crisis of failing therapies becomes real. Being caught in a raging wave of overwhelming cancer is brutal for all and people’s worst fears emerge. Sometimes these feelings are amplified by events that occurred long before we meet a patient, and sometimes we wind up grappling with unstated factors in a family’s history.