Cancer vaccines targeted by many as the ‘holy grail’ for tumors
Treatment protocols are short, adverse effects are few. These new therapies challenge everything oncologists know about treatment of the disease.
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 to cancer.”
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.
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 future.”
Harnessing the immune system
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 check.”
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.
Advantages of cancer vaccines
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 potential.”
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 immune response.”
The cost of good health
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 Today.
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 faulty antigen.
“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.”
On the horizon
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 year.
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.
The future of vaccines
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 cancer vaccines.
“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 financial disclosures.
Is the cost of sipuleucel-T in line with the cost of other cancer treatments?
It’s a first-in-class active immunotherapy and should be offered to all appropriate candidates, those patients with metastatic, castration-resistant prostate cancer.
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.
My concern is that it is expensive.
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.