Suggested Reading – Graeber

Charles Graeber, The Breakthrough: Immunotherapy and the Race to Cure Cancer, Twelve, 2018.

“Cancer kills millions of people every year and is one of humanity’s greatest health challenges. By stimulating the inherent ability of our immune system to attack tumor cells James Allison and Tasuku Honjo have established an entirely new principle for cancer therapy. In 1994–1995, Allison studied a known protein that functions as a brake on the immune system. He realized the potential of releasing the brake and thereby unleashing our immune cells to attack tumors. He then developed this concept into a new approach for treating patients.” 1

The above was not written by Graeber. It was written some weeks after his book was published, by the Nobel Foundation to explain why James Allison was awarded the 2018 Nobel Prize in Medicine. This is the stuff that we now call immunotherapy. A decade before immunotherapy was derided as useless and to be avoided at all costs. 2 It’s now the stuff that cures cancers: not all of them, but some – and more, it seems, each passing month. It’s the stuff of Charles Graeber’s book. It’s the breakthrough.

Graeber tells the story of the people who attacked cancer via immunity. The story of doctors and patients: who they are, where they came from, what happened to them. He writes it in laymen’s language, through the eyes of the people involved: some desperate for cures, and others staying up nights to find them. It conveys the excitement of success and the disappointment of failure. It describes both long, dogged studies and moments of sudden inspiration that has led to this lifesaving breakthrough.

It tells the story of dendrites and macrophages (literally, “big eaters”) – big cells that eat up what doesn’t belong in the body. They collect garbage. They mostly eat up old body cells that have retired and self-destructed. Occasionally, when they come across something that’s not part of the body, something that’s different, peaks their interest, they grab a chunk of it and head over to lymph nodes to show it around. Graeber compares the lymph nodes to “Rick’s in Casablanca. Good guys, bad guys, reporters and soldiers, macrophages, dendrites, T and B cells, and even diseased cells, everyone goes to Rick’s”. There, macrophages show off their finds to T cells.

Watch those T cells. Especially, watch their receptors. I think of T cells as fuzzy little balls, the fuzzy hairs all over their surface being receptors – T Cell Receptors, or TCRs. They are touchy-feely and pay attention to everything they touch. Each TCR is programmed to recognize one, and only one thing like a DNA sequence, a thread on a virus or something else that is not part of the body. When it finds its thread it sticks to it and goes into action. If what it sticks to is a cell, it kills it. It sends out messengers called cytokines (moving cells) as a call for help. These cytotoxic T cells (cytotoxic means cell-killer) have a protein called CD8 + on their surface, so are also called CD8 + T cells. There are other kinds of T cells too, all of them being made in the thymus, looking pretty much alike to early observers, so all being called T cells (for thymus) as opposed to B cells, which are made in bone marrow and do similar stuff, but differently.

This is immunity. At least a key part of it, and the part that is perhaps most critical to curing cancer.

If T cells can recognize and kill stuff that doesn’t belong in the body, why don’t T cells recognize and kill cancer cells? That is the quest of Graeber’s characters.

In 1968 Dr. Steven Rosenberg, a young surgical resident at a VA hospital, was given a patient with belly pain who needed routine gall bladder surgery. He noticed that the patient had a strange set of scars across his abdomen, indicating previous surgery, and dug up records to find that 12 years earlier he was diagnosed with stomach cancer and had most of his stomach removed. They found metastases through his liver and abdomen and so deemed his disease incurable. But here he was, 12 years later, cancer free, perfectly healthy except for his gall bladder. He should have been dead. What happened to the cancer? Rosenberg concluded that the patient had cured himself: it was his immunity. The immune system is able to cure cancer! This sent Rosenberg on his career: harnessing the immune system to treat cancer.

He and others picked at the story of immunity over decades. It wasn’t quick, even if Graeber tells it quickly. Jim Allison, with a recent biochemistry PhD in a (then) obscure Texas lab associated with a Houston hospital called M.D. Anderson, was trying to figure out how T cells worked. What, exactly, is this thing on the T cell that lets it recognize other stuff (antigens) and spring to life? He finds the answer (explained in the book), but cannot get a major journal to publish his results. His results get noticed anyway by an eminent biologist who duplicates them, setting Allison on the world stage.

Allison and others probe deeper into T cells. They find different kinds of T cells with different gadgets on their surface. Killer T cells have the fuzzy TCRs. They also have switches that can be switched on and off, like a receptor called CD28 that must be switched on for the T cell to work. Allison’s students found another molecule, a protein called CTLA4 that looked something like CD28 and that seemed to turn on the killer T cells when activated. Others, especially at Bristol Meyers Squib, also found the CTLA4, and made an antibody to block it, beating Allison’s group to that punch. But BMS didn’t get the story quite right: Allison found that CTLA4 does not turn on T cells: it turns them off! It stops them from working, like a brake, strong enough to override the CD28 on-switch. It’s part of the system that keeps T cells from attacking the body. Blocking it lets go of the brake and sends the cells on their way. When Allison’s lab gave the CTLA4 antibody to some mice implanted with tumors, they were cured. Cured! The lesson was that one way tumors survive is by learning to make CTLA4, putting the brakes on the T cells that would otherwise attack them. Block the CTLA4, and T cells can attack the cancer. This was the first of a class of “checkpoints” on T cell activation. Allison’s CTLA4 antibodies went on to become ipilimumab – the first immune therapy drug approved for cancer.

Another switch on the T cell is called PD-1 (PD for Programmed Death, the initial thought being that throwing this switch caused the cell to self-destruct and die. It now seems this isn’t quite true, but nevermind.) If the PD-1 switch is thrown, it turns the cell off. It gets thrown by contacting a matching ligand (a binding protrusion) called PD-L1 that grows on the surface of many tumor cells for the sole purpose of bindng to the PD-1 switch and throwing it. Block PD-1 or PD-L1, and T cells can survive and do their work. It was first found by Tasuku Honjo and colleagues in Tokyo – Honjo eventually shared the Nobel Prize with Allison. The story is a long one and fascinating, and Graeber tells it well.

Graeber tells the story of Jeff Schwartz, diagnosed in 2011 with stage 4 kidney cancer, who happened to walk through the right door at the right time, getting the last slot in the twelve-patient Phase-1 study of a chancy treatment would come to be called PD-L1 blockade.

He tells the nearly forgotten story of Dr. William Coley who in 1891 noticed that a cancer patient who contracted a severe infection in the hospital was cured of his tumor, and conjectured that his activated immune system was able to attack the tumor as well as the infection. Coley developed a mix of toxic bacteria that was able to stimulate the immune system to cure cancers in about 20% of cases, but the toxins themselves killed so many patients that the treatment got lost to history. He tells the story of CAR T cells. These are T cells that are removed from the patient’s blood then treated in the lab (transduced) to change their T cell receptors to ones that recognize proteins from the tumor. A few proteins like one called CD19 rarely appear on healthy cells, but do appear on carcinogenic B cells of acute lymphoblastic leukemia (ALL). The CAR scheme is to modify the T cell receptors to trigger on CD19. This is done using, of all things, HIV. HIV viruses, which can infects T cells and cause the loss of immunity seen in AIDS, are stripped of most of their innards (but not their infecting ability to infect T cells) and reprogramming them to express the CD19 antigen. At the University of Pennsylvania lab of Dr. Carl June, T cells were taken from a patient – a 6-year-old girl with ALL named Emily, were infected with the CD19-modified HIV, and were returned to the girl. But it went badly. Emily contracted what we now call a cytokine storm: she developed a 107° fever, swelled up like a hot water bottle, had multiple organ failure, and lapsed into coma. What happened was that the T cells attacked the cancer with unprecedented vigor, generating myriads of cytokines, especially one called IL6, forcing the rest of her body into uncontrollable overdrive. But there was a stroke of luck: IL6 is also responsible for the inflammation of rheumatoid arthritis, and just a few months earlier the FDA had approved a new antibody called tocilizumab that blocked its effects. Given to Emily, it calmed down the cytokines. “A week later, she opened her eyes to the tune of “Happy Birthday” sung by the hospital staff. She was exactly seven years old and had made it to the other side.” If Dr. June had not known and stocked tocilizumab because his own daughter suffered from rheumatoid arthritis, this story would have come out very differently.

There’s more – much more. I leave it to you to find it. The book is a page turner. Nearly 200 pages tell the story of immunotherapy for cancer (as of 2018). Another 25 pages of Appendix provide an update to the state-of-the-art as of mid-2018, a brief summary of CTLA4 and PD-1/PD-L1 checkpoints therapy, and a fascinating history of diseases and their treatments dating back to ancient times. Even the over 50 pages of endnotes make fascinating reading.

1 James P. Allison – Facts – 2018. Nobel Media AB 2019.

2 Siddhartha Mukherjee’s 2011 Pulitzer Prize winning book, The Emperor all Maladies: a Biography of Cancer, is an excellent history of the development of chemotherapy – read it too. But it makes no mention of immunotherapy. It wasn’t here yet.