Since the approval last year of the first-in-class therapeutic cancer
vaccine sipuleucel-T, there has been increasing interest in using cancer
vaccines as a treatment vanguard. Scientists are learning new things every day
about the best ways to harness the immune system to fight cancer, stimulating
the immune system to recognize cancer cells that typically go unrecognized.
According to Clinicaltrials.gov, a search for “cancer vaccine”
yields a list of 1,136 trials currently ongoing for vaccines that treat a host
of cancers, including lung cancer, breast cancer, pancreatic cancer, prostate
cancer, brain cancer and melanoma, among others. Many are in phase 1 and phase
2, but some are as far along as phase 3.
According to Charles Drake, MD, PhD, associate professor of
immunology, medical oncology and urology at Johns Hopkins Sidney Kimmel
Comprehensive Cancer Center, there are two reasons contributing to the interest
in cancer vaccine research.
“The first reason is that the first therapeutic cancer vaccine,
sipuleucel-T (Provenge, Dendreon), has been approved by the FDA to treat a
solid tumor,” Drake told HemOnc Today. “There have been
a fair number of phase 3 trials that haven’t been successful, and now that
there has been a successful trial, there is renewed interest in the field. The
second reason is that within the last 10 years, there has been increasing
understanding of the reasons why the immune system doesn’t respond so well
According to John Kirkwood, MD, professor of medicine at the
University of Pittsburgh and a member of the HemOnc Today Editorial Board,
cancer vaccines are the unrealized “holy grail” for most tumors, as
they offer the opportunity for the ultimate specificity. The success of cancer
vaccines is based on the concept of immunologic memory, the same characteristic
that applies to vaccines given in childhood. Even when exposed to a pathogen,
the immune system is activated and it eradicates the pathogen before the host
even has an infection. The hope, Kirkwood said, is that this immunologic memory
will help prevent the relapse of cancer; however, more work must be done to
understand just exactly how the immune system functions against cancer so that
optimal vaccines can be created.
Nora Disis, MD, professor of medicine at the University of
Washington and a member of the Fred Hutchinson Cancer Research Center, sees a
tremendous amount of excitement surrounding the use of sipuleucel-T and other
Photo by Clare McLean/UW Medicine
“We have many different marker antigens that we think will make
good vaccines,” Kirkwood said in an interview. “But first we need to
learn how to immunize before we learn to vaccinate. We are just figuring out
how to use immunomodulators to better immunize so that we can make vaccines
more potent. We need to know more specific details about the mechanism of
action to be able to apply these therapies more effectively in the
Cancer develops because it manages to escape the immune system,
according to Thomas Schwaab, MD, PhD, assistant professor in the
departments of urology and immunology at Roswell Park Cancer Institute.
“The body ultimately has its own police-like mechanism that roams
the body to make sure that anything abnormal is taken care of,” Schwaab
said in an interview. “Cancer escapes this immune surveillance. We need to
either get the cancer to look more suspicious to the immune system, or we need
to get the immune system to identify the cancer.”
Wasif Saif, MD, MBBS, professor of clinical medicine at Columbia
University College of Physicians and Surgeons, said harnessing the immune
systems of patients can be a powerful tool to treat cancer.
“Cancer cells are clever because they are capable of turning the
immune cells into traitors, which subsequently help guard them,” Saif told
HemOnc Today. “Vaccines can prevent the masking effect of the
cancer cells. One of the big problems with cancer treatment is that some
malignant cells can still be left, and these cells can regrow and cause
morbidity and mortality. Vaccine therapy can help us to program the immune
system to recognize those cells and either scavenge them or keep them in
Vaccines are not the only way to harness the immune system to treat
cancer. Recently approved by the FDA for patients with metastatic melanoma,
ipilimumab (Yervoy, Bristol-Myers Squibb) is an anti-cytotoxic T-lymphocyte
antigen 4 (CTLA-4) blocking antibody that works by taking the brakes off the
body’s natural regulatory response against cells that are trying to
generate an immune response. These brakes are applied to the T cells to prevent
them from recognizing certain proteins that, if recognized by the immune
system, would cause the development of autoimmune disease. Once these brakes
are taken off, the regulatory cells have the power to recognize the cancer.
“Just activating the immune system with a vaccine is one approach,
but there is also some understanding about other mechanisms, called
immunological checkpoints, like CTLA-4, that keep the immune system from
responding to cancer,” Drake said.
By far, one of the most attractive qualities of a therapeutic cancer
vaccine is that they are associated with less toxicity compared with other
treatments for cancer, namely chemotherapy. Whereas adverse effects of
chemotherapy, such as fatigue, nausea and vomiting, are common, adverse effects
of a cancer vaccine are rarer and may include a flu-like syndrome and possibly
a rash or irritation at the injection site.
“The side effects of a cancer vaccine are acceptable to the vast
majority of patients,” Drake said. “Very few patients come off
vaccine trials because of side effects.”
According to Drake, the treatment course of a cancer vaccine is also
relatively short, which represents another advantage to the patient. The
prostate cancer vaccine sipuleucel-T, for example, is given in three
injections, 2 weeks apart. This makes the treatment course last only 6 or 7
weeks vs. the 30 weeks needed for 10 cycles of docetaxel (Taxotere,
Sanofi-Aventis), the traditional chemotherapy for prostate cancer.
The advantages of using the immune system to combat cancer has been
twofold, according to Duane Mitchell, MD, PhD, assistant professor of
neurosurgery at Duke University and associate director of the Duke Brain Tumor
Immunotherapy Program. One is the known specificity of the immune system, which
can selectively target and kill infected cells without harming normal cells.
The other, again, is the all-important concept of immune-system memory.
“Once the immune system is appropriately triggered to recognize a
foreign antigen, there is a capacity of long memory in the immune system to
protect the host for a long period of time after the initial exposure,”
Mitchell said in an interview. “One of the hopes is that we can not only
specifically eliminate cancer cells with a cancer vaccine, but also provide a
potentially long-lived protection to the host against cancer. Our current
treatments, like chemotherapy and targeted agents, do not have that
According to Nora Disis, MD, professor of medicine at the
University of Washington and a member of the Fred Hutchinson Cancer Research
Center, another benefit of using a patient’s immune system to eradicate
the potential for harm is that, unlike chemotherapy or other biologic
therapies, in which the big concern is whether the treatment will circulate
throughout the body to where all the cancer is, T cells circulate throughout
the body wherever there is cancer and work to eradicate it.
“T cells will crawl out of the vasculature and go deep into
metastases and continue to grow and divide until cancer is eradicated,”
Disis told HemOnc Today. “It doesn’t matter where in the
body, [these T cells] will go there and continue to work to eradicate the
cancer. That’s in the ideal world, where you could stimulate the ideal
The cost of cancer vaccines has been called into question and may be a
potential roadblock for patients who want access to the treatment. A treatment
course of sipuleucel-T, for example, costs $93,000. Sipuleucel-T has been
approved for payment by most insurance carriers, including Medicare, according
to Schwaab, and is comparable in cost to many other courses of treatment.
“Any cellular therapy or immunotherapy dealing with taking cells
out of the human body, culturing them, manipulating them and putting them back
into the body requires a certain degree of labor, which means a big component
of the cost is simply labor,” Schwaab said in an interview. “But the
cost of a treatment course of docetaxel is actually in the same ballpark.”
Drake said the cost of docetaxel, given in 10 cycles, costs $30,000 to
$50,000. Docetaxel confers a survival benefit of 2 months, however, whereas
sipuleucel-T is associated with a survival benefit of 4 months.
“When you look at the cost in relationship to what it costs to give
chemotherapy, or even some of the targeted agents, like bevacizumab, [the cost
of sipuleucel-T] is not as outrageous as you may think,” Drake said.
“The other thing that contributes to the cost of sipuleucel-T is the fact
that it took nearly 20 years to develop, so the company needs to recoup some of
its development costs.”
Another example to consider in cost comparisons is bone marrow
transplant. According to Larry W. Kwak, MD, PhD, chairman of the
department of lymphoma and myeloma and associate director of the Center for
Cancer Immunology Research at MD Anderson Cancer Center, this has been an
approved therapy for more than 20 years and is the standard of care for many
diseases. Its cost is approximately $80,000.
“The price tag of these immunotherapies is not out of line with
other effective treatments for other cancers,” Kwak told HemOnc
According to Disis, the FDA approval of sipuleucel-T represents a
significant advance after decades of clinical trials involving cancer vaccines.
It represents the first-in-class of therapeutic cancer vaccines that target a
“There is a tremendous amount of excitement about sipuleucel-T, as
there would be with any first-in-class novel agent that has been approved for
therapeutic use,” Disis said. “As a tumor immunologist, I see
sipuleucel-T as the opening of a door behind which there are a number of agents
that are the next generation of cancer vaccines.”
The next generation may be closer than once thought. Results from two
randomized phase 3 trials this year may pave the way for more cancer vaccines
in the near future. In a study published in The New England Journal of
Medicine, a gp100 peptide vaccine formulated to treat advanced melanoma
demonstrated higher response rates and longer PFS.
In the trial, 185 patients with metastatic melanoma were randomly
assigned to interleukin-2 alone or interleukin-2 combined with the vaccine. The
response rate was 16% in patients who received the vaccine with interleukin-2
vs. a response rate of 6% in those who only received interleukin-2
(P=.03). The PFS for those who received the vaccine was 2.2 months vs.
1.8 months for those who only received interleukin-2 ( P=.008).
In a study published in the Journal of Clinical Oncology,
patients with follicular lymphoma fared better when they were vaccinated with
hybridoma-derived autologous tumor immunoglobulin idiotype (Id) conjugated to
keyhole limpet hemocyanin (KLH). The 177 patients in the trial had reached a
complete response with chemotherapy before being randomly assigned to Id-KLH
with granulocyte-monocyte colony–stimulating factor or KLH alone with
GM-CSF. The median DFS was 44.2 months for patients who received the vaccine
compared with 30.6 months for those who did not ( P=.047).
“Now we have a field that has three positive phase 3 trials, which
is the gold standard,” Kwak said. “There is no question that the
principle of cancer vaccines has been proven, and in three diverse tumor types.
There will no doubt be more phase 3 trials coming along. This is just the tip
of the iceberg.”
According to Drake, one of the vaccines that is furthest along in the
pipeline is another prostate cancer vaccine, called PROSTVAC-VF/TRICOM and
manufactured by Bavarian Nordic Immunotherapeutics. It uses a modified smallpox
vaccine to immunize against PSA. In a randomized, phase 2 trial published in
the Journal of Clinical Oncology, patients who received the
vaccine had an 8.5-month longer OS compared with patients in the control arm.
This was a hypothesis-generating outcome, as OS was not the primary endpoint of
the trial. A phase 3 trial of this vaccine is expected to launch later this
At the Duke Brain Tumor Immunotherapy Program, Mitchell and colleagues
are working on developing immune treatments for high-grade malignant brain
tumors in both adult and pediatric patients. The researchers have established
the proof of concept that it is possible to safely engender an immunologic
response in patients with brain tumors. Mitchell said there have also been
suggestions of good clinical response compared with historical controls.
For pancreatic cancer, Saif is currently running a phase 3 trial of a
hyperacute immunotherapy, called algenpantucel-L, which is composed of
irradiated, live, allogeneic human pancreatic cancer cells expressing the
enzyme alpha1,3 galactosyl transferase. Hyperacute immunotherapy is based on
the hypothesis that alpha-1,3 galactosyl transferase epitopes in human cancer
cells trigger an immune response, called hyperacute rejection, an inflammatory
reaction/immune response that is thought to be responsible for generating
immunity against tumor antigens.
In a phase 2 study presented at the 2010 ASCO Gastrointestinal Cancers
Symposium, patients who received algenpantucel-L with standard adjuvant therapy
had a 12-month DSF of 91% vs. 63% who received standard treatment alone. The
24-month DSF was 54% for those who received algenpantucel-L vs. 32% for those
who received standard therapy alone.
Although many experts agree that vaccines alone are not the single wave
of the future for cancer treatment, they said vaccines will definitely play a
role in the treatment of cancer.
“When patients have large, bulky tumors, the immune system is not
going to handle those masses internally,” Drake said. “We need to use
our conventional tools, like chemotherapy, radiation therapy and surgery, to
get the patient to the point where they have the least tumor burden possible.
Then we need to be smart and use cancer vaccines and checkpoint blockade agents
together. The combination of our conventional tools, vaccines and checkpoint
blockade agents is the wave of the future, but that future is not as close as
I’d like it to be.”
Currently, cancer vaccines are typically tested in patients with
advanced, metastatic inoperable cancers, Kirkwood said. The next, most
herculean task is to test these vaccines in patients with earlier stage
cancers, as adjuvant treatment. But even that is not the ultimate goal of
“Our hope is that we may also use vaccines to prevent cancers, much
like we use the HPV vaccine to reduce cervical cancer in women, and the
hepatitis B vaccine to prevent liver cancer,” Kirkwood said. “The
prevention of other, nonviral cancers is the hope for the future because if you
could prevent them, there may be an even greater benefit than we suspected of
using vaccines in the adjuvant setting.” – by Emily Shafer
For more information:
- Hardacre JM. J Clin Oncol. 2011;29(Suppl 4):236.
- Kantoff PW. J Clin Oncol. 2010;28:1099-1005.
- Schuster SJ. J Clin Oncol. 2011;29:2787-2794.
- Schwartzentruber DJ. N Engl J Med. 2011;364:2119-2127.
Disclosures: Dr. Disis is a consultant for VentiRx. Dr. Drake is
a consultant for Bristol-Myers Squibb, Dendreon and Amplimmune. Dr. Kirkwood is
on the steering committee for the GlaxoSmithKline MAGE-A3 vaccine trial. Dr.
Kwak is a consultant for Biovest and Antigenics, and receives research funding
from Celgene. Dr. Schwaab is a scientific adviser to Dendreon. Dr. Saif
receives grant funding from Newlink. Dr. Mitchell reported no relevant
Sipuleucel-T is the first therapy to demonstrate a survival advantage in
cancer using an immunotherapeutic approach. This agent, along with ipilimumab
(Yervoy, Bristol-Myers Squibb), an antibody demonstrated to prolong survival in
patients with relapsed melanoma, are the first immunotherapies to work in
cancer. Both of these therapies demonstrate statistically significant and
probably clinically meaningful benefit to patients overall.
What is challenging right now is to identify those patients who are more
likely to benefit and who are benefiting. As we learn more and understand more
about immunology, immunotherapy and cancer therapeutics, we’ll be able to
define, for sipuleucel-T, for ipilimumab, and for any other therapies, the
patients who are actually responding and benefiting, and those who are not.
These therapies, both sipuleucel-T and ipilimumab, do not appear to be
out of line with the overall expense of cancer therapeutics, and therefore
there is no reason not to offer these patients these therapies. As we learn
more, we will find those patients who are likely to benefit and be able to
improve the cost-benefit ratio.
Philip Kantoff, MD, is a professor of medicine at
Harvard University, and chief of solid tumor oncology at Dana-Farber Cancer
Institute. He has served as a consultant to Dendreon, BNIT and Bellicum.
In any randomized trial, you have to ask yourself whether the test group
had a better outcome than the control population, or is it that the control
group did worse, for some reason, as compared to the test group? In the current
era, with increasing recognition of the importance of cost-benefit and
diminishing financial resources for health care, I think sipuleucel-T provides
another option that is potentially useful, but that there is way too little
information to put a good context on where it should fit into the overall
therapeutic armamentarium. I am tremendously concerned at the cost of the
therapy for the indication cited, but also for the segments of the medical
community giving sipuleucel-T to patients irrespective of the indication for
which it was approved by the FDA. There is a very limited, very finite
indication for patients with metastases and no or minimal symptoms. Some
physicians are referring patients for sipuleucel-T therapy for extensive
symptomatic disease, patients with failing physical health, or in the adjuvant
setting, where there are no metastases at all, and the published data just
don’t support such use. Consequent upon that, I have no idea whether the
members of the oncology community with access to this treatment are necessarily
using it according to the FDA approval.
I do understand that there were considerable costs in developing
sipuleucel-T, and some of the cost of purchase is related to recouping the
development costs. However, if it is being used inappropriately, beyond the
indication, I’d be very concerned. In addition, I’m not yet convinced
that it has a huge impact on patient survival. There are other options for this
specific indication, many of which are also very expensive, but some of which
are much cheaper and probably about as effective. The median survival benefit
of sipuleucel-T is modest, given the key clinical indication, and it was given
to a very particular population of patients, some of whom may not have needed
treatment at that time. While there was a small survival benefit, it was in a
heterogeneous group of mostly asymptomatic patients, and the real clinical and
population benefit remains to be proven, as far as I’m concerned. The jury
is still out on the role of sipuleucel-T.
Derek Raghavan, MD, PhD, is president of the Levine
Cancer Institute of Carolinas Healthcare System, and a HemOnc
Today Editorial Board member. He reports that he is a member of the
international advisory board of Sanofi-Aventis.