By: Bryan Tutt
For years, researchers have studied various ways to boost the body’s natural ability to fight cancer. While cytokines and monoclonal antibodies are routinely used in cancer treatment, research into other immunotherapies, like T cell therapies and therapeutic vaccines, is just beginning to pay off. In the past year, promising results have been reported for randomized clinical trials of therapeutic vaccines for several different types of cancer.
Some of these results have caught the attention of major media outlets. Successful phase III trials of a follicular lymphoma vaccine tested at The University of Texas MD Anderson Cancer Center led Time magazine to name the vaccine’s developer, Larry Kwak, M.D., Ph.D. (a professor in and chair of the Department of Lymphoma and Myeloma), among this year’s list of the world’s 100 most influential people. Also making news was the successful trial of Dendreon Corp.’s sipuleucel-T (Provenge) vaccine, which received U.S. Food and Drug Administration (FDA) approval for use in patients with prostate cancer. Another ground-breaking phase III trial, which was conducted in patients with metastatic melanoma at MD Anderson and other centers, was among the first to demonstrate a positive effect of a vaccine against metastatic disease.
Successful vaccines and their development
“There have been some exciting breakthroughs in therapeutic vaccines,” said Patrick Hwu, M.D., chair of the Department of Melanoma Medical Oncology at MD Anderson and the senior investigator for the study of theGP100 peptide vaccine in patients with metastatic melanoma. In this trial, patients who received the therapeutic vaccine plus interleukin 2, which is commonly used to stimulate the proliferation of T cells in patients with metastatic melanoma, had a 22.1% response rate, while those who received only interleukin 2 had a 9.7% response rate. Patients who received the vaccine plus interleukin 2 also had a longer median progression-free survival (2.9 months) than those receiving only interleukin 2 (1.6 months).
“The melanoma study showed us that combination therapy is more effective,” Dr. Hwu said. “The vaccine helps to make T cells, and interleukin 2 helps to drive those T cells. The T cells are the soldiers that kill the tumor cells.” He added that studies are under way or are being planned to combine other vaccines—including GlaxoSmithKline’s MAGE vaccine, which is now in phase III trials in patients with melanoma and other types of cancer—with cytokines like interleukin 2.
Dr. Kwak agreed that vaccines are only part of the overall treatment strategy. “In lymphoma, it is fairly easy to get patients into remission with standard chemotherapy,” he said. “The paradox is that they eventually relapse because chemotherapy doesn’t get rid of every last tumor cell. The role of the lymphoma vaccine is to come in during that minimal disease state and mop up the residual tumor cells.”
In a phase III trial of the lymphoma vaccine, 117 follicular lymphoma patients were given the idiotype protein vaccine or a placebo while in remission. The 76 vaccinated patients had a median time to relapse of 44.2 months, compared with 30.6 months for those who received the placebo. Dr. Kwak said researchers are in the process of submitting their data to the FDA for approval of the vaccine, and he added that several patients from an earlier trial of the vaccine are still in remission after 12 years of follow-up. “These patients have not needed anything else—not even rituximab, which is often given as maintenance therapy for lymphoma,” he said.
“We found that the vaccine keeps patients in remission longer, but our goal is to make that even better by developing a second generation of more potent vaccines,” said Sattva Neelapu, M.D., an assistant professor in the Department of Lymphoma and Myeloma and the principal investigator for the lymphoma vaccine’s phase III trial.
Dr. Neelapu said a therapeutic vaccine can induce two types of immune responses, an antibody response and a T cell response. “Right now we don’t know whether both are required or one is more dominant than the other for vaccine efficacy,” he said.
Dr. Neelapu’s laboratory is studying the mechanisms within the tumor cell microenvironment that impair immune response. “One of these mechanisms is mediated by regulatory T cells. If we can get rid of those regulatory T cells before or after vaccination, the vaccine is more likely to be effective,” he said. “The other mechanism we have found in lymphoma is that the antitumor T cells within the tumor upregulate an inhibitory molecule on the cell surface called programmed death-1. If we block this molecule—with an antibody, for example—then the T cells can recognize and kill the tumor much better.”
Another therapeutic vaccine developed at MD Anderson, the PR1 peptide vaccine, was given to patients with chronic and acute myelogenous leukemia in a phase II study. Jeffrey Molldrem, M.D., a professor in the Department of Stem Cell Transplantation, said that patients with minimal disease (less than 15% blasts in their bone marrow) responded best, but he added that 12 of the 53 patients not in remission at the time of vaccination had an objective clinical response, including eight who had a complete response and were still in remission up to 7 years after vaccination.
The PR1 vaccine is derived from two proteins (proteinase 3 and neutrophil elastase) that are overexpressed and aberrantly expressed in myelogenous leukemia cells—in the blasts and in the leukemia stem cells in particular. To help the immune system create a response to these proteins, the vaccine must first attach itself to leukemic cells to be recognized by the immune system. “The vaccine binds to a surface protein very frequently expressed in the Caucasian population, which makes up a large percentage of leukemia patients in the United States,” said Jorge Cortes, M.D., a professor in the Department of Leukemia and the principal investigator of an ongoing phase II trial of the PR1 vaccine combined with interferon in patients with chronic myelogenous leukemia. Enrollment in this study is on hold because the company that was manufacturing the vaccine decided to stop doing so. Dr. Cortes said there has been some response in the five patients currently participating in the trial—they received the full four-dose regimen and are being monitored—but there are too few patients to draw any significant conclusions. MD Anderson has begun manufacturing the vaccine, and Dr. Cortes hopes to resume enrolling patients soon.
The production of vaccines for research is being facilitated by a new partnership between MD Anderson and Texas A&M University System’s National Center for Therapeutic Manufacturing. “This new partnership will reduce costs of vaccine production and allow us to produce more vaccines, antibodies, and biologic agents such as recombinant cytokines for research,” said Dr. Molldrem. While vaccines derived from the PR1, GP100, or MAGE peptides can be mass-produced, the lymphoma vaccine is an idiotype protein custom-made for each patient from his or her own tumor cells. “My group is now looking at more streamlined methods of producing the vaccine using a DNA vaccine format in which you don’t have to express protein but instead clone the patient’s DNA,” said Dr. Kwak. This technique could make the vaccine more effective and also reduce the cost of producing it.
Other immunotherapy research
In addition to vaccines, other approaches to stimulate patients’ immune systems are being investigated. Dr. Molldrem said his group has developed an antibody that recognizes both the PR1 peptide and the human lymphocyte antigen HLA-A2. “These are present on the surface of both leukemia cells and leukemia stem cells,” he said, “but very little of the combined molecule is present on the surface of normal hematopoietic cells.” In cell culture studies, the antibody killed leukemia cells but not bone marrow cells or cord blood cells from healthy donors. Animal studies have also been successful, and Dr. Molldrem expects trials of the antibody in patients to begin within the next year. “We’re also working on PR1-specific T cells for adoptive cell therapy in patients following stem cell transplant,” he said.
Clinical trials of T cell therapy for melanoma patients have already begun. “We’ve treated more than 25 patients who have metastatic melanoma by taking the tumor out and growing T cells from the tumor in the lab—up to 150 billion cells—which are then reinjected into the patient,” Dr. Hwu said. Response rates have ranged from 40% to 50%, with some responses lasting up to 2 years so far. “There are many ways to stimulate the immune system, and we have to combine them rationally,” he said. “In early stages of disease, we’re using vaccines plus interferon; in the later stages, we’re using vaccines plus interleukin 2 and T cell therapies. We’d like to combine these with antibodies that stimulate the immune system, like anti-CTLA-4, which takes the brakes off the immune system.”
Padmanee Sharma, M.D., Ph.D., an assistant professor in the Department of Genitourinary Medical Oncology, has been working with anti-CTLA-4, an antibody that blocks an intrinsic regulatory mechanism on T cells. Blocking the inhibitory signal allows the T cells to work for longer periods and to be more effective against tumors. A phase III clinical trial of anti-CTLA-4 in patients with metastatic prostate cancer is currently enrolling patients at MD Anderson and other institutions. “It’s an exciting agent, and it has shown dramatic, durable responses in a previous trial with melanoma patients,” Dr. Sharma said. She explained that because the antibody targets a molecule on T cells, it is not a tumor-specific agent and may therefore boost immune responses against various types of cancer.
In a previous trial of the NY-ESO-1 DNA vaccine in patients with metastatic prostate adenocarcinoma, Dr. Sharma’s group found that the vaccine induced an immune response but that the response was suppressed by regulatory T cells and other mechanisms that regulate immune responses. Because the NY-ESO-1 DNA vaccine activates T cells and anti-CTLA-4 blocks an intrinsic inhibitory mechanism in T cells, Dr. Sharma and her group are in the process of planning a trial combining the two drugs. “We need to be able to turn on antitumor immune responses and simultaneously block inhibitory pathways that act to turn them off,” she said.
Now that their lymphoma vaccine has had a positive trial, Dr. Neelapu said he and other researchers at MD Anderson are doing follow-up studies to learn why certain patients responded to the vaccine and others did not. “We are looking at genetic markers and immunological markers from these patients,” he said.
“None of these studies were home runs,” said Dr. Hwu. “In our melanoma study, the response rate doubled from 10% to 20%, but that still leaves 80% who did not respond.” His lab continues to study biomarkers in patients from the previous trial of the GP100 vaccine and in patients participating in ongoing studies. “We’re trying to customize treatment with the MAGE vaccine by looking at the expression of certain genes in the tumor to develop profiles that will determine who responds to the vaccine and who doesn’t,” said Dr. Hwu. In fact, he added, MD Anderson has an immune-monitoring core laboratory to analyze cell-mediated immune responses in samples from participants in clinical trials of new immunotherapies or drugs.
“I think response rates from vaccines are going to get incrementally better as we learn how to target these therapies,” Dr. Hwu said. “I’m excited about the future.”
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