Book summary and review of “The Breakthrough: Immunotherapy and the Race to Cure Cancer”

Book Outline and Review

For decades, cutting out tumours, burning them with radiation, and poisoning them were the only three conventional treatment approaches available to patients with cancer.

However, beginning with rituximab and imatinib in the 1990s, a fourth class of cancer treatment has joined the trio of surgery, radiotherapy, and chemotherapy:

these are narrowly targeted “precision” medications that were made possible by a newer and deeper understanding of cancer biology.

We are now at the beginning of what looks to be a transformative and transitional era in cancer care, with the advent of a fifth method that could someday replace all the others: cancer immunotherapy.

“The Breakthrough” is a popular science book by Charles Graeber, and it looks into the history of cancer immunotherapy, beginning with surgeon William Coley’s work with toxins in the 1890s, followed by immunotherapy’s long rest 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 an especially exciting and promising approach because, ultimately, cancer represents a failure of the immune system. Since we regularly develop mutant cells that potentially could become cancer, that the immune system fails to target. 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 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 root of a deadly tumour.

Cancer immunotherapy is certainly not a new concept. In the 1670s, before anyone knew the immune system existed, a few physicians noticed that patients with cancer who developed 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 who had undergone mastectomy, in an attempt to infect those wounds and use “laudable pus” to eliminate residual tumors.

It was 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 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 the discovery of X-rays in 1895 and trials of aminopterin and nitrogen mustard chemotherapy in the 1940s, threatened to relegate immunotherapy to the “historical interest only” file. However, recently there has been a spring of renewed interest in immunotherapy, and as industry sponsors jump on the immunotherapy bandwagon, a huge number of trials are now in progress.

The book is written for the lay reader, and the sections about hematology and immunology are written for a general audience. 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 lab tests after fluid administration, changing medicines, putting off evaluation of new symptoms that might lead to another diagnosis that could make the patient ineligible, etc.).

“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.