Drew Pardoll, M.D., Ph.D.
Professor of Oncology, Director of Cancer Immunology
The Sidney Kimmel Comprehensive Cancer Center
at Johns Hopkins, Baltimore, Md.
Immunotherapy as a treatment for cancer is a dream that is more
than 110 years old. But we have now reached an inflection point: in
the past three years, a number of immunotherapies have emerged
that work in different ways to achieve amazing, long-lasting
responses that can be measured in years not months.
It all started in the 1890s, when William Coley noticed that the
immune system’s response to a bacterial infection seemed to spill
over and cause tumor regression in some cancer patients. So, he
began to treat his cancer patients by infecting them with certain
kinds of bacteria. Although Coley reported some successes, his
approach to cancer treatment was never widely adopted.
Since Coley’s efforts, we have gained immense scientific insight
into the pathways, molecules, and cells that regulate the immune
system and execute its functions. Integrating this understanding of
the immune system with our knowledge of the biology of cancer is
beginning to allow us to intelligently design immunotherapies that
are working for a significant number of patients.
This progress is very recent. Before 2010, which is when the
FDA approved the first therapeutic cancer vaccine, sipuleucel-T
(Provenge), for the treatment of prostate cancer, investigational
immunotherapies would cause tumor regression in a few patients,
but not enough patients for the immunotherapies to become
established treatment options.
In the past, the development of immunotherapies called therapeutic
cancer vaccines was plagued by failure in large phase III clinical
trials despite some positive patient responses. But now that
immunologists have gained more knowledge of the molecules and
cells involved in activating the immune system, I believe that over
the next three years, therapeutic cancer vaccines will become a
core component of cancer immunotherapy combinations.
Therapeutic cancer vaccines like sipuleucel-T act as if you
are pushing on the accelerator of your car. We also have
immunotherapies that disable the “parking brake”! Ipilimumab
(Yervoy), the first of this class of cancer immunotherapy, was
approved by the FDA for the treatment of metastatic melanoma in
The development of ipilimumab resulted directly from a series
of milestone discoveries by scientists in the field of immunology.
What is most exciting about ipilimumab, is that some patients who
responded are still alive three, four, five years after receiving their
treatment. This is something that has rarely happened before for
patients with metastatic melanoma, and it indicates that even after
their treatment was stopped, these patients’ immune systems are still
keeping their tumors in check.
In 2012 and 2013, the results of early-stage clinical trials testing
immunotherapies that disable a second immune-system brake,
called PD1, showed even more dramatic results. These studies
reported frequent clinical responses not only for patients with
metastatic melanoma, but also for those with kidney or lung cancer.
Although these PD1-targeted treatments are not approved by the FDA
currently, patients’ responses seem to be long-lived, and everyone
involved in the development of these drugs expects that they will
soon become widely available.
In the past, insufficient scientific understanding of the immune
system has been a barrier to advancing immunotherapy as a
treatment for cancer. Now that we have expanded our knowledge,
we are no longer shooting in the dark; we are using science to guide
the development of new approaches. Particularly exciting is the
idea of combining immunotherapies that work in different ways. We
have already seen this in the clinic, where a small clinical trial has
confirmed the scientific prediction that a combination of ipilimumab
and a PD1-targeted immunotherapy would be better than either
There is also a lot of reason to believe that some molecularly targeted
therapies combined with epigenetic therapies will have huge effects
on how the immune system interacts with a tumor. This opens
the door to the possibility that combining these treatments with
immunotherapies will provide additional clinical benefit.
When I was an oncology fellow, I was taught that there were three
pillars of cancer treatment: surgery, radiotherapy, and chemotherapy.
In the late 1990s, we added a fourth pillar, therapies that target
specific cancer-driving defects. I have such confidence in the
potential of immunotherapy that I think the years from 2010 to 2015
will be looked at historically as the time that immunotherapy became
the fifth pillar of cancer treatment.
There are barriers to this becoming a reality, but they are not
scientific. They are regulatory and financial. To use a military analogy,
we have the weapons but not the funds to test or manufacture them