Sharon Begley is the senior science writer at STAT. Her most recent book is “Can’t. Just. Stop.: An Investigation of Compulsions.”
They sure don’t do human studies like they used to. After a young physician at New York Hospital named William Coley lost a patient to cancer in 1890, he began combing through hospital records for clues about who had survived the usually fatal disease. Reading one case, Coley noted that the patient’s seemingly miraculous cure followed a raging strep infection that appeared to melt away the man’s head-and-neck sarcoma.
Intrigued, Coley got a chance to test his hunch (no ethics board’s approval or patient’s informed consent required!) the following year, with a man suffering from a neck tumor and given only weeks to live. Coley “basically winged it,” journalist Charles Graeber tells us in “The Breakthrough: Immunotherapy and the Race to Cure Cancer.” The doctor injected the patient first with a little bacteria and then with a lot, at one site on his body and then another, and finally with bacterial toxins collected from a corpse (“the good stuff, potent and fresh,” Graeber reports) and shot right into the ghastly tumor.
After suffering near-lethal fevers, the patient rallied. His tumor seemed to break down before Coley’s eyes. Although infection-causing injections killed two of Coley’s next 12 patients, the doctor was convinced: If the immune system can be unleashed, it will kill tumors.
Coley was 100 years ahead of science’s understanding of the immune system. He was dismissed as a charlatan, and once he started bottling and peddling his cancer-fighting toxins, he was also called a snake oil salesman. Generations of oncologists and cancer biologists either heard nothing about Coley’s observations or lumped them together with cancer quackery. Immunology became a vaguely disreputable backwater in cancer research. Stalwarts like Steven Rosenberg kept it alive, but they seemed to epitomize the cycle of soaring hopes and dashed dreams: interferon, interleukin-2 and other immune-boosting drugs came — were fleetingly heralded — and mostly went.
It took an immunologist, not a cancer biologist, to crack the code. James Allison realized it wasn’t that the immune system needed boosting. Instead, molecules on tumor cells that thwarted the immune system needed to be disabled. Allison figured out how to disable those molecular brakes, or checkpoints, and allow the immune system to rip: His discovery led to the first approved “checkpoint inhibitor” cancer drug, in 2011, and won him a share of the 2018 Nobel Prize in medicine.
If you read about cancer discoveries in the media and have a good memory, you are likely to react to the title of Graeber’s book with a lot of eye rolling and maybe some understandable anger. Despite decades of cancer “breakthroughs” — potent chemotherapies and molecularly targeted drugs — roughly 600,000 people in the United States die of cancer every year.
But Graeber makes a persuasive case that cancer immunotherapy has earned the description. With checkpoint inhibitors like Allison’s, which target the molecular brake called CTLA-4, followed by inhibitors of brakes called PD-1 and PD-L1 and then genetically engineered T cells called CAR-Ts, once-hopeless cancer patients are actually obtaining something physicians have been loath to mention: a cure.
“Breakthrough” is full of gripping stories of white-knuckle experiments, of mice that lived, of pioneers who had to wrangle fellow scientists into investigating the interaction of the immune system and cancer. These determined few valiantly fought a cancer hierarchy that viewed the whole thing as a dead end. Gatekeepers at prestigious science journals rejected research papers in the stubborn belief that the immune system can’t attack cancer — data be damned. Eventually, the data could not be denied.
Graeber deserves credit for telling stories of both the successes and the failures of immunotherapy. On the one hand, there’s the saga of Jeff Schwartz, who was diagnosed with Stage 4 kidney cancer in 2011. After surgery and chemotherapy, Schwartz’s doctors gave him six months; he suspected they bailed on him because they had “nothing left to bill for.” Schwartz’s white-cell count and other lab values were so terrible, the doctor running a clinical trial feared that Schwartz would die on him and make the experimental immunotherapy drug look bad. He squeaked into the study anyway — and today is cancer-free. On the other hand there’s Brad Jasper, who was diagnosed with metastatic melanoma in 2001. Jasper entered a clinical trial for Allison’s CTLA-4 inhibitor ipilimumab in 2004, went into remission for several years but died in 2014.
“Ipi,” the field’s first success and one rightly applauded for turning an almost-always fatal cancer into a survivable one, seems to cure only one-fifth of patients. The PD-1 and PD-L1 inhibitors, including one that has helped former president Jimmy Carter survive the melanoma that spread to his brain, also work for only a minority of patients. Researchers hope that combining the immunotherapy drugs with each other or with chemotherapy or radiation might increase that fraction; some 1,500 clinical trials are testing such combinations.
Graeber meets the goal of every writer: to leave the reader wanting more rather than less. There are very few places in this brisk account where you slog through more biochemistry than you ever wanted to see in several lifetimes. But he sometimes overshoots in his brevity. The PD-1/PD-L1 story goes by too quickly, especially when it’s introduced by the tantalizing mention that the main players are “currently wrapped up in lawsuits.” It would have been fascinating to read more on who did what when, rather than getting the limp cop-out that credit “will be decided by history.”
As it happens, after Tasuku Honjo of Japan was awarded half of this year’s Nobel Prize in physiology or medicine for his discovery of the gene for the PD-1 receptor, two other scientists who made key PD-1 and PD-L1 discoveries went on the record grousing about the award, an almost unheard-of breach of scientific comity. Graeber spoke to at least one of those who was passed over but pulls his punches on the question of whether Honjo got more credit than he deserved.
This chapter of the cancer immunology story still needs writing, as do other tales of the research and the scrambling — and catch-up-playing — of multiple drug companies. For now, Graeber has given us a riveting account of science that truly deserves an accolade that has been all too frequently awarded, but almost never actually achieved, in cancer research: Unleashing the immune system on tumors is indeed a breakthrough.
By Charles Graeber
Twelve. 320 pp. $28