Book Review
Off to the Races
The Breakthroughs of Immunotherapy
In this edition, ASH Clinical News Associate Editor David Steensma, MD, reviews
The Breakthrough, which traces the evolution of immunotherapy to treat – and
potentially cure – cancer.
Have you read any hematology-related books recently? Let us know what we should
read and review by emailing us at [email protected].
F
or 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 “preci-
sion” medications that were made pos-
sible 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 immuno-
therapy’s long fallow period, and ending
with the ultimate triumph of the believ-
ers 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 attrac-
tive 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 num-
ber 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 elimi-
nated, 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 transplanta-
tion to my patients with myelodysplastic
syndromes or leukemia, I emphasize that
the main goal of this species of transplant
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ASH Clinical News
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 hood-
winked 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 sponta-
neous 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 immuno-
therapy 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 com-
plete 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 discov-
ery of X-rays in
1895 and trials of
aminopterin and
nitrogen mustard
chemotherapy in
the 1940s, threat-
ened to relegate
immunotherapy to
the “of historical
interest only” file,
alongside cup-
ping and purging,
ear candles, and
aromatherapy for
“wandering womb.”
When Dr. Coley’s
daughter Helen ap-
proached the heads
of major hospitals
and research insti-
tutes in New York,
including C.P.
“Dusty” Rhoads
at the Rockefeller
Institute and James
Ewing at Memorial
Hospital, she
title: The Breakthrough: Immunotherapy and the Race to
was dismissed.
Cure Cancer
To leaders like
author: Charles Graeber
length: 320 pages
Rhoads and
published: November 2018, Twelve/Hachette Book Group
Ewing, immuno-
therapy seemed
Transformed Cell is appropriate, because
far less appealing than other promis-
Dr. Rosenberg and others’ 20th-century
ing approaches of the day, like urethane
work on interferon-alpha, interleukin-2,
treatment or the decades-long search for
and tumor-infiltrating lymphocytes is
cancer-causing viruses. Yet, there were
discussed in The Breakthrough.
always a few true believers.
Mr. Graeber is a nonfiction writer – a
The Breakthrough is a quick and
frequent contributor to Wired, The New
compelling read, sprinkled with patient
Yorker, and The New York Times. He is
anecdotes. While reading, I was reminded
perhaps most widely known for his 2013
of The Transformed Cell: Unlocking the
best-seller, The Good Nurse: A True Story
Mysteries of Cancer, by Steven Rosenberg,
of Medicine, Madness, and Murder, about
MD, PhD, and John Barry, which I
New Jersey registered nurse and serial
bought in medical school and found
killer Charles Cullen (also known as “The
inspiring. (With respect to “of historical
Angel of Death”). Mr. Cullen was impli-
interest only,” I bought Dr. Rosenberg’s
cated in the deaths of hundreds of patients,
book at an actual brick-and-mortar
is currently serving multiple consecutive
bookstore.) The comparison with The
May 2019