introduction

prelude
1.
Patient 101006 JDS
2.
Simple idea
3.
A faint light in the darkness
4.
Eureka
5.
removal, equilibrium, escape
6.
A fierce struggle
7.
chimera
8.
After the gold rush
9.
just now

Acknowledgements

Appendix A Immunotherapies Currently in Use or Soon to Become Available
Appendix B: A Brief History of Innovative Cancer Immunotherapy
Appendix C: A Brief History of Disease, Civilization, and Immunity in Anecdotes

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Translator's Note
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How Immunity Fights Cancer
The mystery of immunotherapy, which has persisted for 100 years, has been solved, and a breakthrough in cancer treatment has been discovered!

How did immunotherapy, once denounced as pseudoscience, become a cutting-edge field of modern medicine? From the workings of the human immune system to the history and present of cancer immunotherapy, its possibilities and limitations, and the challenges yet to be solved, this captivating medical research is meticulously and dynamically portrayed. The long journey of unraveling the tricks of cancer cells and harnessing the innate immune system to fight cancer becomes a reality, a drama interwoven with the challenges, failures, and triumphs of countless scientists and doctors who have dedicated their lives to this research, the unwavering hope and dedication of countless patients, and the undying humanity of humanity.


The idea of ​​treating cancer by using the innate immune system
A touching and exciting story that becomes reality

'Why doesn't our immune system fight cancer?' For decades, doctors and scientists have puzzled over this perplexing riddle.
The answer lies in the fact that cancer uses a number of tricks to turn off the normal immune response.
Only recently have scientists figured out exactly what the trick is and figured out how to defeat it.
Many people call this method “the penicillin moment” in cancer treatment.
This opens the way to the development of immunotherapy drugs that activate the body's own immune cells to fight cancer cells, unlike existing treatments that attack the cancer cells themselves. Improved treatments that enable more precise and effective treatments are continuously appearing and joining the long line of clinical trials.
And through this very cancer immunotherapy, patients with terminal cancer who were considered incurable are miraculously cured.

In this book, New York Times bestselling author and medical journalist Charles Graeber depicts the struggles, trial and error, and discoveries that countless people went through to make cancer immunotherapy, once considered pseudoscience or a miracle, a new paradigm in cancer treatment today, and explains in an easy-to-understand way how our body's immune system works and the principles of cancer immunotherapy.


This book meticulously examines numerous medical papers and literature, including the records of Dr. William Coley, who witnessed a patient's cancer melt away after an intense immune response following an injection of "monococcus" over 100 years ago, and interviews doctors, researchers, and patients, including 2018 Nobel Prize winner in Physiology or Medicine James Allison, to detail the remarkable scientific discoveries of our time.
Behind these achievements are the stories of geniuses, skeptics, people of true faith, and, above all, patients who risked their lives and many more who lost theirs, all of whom contributed to pioneering, refining, and testing this new and promising science.

As the translator says, this book “vividly shows the relationship between cancer, the greatest disease facing humanity today, immunity, the miraculous healing method latent within our bodies, and the relationship between them, by tightly combining history, science, and human drama like three threads twisted together.”

expectation

The 2018 Nobel Prize in Physiology or Medicine went to Professors James Allison and Tasuku Honjo for their discovery of cancer treatment through immune checkpoint inhibition.
“We have established a completely new principle for cancer treatment by stimulating the immune system’s unique ability to attack tumor cells.
The fact that the reason for selecting the treatment, “Treatment through immune checkpoint inhibition has now revolutionized cancer treatment and fundamentally changed the way we look at cancer,” is not just empty rhetoric can be seen immediately when you look at how many cancer research institutes and pharmaceutical companies are actually jumping into the development of immuno-oncology drugs.


As of June 2018, approximately 940 new immuno-oncology agents are reported to be undergoing testing with the goal of breakthrough designation and FDA approval.
In addition, 1,064 new immunotherapies are in preclinical development in numerous laboratories.
In just a few years, 2,004 new anticancer drugs are being studied.
This pace of change is highly unusual in medicine and unprecedented in the field of cancer treatment.
By the time readers finish this book, the numbers and the science behind them will have advanced significantly.” _Page 283

history

The idea that we could use our innate immune system to fight cancer wasn't always so welcome.
Rather, it was the opposite.
There have been occasional reports of terminally ill cancer patients whose tumors disappeared after a bout with a bacterial infection, but these have often been dismissed as nothing more than mystical anecdotes.
This is because the science of the time could not understand why such things were happening.


However, there were pioneers who noticed this mysterious phenomenon and thought about it in relation to the immune system.
A representative example is William Colley, who is introduced in Chapter 2 of the book.
In the late 1800s, New York physician Colley reads a medical report that a terminally ill cancer patient named Fred Stein had his tumors disappear after being infected with a deadly "pyrexia" bacteria. He sets out to see for himself what he has found.
Experiments to induce an immune response by injecting a single virus into a patient whose cancer was too advanced to be treated were a great success.
A patient whose tumor had progressed so far that it seemed hopeless even after surgery suffered from a high fever and an immune response for several days after being 'vaccinated' with a single virus, but the tumor melted and flowed away, and he made a clean recovery shortly thereafter.


After confirming the effectiveness several times, Coley developed and sold a treatment called 'Collitoxin' by weakening the single bacterium, but the cheers were short-lived.
The American Cancer Society listed his toxin as an "unproven cancer treatment" (a decision they reversed a decade later, but its reputation never recovered), and it was eventually tabooed in the medical community, overshadowed by the then-popular radiation therapy and the subsequent chemotherapy (even though Coley's immunotherapy actually showed superior results).


Even as time passed and many of the components of the human immune system were discovered, immunotherapy was often ridiculed.
Any medical student with sound thinking should not have even come close to researching cancer immunotherapy.
Of course, there were times when cancer immunotherapy was considered a miracle cure and received a lot of attention.
For example, in 1980, interferon, which became possible to mass-produce thanks to the development of genetic recombination technology, was a substance that was so highly anticipated that it was featured in a cover story in Time magazine titled “Penicillin for Cancer.”


There was an investment boom in biotechnology companies producing interferon, but it was short-lived.
It was similar when Dr. Steven Rosenberg of the National Cancer Institute in the United States announced the results of a trial on patients of a drug called interleukin-2, which stimulates the body to produce large quantities of T cells.
The phrase "breakthrough in cancer treatment" was used in articles, but interest soon waned when it became known that the results were not satisfactory enough for the public who were hoping for a perfect breakthrough.

It was only after countless researchers, often observing clinical cases of patients who improved through cancer immunotherapy, experienced countless frustrations, failures, and the joy of discovery, that the reason the human immune system does not respond to cancer cells and how the immune system can be made to recognize and attack them was discovered.
It took this long time for it to be accepted in the oncology community because it was a drug with a ‘slightly different treatment philosophy’ that worked on the immune system to attack cancer cells rather than directly attacking cancer cells.


science

The human immune system is so complex, and new cancer immunotherapy agents and combination therapies are constantly emerging, that even doctors find it difficult to fully grasp them. However, this book presents this information in an engaging way, using simple and intuitive analogies so that even the general public can understand it.
(The main contents are briefly summarized in Appendix B.)

Why the immune system doesn't attack cancer cells has long been a mystery.
Some oncologists have speculated that something might be preventing immune cells from attacking cancer cells, but this view has often been dismissed as far-fetched or hopeless.
Then, in 2011, several important facts were discovered.
In fact, several groundbreaking studies, including the discovery of the T cell receptor in 1984, have revealed some of the processes required for T cells to detect and attack antigens, and researchers have been focused on how to accelerate the immune response.


But what was finally revealed was not the accelerator pedal, but the brake.
There are several checkpoints in T cells to prevent immune cells from attacking normal cells, and James Allison discovered that a molecule called CTLA-4 is one of these brakes, and that cancer cells can take over this brake to block the immune response and proliferate freely.
And “when we developed a drug (antibody) that binds to this brake and blocks it from being used by cancer cells, the immunosuppression was lifted and the T cells started attacking the cancer again.


“It’s like cancer has tied up the immune system’s feet so that it can’t step on the brakes.” (p. 321) Professor Tasuku Honjo and other researchers went a step further and discovered the mechanism by which a protein called PD-1 on the surface of T cells and an antigen called PD-L1 present on cancer cells combine to prevent an immune response, and discovered an antibody that blocks this, thereby opening the door to the development of treatments with fewer side effects.
The main characters of this book are anti-CTLA-4 antibodies and PD-1/PD-L1 antibodies.
And new treatments, including vaccines, cell therapy, combination therapy, and bispecific antibodies, including a therapy that creates genetically modified T cells (CAR-T) and injects them into patients (Chapter 7), are opening a breakthrough in cancer treatment (Appendix A).


people

The book breathlessly portrays the stories of countless people who played leading and supporting roles in achieving these innovations, “stories of people who fought desperately on the edge of life’s precipice and miraculously recovered.”
Dr. Kang Byeong-cheol, a pediatrician and translator of science/medical books who was in charge of the translation, said, “I was so impressed by the vividness and speed of the descriptions that I sat down without thinking much about the original book, and ended up staying up all night to read it all.”
Let's hear a little more from the translator.


“The heart of this book is human drama.
The book is full of stories of doctors and scientists who dedicated themselves to their studies with human compassion and warm empathy for suffering patients, such as Jim Allison, an immunologist born from humble beginnings but who discovered the immune checkpoint with his free spirit and brilliant insight and won the 2018 Nobel Prize; Lloyd Old, who believed in the possibility of cancer immunotherapy despite prejudice and coldness and opened the way for numerous talented people; Robert Shriver, who established a new relationship between cancer and the immune system together with Old; and Carl June, who lost his wife to cancer and eventually jumped into cancer immunotherapy research and pioneered new frontiers.
Their stories are no less impressive than the myths and heroic tales woven by gods and giants.
Paradoxically, the more heroic stories come from ordinary people.
The stories of patients who, even in the depths of despair, never give up their will to live and their positivity, survivors who share their stories of hard-won survival to help others, and neighbors who willingly help, share, and stand in solidarity with one another are truly heartwarming.

While the stories of patients battling cancer without giving up hope are moving, one of the book's charms is its vivid glimpse into how medical research is conducted.
Researchers who have conducted similar studies sometimes engage in fierce competition to be the first to publish a paper (see the anecdote about Mark Davis and Susumu Tonegawa surrounding the discovery of alpha chains, pp. 152-153), and they also generously share experimental materials and research results.
While some eccentric individuals solve problems with ingenious ideas, there are also many who make the mistake of being caught up in bias and failing to objectively interpret data.
There are those like Dr. Steven Rosenberg, who turned down a pharmaceutical company offer that offered him the chance to make a fortune and instead stayed in the lab.
The book also shows the process of new drug development and clinical trials.


“The book features vivid figures who gave their all to gradually roll the wheels of science forward, their obsession, their jubilant successes, and their bitter failures intertwined. As you read, lost in the public's misunderstanding, the scientific community's infighting, and the lives of pioneers with great vision, you will soon grasp the fundamentals of science” (Translator's Note).

assignment

Although the original title is 'The Breakthrough', the book does not mislead readers by claiming that immunotherapy is a miracle treatment that can cure cancer.
It is also important to note that existing immunotherapy drugs do not work on all cancers, that there are specific drugs that work well for specific cancers, that the side effects of the drugs, and that responses vary from patient to patient.
While there were those like Jeff Schwartz (Chapter 1) and Emily Whitehead (Chapter 7) who miraculously returned from the brink of death, there were also cases like Brad McMillan (Chapter 6), who, after decades of innovative treatments, ultimately failed to recover, and another girl who received the same treatment as the survivors but did not survive.
The book calls us to remain humble even in the face of remarkable achievements, and shows that there is still a long way to go.
Among the challenges that need to be addressed is the high cost of cancer immunotherapy.


“The question this book doesn’t address is how many people can afford the financial burden that comes with such a bright outlook.
Boy (the brand name for ipilimumab, an anti-CLTA-4 agent) is administered in four doses, with a total treatment cost of over $120,000.
The cost of taking Merck's anti-PD-1 antibody Keytruda, which is used to treat advanced melanoma, for one year is $150,000.
While the constant stream of good news is welcome, there is an urgent need to find a solution to the economic burden of illness and death that everyone inevitably experiences.
Everyone has the same chance of getting cancer.
However, if the benefits of medical advancement cannot be enjoyed by everyone, even if innovative treatments are developed, it will be a regression for humanity as a whole.” _281-282

It is clear that immunotherapy will be a tremendous innovation and a last resort for countless cancer patients.
The question then remains: how accessible is this treatment?
We hope this book will inform the world about the existence of immunotherapy and the progress of its treatment, and serve as a catalyst for social discussion regarding patient accessibility.