The End of the Beginning
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Michael Kinch
Michael Kinch is Associate Vice Chancellor and Director of the Center for Research Innovation in Biotechnology at Washington University in St. Louis.
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The End of the Beginning - Michael Kinch
Introduction
It was the same campus, the same sunny day, and almost the exact same parking spot I had occupied just a few weeks before. However, the circumstances could not have been more different. On my previous trip, I was an invited guest, hosted by a former colleague to present the highlights from the cutting-edge oncology research we were conducting at a biotechnology company just a few miles up the road from the National Institutes of Health (NIH) Bethesda, Maryland, campus where I was currently standing. The name of the company was MedImmune, a conflation of two words meant to reflect a focus on developing novel ways of unleashing the power of the immune system to promote medicine. While the company had already made a name for itself in infectious diseases, I had been tasked with building a portfolio of products to target cancer. The company was largely focusing its efforts to unharness the power of monoclonal antibodies, the guided missiles of the immune system that can be as specific and destructive as the most advanced smart bombs that were used in the second Gulf War just two years before.
I had been recruited from Purdue University, where my academic work as a professor had led to the discovery of ways monoclonal antibodies could be created and deployed to seek out and destroy metastatic cells. These rogue killers comprise the most invasive and deadly tumor cells and tend to elude both the surgeon’s knife and chemotherapy. My tenure at Purdue had been granted just a year or two earlier and I was happily obsessed with understanding the processes behind metastasis. Nonetheless, throughout these halcyon academic years, I had always been gripped with a passion to apply research to alleviate human suffering in the real world,
which was quite distinct from trying to cure experimental mouse tumors, the mainstay of academic research.
Nineteen ninety-eight was a pivotal year, though this was not clear to me at the time. I was in my third year as an assistant professor at Purdue and had published a scientific manuscript detailing a project initiated while transitioning from my postdoctoral studies at the Lineberger Cancer Center at the University of North Carolina to my start at Purdue. We had identified a type of cellular behavior distinguishing benign cells from their malignant counterparts and I hoped these differences might provide a new opportunity for targeting cancer.
I have been extraordinarily lucky to be in the right place and time at key points. Working in 1995 with colleagues at Chapel Hill and at nearby Glaxo Pharmaceuticals (located down the road in Research Triangle Park, North Carolina), we innovated a novel approach to create monoclonal antibodies to characterize or, if we were very lucky, actually convey some use in targeting metastatic cancer. Our rationale back in 1995 was based upon emerging evidence for a new approach using monoclonal antibodies as a much-needed alternative to conventional chemical toxins. Only one monoclonal antibody had ever been approved for cancer at the time.
The drug Rituxan® (rituximab), as we will see, had been developed by a start-up biotechnology company in San Diego (IDEC Pharmaceuticals) and marketed by another biotechnology company located outside San Francisco (Genentech). Rituximab had overcome all the hurdles necessary to be approved by the Food and Drug Administration (FDA) in 1997 and it was to be used in the battle against a type of blood cancer known as a lymphoma. Early sales of the drug were promising but not overwhelming. The reason for the lag in sales was in part because monoclonal antibody drugs were not very familiar to most physicians (or even many scientists). However, this drug would go on to log peak annual revenues of more than $7.3 billion in 2015 alone and become the twelfth-highest selling drug in history (undoubtedly fated to move even higher because antibody drug sales are not as susceptible to generic competition as more conventional medicines are).
Looking back to 1998, the commercial view of monoclonal antibody therapeutics was not terribly optimistic. For one thing, the nascent field was considered, by many industry experts, to be unrealistic based on economics alone. Such views were justified based on the high costs needed to manufacture these large molecules, which might cost hundreds of dollars per dose (as compared with pennies for many conventional medicines). Moreover, key patents filed by early biotechnology pioneers meant a substantial portion of revenues—as much as one-third for some medicines—would have to be surrendered to competitors. To break even, some antibody drug companies contemplated asking prices of up to $10,000 for a single course of treatment—an outrageous proposition at the time.
Ten thousand dollars today seems almost like a bargain, when insurance companies are, with increasing frequency, asked to spend hundreds of thousands or even millions of dollars on some medicines. However, this price tag seemed utterly absurd to many in the late 1990s. Hence, many conventional pharmaceutical companies focused on standard medicines comprised of small and less complex molecules (think of aspirin). In contrast, monoclonal antibodies were large and unwieldy beasts (e.g., a thousand times larger than aspirin). To manufacture a single antibody requires the precise arrangement of four large proteins, each situated in just the right way, to ensure an antibody drug is stable, safe, and efficacious.
This complex construction could not be performed in the massive fermentation tanks used to manufacture small molecules but instead required something with far greater sophistication: the honed skills of human or other mammalian cells. Yes, these cells actually served as the factories, and the technology needed to engineer the production of proteins in these tiny workshops had only been enabled in the 1970s and 1980s. All the antibody drugs described herein were produced by cells obtained from discarded human or animal tissues and then modified using genetic engineering to produce the antibody of interest.
The high costs of growing the antibody-producing cells, purifying their protein products, and ensuring the resultant drug remained viable accounted for for the bulk of the expense of monoclonal antibody drugs. These costs were compounded by an enormous amount of intellectual property (patents and royalties) that drastically increased the cost of manufacturing antibodies. Consequently, there were few biotechnology companies, or more accurately, investors, willing to take the plunge into such a risky enterprise. In my years as an academic, I spoke with representatives from many conventional pharmaceutical companies and most indicated their unease with utilizing monoclonal antibodies for any indication, and certainly not for cancer.
Cancer at the time was a relative backwater in drug development. I vividly recall one conversation with a pharmaceutical company executive, who stated cancer would likely forever remain so as there had never been a single blockbuster
in the field (blockbuster being an industry vernacular for a drug generating a billion dollars in annual revenue). The real money,
she continued, was in a drug a person would need to take every day for the rest of their life (such as a medication for hypertension or high cholesterol). One problem with oncology was that treatment tended to be short-term (weeks or months) and if you were effective, therapy may never be needed again. The alternative was the patient would expire from the disease. Either way, the patient would not take the medicine for very long. Given the crass connotations, I recall being quite shaken and can recall the details of this conversation as if it occurred yesterday. Simply put, there was not much interest in cancer or antibodies in the 1990s world of pharmaceuticals.
One exception was MedImmune.
The firm was originally founded in 1988 by an entrepreneurial pair of physicians, Wayne Hockmeyer and Franklin Top, who had retired from leadership roles at the Walter Reed Medical Center. Founded as Molecular Vaccines, Inc., in May 1987 (the name was changed to MedImmune in October 1990), the company had opened its doors in a small research laboratory in an utterly nondescript building on Firstfield Road in Gaithersburg, Maryland, lodged between a sleepy post office and a row of apartment buildings that were not aging terribly well.
Hockmeyer and Top had partnered with a venture capitalist to build upon research they had begun at Walter Reed years before. A lead project had sought to develop antisera to prevent respiratory syncytial virus (RSV) infection in premature infants. RSV causes cold-like symptoms in most children and adults every year or so. Although a simple infection to you and me, this same virus can cause irreparable lung damage and frequent death in premature infants. The risk from RSV persists for a year or two as the lungs are particularly vulnerable and slower to develop and heal in these frail babies. The first serum-based RSV therapies to be deployed by MedImmune were indistinguishable in many ways to the antisera deployed to treat diphtheria and rabies as pioneered by Louis Pasteur and Robert Koch more than a century before. However, the two former army men, Hockmeyer and his former commanding officer, Top, were not content to focus only upon these sera-derived therapeutics, but had plans to utilize the newly developed power of monoclonal antibody technology.
Within a decade, MedImmune had overcome many adversities to gain an FDA approval both for their antisera (known as RespiGam®) and the monoclonal antibody product destined to replace it: Synagis®. As the latter product closed in on a $1 billion in annual sales with the start of a new millennium, the company had already begun to expand its pipeline to include vaccine technologies to prevent infection by human papilloma virus (a subject addressed later in this book), and were actively exploring both antibody and vaccine technologies for use against an array of infectious diseases. The key in biotechnology, as in investigative reporting, is to follow the money. In this regard, the biotech community, unlike their more staid pharmaceutical cousins, had begun to believe the money led to oncology.
This paradigm shift in the private sector view of cancer had begun at about the same time as my troubling conversation with the pharmaceutical executive about the reluctance of the industry to embrace oncology. In 1998, a drug named Taxol® reached the blockbuster milestone of grossing more than $1 billion in annual revenues, the first cancer drug to reach this landmark. In that same year, a pioneering company of the biotechnology sector with the name of Genentech gained an FDA approval for a second monoclonal antibody for cancer, a drug known as trastuzumab (Herceptin®). Trastuzumab was targeted at the highly organized community of breast cancer patients, who helped advocate and advertise the advantages of Herceptin over more traditional breast cancer treatment therapies. You could feel a seismic shift as this motivated and well-informed breast cancer community was suddenly filled with hope. The success of trastuzumab triggered an overdue deluge of investment targeted to develop new breast cancer medicines.
Beyond breast cancer, the concerns about the relatively small market of individuals requiring oncology drugs were offset by the recognition that a cure for cancer, even a partial cure that extended life by a few years, could command high prices. Adjusting their mindset, biotechnology and pharmaceutical corporate executives were suddenly driven by the expectation that a new blockbuster could arise from medicines delivering large sums per patient, even if this came from a small number of people treated for a short time. In other words, small populations could generate profits if the outcome could justify a high price. This approach to generate prodigious earnings from a small population would soon dominate the biopharmaceutical industry, displacing the concept of more widely used and lifelong products that yielded lower revenues per patient, but were prescribed year after year.
As MedImmune was becoming one of the first biotechnology companies to achieve profitability based on revenues derived from their infectious disease products, I hoped the monoclonal antibodies I had developed in North Carolina might serve as a scientific tool. My primary focus, following the work I had started at UNC, would be on a basic scientific question about cancer cell behavior. The goal for these antibodies was to help train new graduate students in how to conduct research. Each student would be assigned a random antibody (there were more than six hundred) to learn the basic techniques provided by antibodies in the laboratory. If one of these young students happened to stumble upon something with these antibodies, then we could take an opportunities approach to pursue it further.
Everything changed when my first student, and then my second, began obtaining exciting results with these antibodies. Their findings revealed unexpected potential for identifying and potentially targeting metastatic cells. Consequently, these side projects soon dominated my laboratory at Purdue. Their discoveries would ultimately determine many of our young family’s life choices, including where we lived and our sources of employment, for most of the next decade, redirecting the careers and personal lives of myself and my wife, Kelly (also a cancer researcher). Unbeknownst to us, we were in the middle of an extraordinary burst in the enterprise of biotechnology in general and cancer immunology in particular.
By the beginning of the new millennium, my research had become obsessed with a molecule functionally altered and overexpressed on cancer cells. This protein, known as EphA2, normally was restricted to the developing embryo and was mostly turned off (or found at very low levels) in benign cells. In its normal function, EphA2 served to decrease cell growth and invasiveness. In contrast, our laboratory had demonstrated cancer cells found a way to reprogram EphA2 to promote tumor cell growth and favor metastasis. Our work culminated in the description of a vicious cycle whereby the malevolent behavior of the EphA2 protein caused it to accumulate within malignant cells, thereby further enhancing the aggressiveness of tumor cells and in turn increasing the levels of EphA2. The cause and effect of EphA2 and disease progression would continue to spiral up to the point where the tumors had become killers dependent upon EphA2. Most importantly, we had uncovered a means by which carefully selected EphA2 monoclonal antibodies (made specially for this purpose) could override this process and essentially short-circuit tumor cells, selectively killing them while sparing benign cells.
As word began to spread about our work in an obscure laboratory in one of many Big Ten schools and in the midst of agrarian Indiana, I began receiving invitations to speak about our work at other universities, as well as an occasional biotechnology company. Returning from a whirlwind trip to the West Coast on a red-eye flight in the early summer of 2001, I stopped by my office to check the mail and ask about my students, with the goal of returning home to catch up on some much-needed sleep. Within seconds after stepping into my office, the phone rang. I was tempted to ignore the call, but fate intervened and I answered.
The caller was the new president of Purdue, Martin Jischke, asking if I could take some time to meet with an alumnus. I was informed this gentleman had founded a biotechnology company, which also happened to work on monoclonal antibodies. Having never spoken with the president, it would have been challenging (and perhaps career-ending) to decline. Nonetheless, my overwhelming sense of exhaustion forced me to try and beg off the meeting. I asked the name of the alumnus. Wayne Hockmeyer
was the reply. I had never heard of him and so asked what company he had founded. The answer, MedImmune,
was vaguely familiar and I struggled to remember why (being notorious for an awful memory). President Jischke then indicated MedImmune had recently launched a drug called Synagis®, which prevented infection from a virus called RSV. That fact jogged my memory and forced a concession that a much-desired nap was not destined to be part of my immediate future. I immediately agreed to meet with him.
The reason for my sudden change in heart was in part because our elder child, Sarah, had developed RSV-triggered asthma as an infant. This entailed months of increasing familiarity with albuterol dispensed by nebulizers, which would ease her breathing during asthmatic events. Sarah, by this time, was a toddler and her asthma bouts were happily becoming a distant memory. More contemporary concerns arose for our son, only six months old at the time. Always a rather energetic child (even in utero), Grant had kicked his mother so hard he tore a hole in the amniotic sac, which caused him to stop progressing at roughly thirty-three weeks of gestational development. He was born prematurely a week later and while not the smallest preemie in the neonatal intensive care unit, his older sister Sarah’s prior history with RSV caused his pediatrician to prescribe Synagis. My wife and I, who both worked with monoclonal antibodies, were amused by the fact our son was one of the rare few who was receiving such medicines (though our insurance company was surely less thrilled by the prospect of covering the shots, which cost roughly $800 per month). Thus, the utterance of the name Synagis by the Purdue president had been sufficient to convince me to meet with Dr. Hockmeyer.
Though I was undoubtedly not at top form (still bleary-eyed from the flight and un-showered), the meeting went surprisingly well. Hockmeyer and I discussed shared interests in monoclonal antibodies. This prompted a generous offer from him to visit MedImmune at its Gaithersburg, Maryland, headquarters. A few weeks later, I found myself giving a seminar in the boardroom of a relatively small, but extraordinarily dynamic organization. I had flown in to give a talk at noon and, as is the custom, met with a few people in the morning. My flight itinerary meant I only had two or three hours before I would have to leave to catch the return plane, particularly given returning to Dulles airport required negotiating the Capital Beltway, a ring road notorious for unbearable delays. As my talk was meant to last but an hour, this was not a major worry. The interest by the dozen or so people during the seminar was infectious and the discussion lasted more than two hours. As the talk concluded, the sustained adrenaline rush and nervous drinking of an endless cup of water meant my bladder was nearing the point of embarrassment and I excused myself ever so briefly. Upon returning, I found the room had quickly cleared out except for the chief executive officer, David Mott, who I had learned had recently taken the helm from Hockmeyer. David is quite direct and got straight to the point: MedImmune was interested in starting an oncology program and wanted me to lead it. I was humbled and dumbfounded. Here I was, a confirmed academic, being asked to sacrifice tenure and jump into a risky biotechnology venture. Compounding this, I had also just been offered a very attractive opportunity at the University of Virginia.
I returned to Indiana and excitedly discussed with Kelly the adventures from my visit to Maryland. We agonized about this sudden new opportunity, which represented an apples-to-oranges comparison with the options provided by academia. In a detailed and enlightening conversation, my wife made me realize the depths of my own ignorance, which is one of her more extraordinary and occasionally annoying talents. Although a switch to the private sector would mean giving up tenure, she could sense (more than even I) the opportunity at MedImmune would fulfill a wish to apply science to medicine, which has always been a passion. We both loved Charlottesville and I had secretly dreamed of working at Mr. Jefferson’s School
even before I had ever seen the place (as the reader will soon see, I am more than a bit of a history nerd). Yet, even as a graduate student studying basic biology, I self-identified as a cancer researcher.
An early motivation for becoming a cancer researcher had been spawned two decades before, when I lost both grandfathers to the disease. During high school, my maternal grandfather, Harold, had been diagnosed with colon cancer on the day after Thanksgiving in 1982 and had died thirteen months later, after an agonizing struggle that ravaged his formerly muscular frame and reduced him to a virtual skeleton as he lay on his deathbed. This disease had figuratively metastasized throughout our close-knit family and tainted our views of the holiday season for many years to come.
What we didn’t know at the time was this same disease was also metastasizing through the family as well. By my senior year in college, an uncle was diagnosed with pancreatic cancer and, like many stricken with this particularly horrible disease, would succumb within months. Furthermore, my paternal grandfather perished within a year from the complications of fighting both colon and prostate cancer.
These family tragedies would ultimately help shape my professional life as a youthful passion for science matured into a desire to even the score with a disease that had taken such a personal toll. By the time my paternal grandfather died from cancer, I was already working toward my doctorate in immunology at the Duke University Medical Center in Durham, North Carolina, determined to apply this learning to cancer. As we have already seen, I would later perform postdoctoral studies at the University of North Carolina, which later led to the EphA2 story.
Just minutes after midnight on September 11, 2001, my wife and I landed at National Airport in Washington, D.C. Arriving at the hotel early in the morning, our plan had been to tour Gaithersburg with a realtor later in the day and on September 12 discuss potential positions at MedImmune. The planned agenda was obviously undermined by the horrific events of the day and, had I possessed any common sense, we would have politely declined a job offer in a town where planes crashed into buildings and instead opted for a safe and happy life in quaint Charlottesville, Virginia. Having never been burdened with such sense, we accepted the position at MedImmune and soon began growing a pipeline of cancer programs, mostly based around monoclonal antibodies.
One follower of our work at MedImmune was a former colleague of mine from Chapel Hill, Geoff Clark, who happened to work down the road at the National Cancer Institute (NCI). During the summer of 2004, Geoff asked me to give a seminar at NCI in Bethesda and I found myself discussing EphA2, MedImmune, and the pipeline of innovative products we were intent upon developing. It was like many other seminars but more memorable to me given the location on the NCI campus in Bethesda, a storied locale with a rich history in the war against cancer.
A couple of months later, I was back at NCI. Only this time, I did not enter through the front doors as an invited guest to expound about the scientific progress of the day but through the side door marked, Patients Only.
For this visit, I was accompanied by my mother and, after being processed, we were given wristbands and sent up to the Medical Genetics Branch. Our visit had been triggered by a recent diagnosis of a close family member, who had been experiencing discomfort in his lower abdomen for much of the past year. As alluded to above, his father had died from pancreatic cancer.
At the age of forty-one, a persistent stomachache in this otherwise healthy young man was diagnosed as invasive colon cancer. Thankfully, the disease responded nicely to chemotherapy, which included another pioneering monoclonal antibody Avastin®, which had been approved by the FDA just weeks before his diagnosis. Given the early onset of the disease, his doctors recommended an early form of genetic testing, which revealed a condition known as hereditary nonpolyposis colorectal cancer (or HNPCC). Also known as Lynch Syndrome, this genetic change is described by many online cancer-based webpages as an autosomal dominant indication with high penetrance.
My mother had called me on the night of diagnosis to ask me to explain exactly what that particular quagmire of words meant. Upon hearing this diagnosis, my mouth went dry as I tried to choke out an explanation. Though my heart and brain were both racing, I explained the diagnosis meant my cousin had inherited a bad copy of a gene from one of his parents and therefore had a high (basically 100%) likelihood of developing cancer. I then reassured her I would do a little more research on Lynch Syndrome and call her back.
As the bile rose in my throat, my thoughts began to resemble the gyrations of a Whirling Dervish. Though from my perspective I was a paragon of composure, it took Kelly a mere split second to reinforce the fact I am not destined to play professional poker (though I tend to be quite popular at neighborhood poker games for some unknown reason). The panic on my face and in my voice were palpable.
I decided to calmly consult my textbook on cancer. The bible of cancer
had been compiled by Vincent T. DeVita, Theodore S. Lawrence, and Steven A. Rosenberg. This thick two-volume set had a section on the subject of Lynch Syndrome, which confirmed patients with the gene mutation almost invariably develop either colon or endometrial cancer. The good news was we knew our family member was recovering nicely (and would continue to do so). Nonetheless, the swirling sensation in my head continued as I found myself trying to calmly explain to my mother that we might want to confirm the exact wording of the diagnosis, but without explaining why and thereby causing undue panic. Within a day, I was staring, mouth agape, at a faxed page of a pathology report verifying the genetic changes and cementing the diagnosis.
Almost immediately, I began calling in every favor ever owed to me. Within a few hours, I had managed to book a colonoscopy and an appointment with the head of the NCI medical genetics program focused on HNPCC. Lynch Syndrome patients are of interest to the NCI, in part because they offer a means to study the science, medicine, and sociological impact of a current or impending cancer diagnosis (the cancer can take decades to develop). In return, NCI offers counseling about treatment options and reproductive decision-making. Our first step was to discuss the situation with a counselor.
After flying my mother to Washington, we met with the head of the program, who interviewed us extensively to gain more information about our family and personal health histories. We entered the meeting under the assumption that my mother’s father, whose death from colon cancer at the age of seventy-one, had inspired my interest in cancer research, represented yet another victim of Lynch Syndrome. Moreover, we assumed my grandfather had likewise passed down the gene to my uncle, who had died of pancreatic cancer, and to his children, one of whose diagnosis with colon cancer had triggered this visit to NCI.
These assumptions were overturned when the genetic counselor learned my aunt (by marriage, who also happened to be her best friend from childhood onward) had been diagnosed with cervical cancer many years before. This fact was new to me as well. The genetic counselor explained that past cases of endometrial cancer were frequently misdiagnosed as cervical cancer. Consistent with this, my mother recalled my aunt’s mother had likewise been diagnosed with cervical cancer. These facts suddenly and decisively favored a likelihood the genetic component of the disease had passed from the maternal lineage and not the paternal lineage I shared with this relative.
Although selfishly reassuring to our side of the family, we were in a quandary. Do we reveal this putative lineage or remain silent? The genetic counselor was adamant we were both ethically and legally obligated to remain silent. The rationale behind this mandate is that such information may be unwanted by others. In other words, it would be selfish (and illegal) for us to reveal something with a potential impact that could affect another person’s life or decisions unless they indicated their desire to discuss it. Although frustrating, we remained silent and the years passed.
Almost a decade later, I had moved to Yale University and was sitting in my living room when the phone rang. The caller was a cousin of my relative (from the other side of the family), who confided he had just been diagnosed with HNPCC following a bout of colon cancer at forty years of age. He had not been aware our shared relative also had this disease until hours before and, knowing my professional background, was calling to ask about the scientific and medical implications of this diagnosis. Thankfully, the story ends well for all the affected individuals, who have resumed happy and healthy lives, having conquered their cancers. Indeed, such outcomes are likely to become even more routine, as we will explore throughout The End of the Beginning.
The title of this book parrots a line from a famous speech given by arguably the greatest speaker, who has blessed the English language. In his Bright Gleam of Victory
speech, Prime Minister of the United Kingdom Winston S. Churchill delivered a victory serenade. Events in North Africa had finally given the nation a reason to celebrate following the successful conclusion of the Second Battle of El Alamein, in which an offensive by General Bernard Law Montgomery’s Eighth Army chased Erwin Rommel’s Afrika Corps westward out of Egypt and through the Libyan desert. Once combined with the United States Army driving eastward from its beachheads near Algiers, the joining of American and British forces had forever expelled the Nazis from the African shores and would soon facilitate the later invasion and capitulation of Sicily and Italy. In a celebratory speech to Parliament on November 10, 1942, Churchill was nonetheless pragmatic enough to counsel, This is not the end. This is not even the beginning of the end. But it is the end of the beginning.
This insight is an apt way to summarize extraordinary advances made in the treatment of cancer in the past few years. A remarkable series of events has allowed us to witness the potential to prevent or utterly eradicate some forms of the disease and, for even the most cautious doctors and patients, to seriously contemplate a cure—a much hoped for but rarely achieved goal of cancer therapy.
The newfound juxtaposition of cancer
and cure
in the same sentence may be attributable to our ability to harness the extraordinary power of the human immune system and redirect it to combat cancer. The breakthroughs made in the war against cancer are not entirely different from the achievements attained by Churchill’s armies in the deserts of Egypt. As we will see, these successes may have even more relevant parallels to another desert war, which occurred in the Iraqi desert in the latter years of 20th century.
One goal of The End of the Beginning is to convey the extraordinary success toward developing cures for cancer, particularly over the past quarter century. To achieve a goal viewed by most as insurmountable just a decade ago, it is necessary to convey an understanding of the history of cancer and the evolution of our understanding of its dynamic interplay with the immune system. In doing so, we will meet the various personalities and weapons used to target elusive tumor cells and the accumulation of breakthrough science facilitating the rapid translation into lifesaving technologies that have begun to dramatically increase the quality and quantity of life for cancer patients, including many lifelong cures.
While dramatic improvements are being made by harnessing the immune system to target cancer, these are not without risk, and we will also touch upon some of the risks these new technologies entail. For many, the risks associated with immune therapies outweigh the benefits. As with the discovery of gunpowder, the airplane, or the power of the atom, understanding is vital to anticipating and preventing the potential for abuse and misuse.
In developing the story, I reach back into my own personal history, not because my own work was particularly impactful but because I happened to be in the right place at the right time to serve as a witness to many of the events described herein. It seems appropriate to fill in some of the gaps with my biography to allow the reader to assess whether I have any credibility in doing so.
I presently serve as an associate vice chancellor and professor at Washington University in St. Louis, a top-five medical school among whose specialties are immunology and cancer research. As we will see, Washington University has helped lead the fight to find new ways to recruit the body’s immune system in the fight against cancer. In this context, I have been actively engaged in the science and application of cancer research and drug development.
Since earning a doctorate in immunology from the Duke University Medical Center, I have split my career equally between the biopharmaceutical industry and academia, most recently leading drug development at Yale University before joining Washington University in 2014. My responsibilities have included leadership in two of the world’s leading biomedical research centers that share the responsibility of analyzing and supporting drug and vaccine research and development.
Prior to Yale, I lived in suburban Washington, D.C., amidst a thriving biotechnology community. My experiences there included helping to guide a medium-sized biotechnology company by the name of MedImmune into a large biotechnology juggernaut. As detailed above, I was tasked at MedImmune with developing a team and a pipeline of products devoted to the eradication of cancer by targeting the body’s immune defenses. I joined MedImmune in 2001 as a team of one. Within five years, we had built a team of more than forty scientists and a portfolio of twenty-one programs. These projects included an overview of the vaccines being deployed to eliminate cervical cancer from the world, as well as the development of cancer-specific smart bombs in the form of armed and unarmed monoclonal antibodies, all of which are profiled in this book.
Over the course of the past two decades, the arsenal of medicines available to treat cancer have improved dramatically. Prior to the development of immune-based therapies, patient care had been made possible for the first time with the introduction of chemotherapies using obnoxious substances. As a brief summary of this era, using the same words I used to teach cancer biology at the Purdue campus of the Indiana University School of Medicine, the goal of cancer therapy is to kill the tumor just before you kill the patient.
These conventional therapies were sometimes effective but always legendarily brutal, often causing an increase in quantity of life only at the expense of a lowered quality of life. Following substantial progress in discovering new chemotherapies in the 1950s and 1960s, the discovery of breakthrough cancer therapies slowed for a time, before being reenergized by the introduction of new science and technologies. As we will see, the application of active immunity (i.e., vaccines) and passive immunity (mediated by antibodies derived from the laboratory rather than created in the body) foreshadowed a new and improved arsenal to be unleashed in the war against cancer.
Over time, a generation of scientists realized it might be possible not just to modify the proteins normally found in the body, such as antibodies, but also its cell-based host defense mechanisms. This realization was put into practice through the implementation of novel treatments, first performed only in the most sophisticated research hospitals in the world, but later made available to the masses through the introduction of equally impactful just-in-time technologies afforded by, among other innovative entities, Federal Express. By blending these past experiences with emerging genomic technologies, we now stand on the cusp of breakthroughs allowing even the most conservatives doctors and pragmatic patients to use the words cancer
and cured
in the same sentence and without a hint of irony.
As one example, we will highlight progress made in the treatment of metastatic melanoma. Only a few years ago, this diagnosis was widely and correctly presumed to be a death sentence. Equally tragic was the fact metastatic melanoma had been a focus of cancer researchers for decades. Despite all this investment, the disease had resisted virtually all attempts to cure it. As a sign of the dark humor of these challenging days, melanoma was described as the "black death