Off to the Races: The Breakthroughs of Immunotherapy

David Steensma, MD
Edward P. Evans Chair in MDS Research and Institute Physician at the Dana-Farber Cancer Institute; Associate Professor of Medicine at Harvard Medical School; Editor-in-chief of ASH Clinical News

ASH Clinical News Associate Editor David Steensma, MD, reviews The Breakthrough, which traces the evolution of immunotherapy to treat – and potentially cure – cancer.

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Title: The Breakthrough: Immunotherapy and the Race to Cure Cancer
Author: Charles Graeber
Length: 320 pages
Published: November 2018, Twelve/Hachette Book Group

For decades, “cut, burn, and poison” were the only three conventional treatment approaches available to patients with cancer. Beginning with rituximab and imatinib in the 1990s, a fourth class of oncology therapy joined the triumvirate of surgery, radiotherapy, and chemotherapy: narrowly targeted “precision” medications that were made possible by a deeper understanding of cancer biology. We are now at the beginning of what looks to be a transformative period in cancer care, with the advent of a fifth method that could someday replace all the others: cancer immunotherapy.

The Breakthrough, a new book by Charles Graeber, reviews the history of cancer immunotherapy, beginning with surgeon William Coley’s work with toxins in the 1890s, followed by immunotherapy’s long fallow period, and ending with the ultimate triumph of the believers in the form of regulatory approval of chimeric antigen receptor T-cell therapies and CTLA-4, PD-1, and PD-L1 immune checkpoint inhibitors.

Immunotherapy is especially attractive because, ultimately, cancer represents a failure of the immune system. Since we humans lack the 20 (!) copies of the TP53 gene that elephants use to aggressively police the genomes in their massive number of cells, we regularly develop mutant cells that potentially could become cancer – twisted versions of “us.” Abnormal cells embedded in our tissues bearing DNA replication errors that have escaped DNA repair, or cells harboring genetic changes resulting from environmental injuries, represent clear and present dangers. Such abnormal cells are almost always safely recognized by immune cells for what they are and cleared. But, on rare occasions when the damaged cells are not eliminated, this oversight can allow a mutant cell to persist, expand, and become the taproot of a deadly neoplasm.

Whenever I describe reduced-intensity allogeneic hematopoietic cell transplantation to my patients with myelodysplastic syndromes or leukemia, I emphasize that the main goal of this species of transplant is not to eliminate and replace all abnormal marrow cells with the conditioning regimen or the donor cells. Instead, the primary intention is to perform an immunologic “Control-Alt-Delete” and reboot the patient’s adaptive immunity in the hopes that a donor’s cells might recognize rogue malignant cells that have somehow hoodwinked the patient’s own T cells into failing to sound an immunological alarm. As one of my patients who was cured by a second transplant from his sister after relapsing following a transplant from his brother quipped, “Well, that’s not surprising – she always was much more of a tattletale.”

But an allogeneic transplant – rolling the dice for graft-versus-leukemia effect – is a drastic, risky way to re-engineer immunity. Better approaches are finally moving into the clinic.

Cancer immunotherapy is certainly not a new concept. In the 1670s, before anyone knew the immune system existed, a few astute physicians noticed that patients with cancer who developed St. Anthony’s Fire (erysipelas) sometimes experienced spontaneous tumor shrinkage. Two hundred years later, this phenomenon was known widely enough among the medical community that doctor-playwright Anton Chekhov mentioned it in an 1890 letter to a journalist friend in Saint Petersburg. In the early 19th century, a few reckless French physicians even used dirty bandages to dress the wounds of women with breast masses who had undergone mastectomy, in an attempt to infect those wounds and use “laudable pus” to eliminate residual tumors.

Dr. Coley conducted the first serious experimental work in cancer immunotherapy in New York in the 1890s. After a patient with advanced, inoperable cancer was cured by a serendipitous soft-tissue infection, Dr. Coley began to inject Bacillus prodigiosus and other bacterial strains into surgically unresectable cancerous masses and lymph nodes to try to reproduce the effect. Dr. Coley noted reduction in tumor size in many patients and even a few complete remissions.

But the hit-and-miss (mostly miss) nature of Dr. Coley’s toxins, along with the advent of radium therapy shortly after Wilhelm Röntgen’s discovery of X-rays in 1895 and trials of aminopterin and nitrogen mustard chemotherapy in the 1940s, threatened to relegate immunotherapy to the “of historical interest only” file, alongside cupping and purging, ear candles, and aromatherapy for “wandering womb.” When Dr. Coley’s daughter Helen approached the heads of major hospitals and research institutes in New York, including C.P. “Dusty” Rhoads at the Rockefeller Institute and James Ewing at Memorial Hospital, she was dismissed. To leaders like Rhoads and Ewing, immunotherapy seemed far less appealing than other promising approaches of the day, like urethane treatment or the decades-long search for cancer-causing viruses. Yet, there were always a few true believers.

As industry sponsors jump on the immunotherapy bandwagon, a huge number of trials of with impossible accrual goals are now proposed for checkpoint inhibitors – highlighting a major problem in contemporary, herd-mentality–driven drug development.

The Breakthrough is a quick and compelling read, sprinkled with patient anecdotes. While reading, I was reminded of The Transformed Cell: Unlocking the Mysteries of Cancer, by Steven Rosenberg, MD, PhD, and John Barry, which I bought in medical school and found inspiring. (With respect to “of historical interest only,” I bought Dr. Rosenberg’s book at an actual brick-and-mortar bookstore.) The comparison with The Transformed Cell is appropriate, because Dr. Rosenberg and others’ 20th-century work on interferon-alpha, interleukin-2, and tumor-infiltrating lymphocytes is discussed in The Breakthrough.

Mr. Graeber is a nonfiction writer – a frequent contributor to Wired, The New Yorker, and The New York Times. He is perhaps most widely known for his 2013 best-seller, The Good Nurse: A True Story of Medicine, Madness, and Murder, about New Jersey registered nurse and serial killer Charles Cullen (also known as “The Angel of Death”). Mr. Cullen was implicated in the deaths of hundreds of patients, is currently serving multiple consecutive life sentences in a Trenton prison, and will become eligible for parole in the early 25th century. The Breakthrough, like Mr. Graeber’s previous book, is copiously annotated, with 107 pages of appendices, footnotes, references, and indices.

The book is written for the lay reader, so long sections about basic hematology and immunology may be a slog for hematologists, however engagingly they are written for a general audience. Still, even buried within the long explanations of what different types of white cells do, there are delightful gems. I did not know, for example, that in 1968, when Australian Jacques Miller, AC, FRS, presented data at an immunology conference suggesting that there might be two different types of lymphocytes called B and T cells, the skeptics – and they are always present, so illegitimi non carborundum – unhelpfully pointed out that “B” and “T” are the first and last letters of “bullshit.”

I appreciated the book’s enthusiasm for its subject, even if I did not really need to know how a Genentech researcher scored Imagine Dragons tickets for his teenage daughter from a grateful early clinical trial participant. At times, The Breakthrough falls into the worn clichés of generalist medical writing: use of terms like “game changer,” “revolutionary,” and, well, “breakthrough,” or descriptions of the long hours, relentless drive, precise German-inflected accents, and sartorial preferences of leading investigators. But these are minor points, and many readers will find the book interesting.

Lay readers or lab-based investigators, for example, may be startled to learn about the games clinicians play to get patients who are borderline-eligible into promising clinical trials (such as repeating labs after fluid administration, changing concomitant medicines, putting off evaluation of new symptoms that might lead to another diagnosis that could make the patient ineligible, etc.). As industry sponsors jump on the immunotherapy bandwagon, a huge number of trials of with impossible accrual goals are now proposed for checkpoint inhibitors – highlighting a major problem in contemporary, herd-mentality–driven drug development.

My favorite chapter was “Eureka, Texas,” about James Allison, PhD, who spent his early days playing blues harp at honky-tonks and working in a tiny lab in Smithville, Texas (1970 population: 2,959). This lab had been hastily built by MD Anderson Cancer Center after receiving an economic stimulus grant from the state. According to Dr. Allison, MD Anderson subsequently “sort of forgot about [us], so they pretty much left us alone.” The Smithville investigators were able to skip meetings, dodge administrative and teaching responsibilities, keep beer in the lab, and collaborate on a series of important experiments. Key insights into the T-cell receptor and costimulatory molecules resulted from this rare intellectual freedom.

The Breakthrough was written just before Dr. Allison and Tasuku Honjo, MD, PhD, from Kyoto University, won the Nobel Prize in Physiology or Medicine in October 2018 for their work on cancer immunology. It doesn’t mention the Prize but instead includes as evidence of recognition of the immunotherapy work a color plate of a large smiling team winning the 2014 William Coley Award for discovering PD-1. There was, therefore, no opportunity to discuss how human PD-1 discoverers Lieping Chen, MD, PhD, of Yale University, and Gordon Freeman, PhD, and Arlene Sharpe, MD, PhD, of Harvard Medical School were passed over for the 2018 Nobel Prize – a Swedish Academy omission perhaps even more egregious than the missed pass interference call that robbed the New Orleans Saints of a trip to Super Bowl LIII. But that controversy, as well as whether the Nobel Prize’s three-awardee limit is still meaningful in the 21st century, given the many key contributors to complex work like cancer immunology, is worth a book unto itself.