Directing the Immune System to Cancer Cells
Before an immune cell can destroy a cancer cell, it must find
it. Many therapeutic antibodies that have been approved by
the FDA for treating patients with a wide range of cancer
types (see Supplemental Table 2, p. 131) work, at least in
part, by helping immune cells find cancer cells. The most
recent additions to this group of immunotherapeutics are
daratumumab (Darzalex) and elotuzumab (Empliciti),
which were both approved by the FDA in November 2015 for
treating patients with multiple myeloma that has progressed
despite treatment with a number of other therapeutics.
Multiple myeloma is one of the most commonly diagnosed
hematological malignancies, or blood cancers, in the
United States, with 30,330 new cases expected to be
diagnosed in 2016 ( 3). In recent years, the development
and FDA approval of new therapeutics—including
proteasome inhibitors like bortezomib and carfilzomib
and immunomodulatory agents like lenalidomide—have
improved outcomes for patients like Congressman Bob
Carr, who was featured in the AACR Cancer Progress Report
2012 ( 87). Despite the advances, many patients whose
disease initially responds to the ne w therapeutics eventually
relapse owing to treatment resistance.
Daratumumab works by attaching to a protein called CD38,
which is found at high levels on the surface of myeloma cells.
This attachment has several effects on the myeloma cells,
most notably flagging them for immune cells, which upon
attaching to another part of daratumumab are triggered to
destroy the myeloma cells. Daratumumab was approved by
the FDA after it was shown in early-stage clinical trials to
lead to tumor shrinkage or disappearance in a significant
number of patients whose multiple myeloma had relapsed
despite several other treatments (167). It is hoped that
future studies will reveal that the immunotherapeutic also
extends survival for patients.
Elotuzumab attaches to another protein that is found at
high levels on the surface of myeloma cells, SLAM7F. This
protein is also found at high levels on immune cells called
natural killer cells (see sidebar on Key Players in the Immune
System, p. 86). Elotuzumab has distinct effects on myeloma
cells and natural killer cells after attaching to SLAM7F on
their surfaces, thus providing a two-pronged attack on
multiple myeloma. It directly activates natural killer cells,
enhancing their ability to kill myeloma cells, and it flags
myeloma cells for a number of immune cell types, which
once directed to the myeloma cells, attack and destroy them.
Elotuzumab was approved for use in combination with
lenalidomide and dexamethasone for treating patients
who have multiple myeloma that has worsened despite
treatment with other therapeutics. This decision was
based on phase III clinical trial results, which showed that
adding elotuzumab to lenalidomide and dexamethasone
significantly increased the number of patients who had
their tumors shrink or disappear, as well as the time before
disease progressed (168).
These approvals, together with the November 2015
approval of ixazomib (see sidebar on Recent Advances
Against Multiple Myeloma, p. 78), have provided patients
with multiple myeloma, like Stephen Herz (see p. 92), not
only new treatment options, but also new hope.
Boosting the Killing Power
of the Immune System
Another approach to cancer immunotherapy is to enhance
the ability of T cells to eliminate cancer cells. If we use
the analogy of a car, this approach is like stepping on the
accelerator, and it can be done in a number of ways (see
sidebar on How Immunotherapeutics Work, p. 82).
One form of immunotherapy that appears to work, in
part, by boosting the killing power of the immune system
is oncolytic virotherapy. Oncolytic viruses are viruses,
which may or may not be genetically modified in some
way, that can infect and destroy cancer cells. As the cancer
cells are destroyed, they release molecules that can trigger
immune cells that have the natural potential to destroy
yet more cancer cells. These immunotherapeutics are
injected directly into patients’ tumors, rather than being
given orally or by intravenous infusion.
The U.S. multiple myeloma
incidence rate has risen about 0.7%
each year for the past 2 decades ( 2).
RESEARCH ( 87).