With the Food and Drug Administration requesting more information about the efficacy of Provenge, an investigational vaccine for hormone-refractory prostate cancer and what many expected to be the first vaccine approved to treat cancer, one may wonder when a therapeutic vaccine will finally reach patients outside clinical trials. But as researchers learn more about the immune system, develop better vaccines, and find how best to study their effects on cancer, vaccines are still expected to be an important player in the future of cancer therapy.
In March 2007, after decades of research, the first therapeutic cancer vaccine appeared close to approval. Provenge (sipuleucel-T), a vaccine to treat hormone-refractory prostate cancer, was recommended for approval (13 to 4) by a Food and Drug Administration advisory committee. The final hurdle was approval by the FDA.
But in May, the agency instead chose to delay review of the vaccine, requesting additional study data, which could be another one to three years. The day of the Provenge announcement, another advisory panel said mifamurtide (formerly Junovan), a vaccine for childhood osteosarcoma, should not be approved.
While the outcome of these two drugs led many to wonder if vaccine therapy may ever reach patients outside clinical trials, vaccine therapy is still a highly researched area in many tumor types in addition to prostate cancer and sarcoma, including breast cancer, melanoma, multiple myeloma, and non-small cell lung cancer.
No therapeutic vaccines have made their way to FDA approval, but success has been seen on the preventive front. Gardasil, which was approved on June 8, 2006, protects against the virus associated with cervical cancer, human papillomavirus, or HPV. Another cervical cancer vaccine, Cervarix, is primed for approval in early 2008. Vaccines to prevent cancer are usually targeted against viruses, such as HPV for cervical cancer and the hepatitis B virus for liver cancer. But vaccines to treat cancer have been more difficult to prove efficacy in clinical trials and, therefore, haven’t had much success with the FDA.
The theory behind therapeutic vaccines is that by programming the body’s immune system to recognize and attack cancer cells, it will spare the normal tissue and destroy the cancer. But as researchers learn more about cancer and immunity, putting that theory to clinical use is becoming more complex.
hief of oncology at Stanford University School of Medicine in California. Researchers have found cancer cells can hide from immune cells, whereas others manipulate the immune system to protect them.
“We’ve learned so much more about the immune system and why it doesn’t do what we want it to do,” says Ronald Levy, MD, c
“That’s why there’s more people writing about why vaccines fail than why they succeed,” Dr. Levy says. But with each failure and each new discovery about the intricacies of the immune system, scientists are using that growing knowledge to develop better vaccines and better ways to test them.
In an article published in the July 1 issue of Nature Medicine, researchers say they may have found one way cancer cells evade the immune system. Myeloid-derived suppressor cells (MDSCs) typically prevent the immune system from attacking healthy tissue, but they may also prevent the immune system from attacking cancer cells. In a normal setting, when a foreign body is detected, a type of killer T cell identifies and marks it for apoptosis, or cell death. But with cancer cells, MDSCs suppress that reaction, allowing cancer cells to multiply unchecked. Research also suggests these cells actually increase when tumor cells are present, perhaps protecting malignancies.
Researchers hope that by shutting down a byproduct of the cellular pathway called ROS, (in part powered by MDSCs), it would eliminate this so-called T-cell tolerance. Research is still in preclinical stages, but scientists hope this information will yield better cancer vaccines.
Cancer vaccines may be successful in the lab, but in the human setting, researchers are finding it harder to prove they’re effective.
Hence, some researchers are calling for vaccines to be evaluated by patient response, more so than tumor response.
In standard clinical trials, scientists are trained to look for tumor response—if the tumor shrank, by how much and how fast, and if it has delayed the cancer from progressing. With vaccine trials, researchers are seeing data that suggest that, although some vaccines haven’t shown effect on tumors, they may have a positive effect on patients, including prolonging overall survival.
The FDA’s review of Provenge was delayed because the agency requested more information from IMPACT, a phase III trial due to be completed by 2010. However, the FDA has agreed to review the drug early if the IMPACT trial shows positive interim data, which is expected in 2008.
The phase III trial data given to the FDA for its approval application was designed to show if Provenge created a statistically significant tumor response rate, which it did not (11.7 weeks with Provenge compared with 10 weeks with placebo). However, follow-up data suggest men receiving Provenge lived longer than those receiving placebo—a median survival time that was more than four months longer (25.9 months compared with 21.4 months). After three years, a third of patients on Provenge were alive compared with only 11 percent on placebo. Advocates of the vaccine, who protested the review delay, hope data from IMPACT will clearly show survival data, and result in a subsequent approval.
“Evidence is accumulating that maybe vaccines are able to keep the tumor in check because of this dynamic process of immunity as opposed to 95 percent of the tumor being destroyed with a chemotherapeutic agent, then the tumor growing back with abandon and the patient not living any longer,” say Jeffrey Schlom, PhD, chief of the Laboratory of Tumor Immunology and Biology at the National Cancer Institute. But with vaccine therapy, “it appears that patients are living longer in the absence of seeing the tumor being shrunk.”
Another reason vaccines may be deceptively unsuccessful is the patient population they are being tested in, including patients with resistant or metastatic cancers. “There’s a time and a place for these agents,” Schlom says. “They’re not to be used or are not useful in patients with advanced cancers, with large tumors, or who have had multiple prior therapies.”
esearchers are questioning if the best way to use cancer vaccines is to prevent recurrence or treat early-stage disease.
But that’s how new drugs are tested. Early-phase trials are often tested in patients who have had several rounds of different drugs and whose cancers have become resistant or have recurred. RIf a vaccine is given after several chemotherapy regimens, it may not provide much benefit to the patient if the previous therapies damaged the immune system so much that the vaccine can’t boost an adequate attack. In addition, once patients have been given several different therapies, their cancer may have become advanced, and a vaccine may be ineffective against the large amount of tumor cells.
Another interesting finding in the Provenge trial is that when researchers looked at the overall survival difference between the vaccine arm compared with the control arm, they found certain patients with prolonged survival were given Provenge followed by Taxotere (docetaxel) afterward, hinting at a synergistic effect of the two drugs. Patients given Provenge and Taxotere had a median survival of 34.5 months compared with 25.4 months of placebo followed by Taxotere.
“This is a new paradigm—that a drug is not just tested on its own, but tested in terms of how it influences patient survival with subsequent therapies,” says Schlom, who co-authored a review article on the paradigm shift in testing therapeutic cancer vaccines published this year in Clinical Cancer Research.
Standard therapies would be considered a failure if they only killed 5 percent of tumor cells, but with a vaccine those tumor cells would act as a boost to the vaccine and actually enhance anti-tumor activity. Follow the vaccine with chemotherapy and it appears to have a significant benefit. But part of the current problem is that in drug development researchers have to study one therapy at a time to prove it’s effective and safe before adding it to a combination.
“The FDA is pretty clear on this,” Dr. Levy says. “They just don’t allow concocting some mixture of therapies without showing that each component of the mixture has merit and has safety on its own.”
Cancer immunotherapy has blossomed just in the past decade and has become a defined science. Schlom recounts a meeting he attended recently where about 25 compounds were either in or close to clinical testing. “Another reason for my cautious optimism is that there are so many ways to enhance immunity,” he says.