|
|
|
|
|
|
|
|
|
|
|||||||
 |
 |
 |
 |
|||||||||||||||||
|
Harnessing the Immune System:
|
|||||||||||||||||
 |
"Hypothetically, once the immune system has been sufficiently stimulated, it would be able to find and destroy every single tumor cell throughout the body." |
- Yong-Jun Liu, M.D., Ph.D., Director, Center for Cancer Immunology Research |
This promising—if preliminary—finding is the first clinical demonstration that complete molecular remission is possible with a peptide vaccine. The 45 patients had myeloid leukemias that had repeatedly failed to respond to every standard therapy, and the patients had life expectancies of less than a year. In response to the vaccine, 11 of the patients experienced objective clinical responses—and in a few patients, the disease went into remission. Four years later, the disease in four of those patients is still in complete molecular remission—there is no evidence of leukemia in amplified DNA, down to one in a million cells. Furthermore, disease progression slowed in patients who had an immune response but did not experience remission.
“Of course, these are early findings,” cautioned Dr. Molldrem, who is the study’s lead investigator. “We have much more research to do, especially in testing greater numbers of patients in each disease group.” Toward that end, Dr. Molldrem and colleagues expect to open three more trials of the vaccine this year.
The peptide vaccine is but one example of promising work taking place in the burgeoning field of cancer immunotherapy. Developing the field is one of M. D. Anderson’s highest research priorities, as evidenced by the creation of the Center for Cancer Immunology Research. Yong-Jun Liu, M.D., Ph.D., director of the center, speaks of the promise immunotherapy holds for cancer treatment.
“I think it is very possible that some type of cancer vaccine will be commercially available within the next decade,” said Dr. Liu. (He refers, of course, not to a ubiquitous cancer prevention immunization, but to a vaccine that would be used in the treatment of a specific type of cancer.)
While scientists have long sought to find a way to use the power of the body’s own immune system against tumors, recent scientific advances make the enterprise a little more feasible.
“A fundamental understanding of the immune system has only been developed over the last four decades or so, and that knowledge is critical for developing cancer vaccines,” explained Dr. Molldrem. “For instance, one of the trickiest parts is to identify which antigens to direct the immune response against in any given tumor type. There can be up to 100,000 different proteins and protein variants getting turned over at different times in a cell, so trying to identify which ones the T-cell actually ‘sees’ is kind of like finding a needle in a haystack. But now we have a molecular scale for understanding how it works, which is an important tool for directing immune reactions against a tumor.”
Dr. Liu stresses that, while there are many promising studies under way, the field of cancer immunology is still in its infancy. “We are still trying to refine what we know about the basic principles of the immune system and how it detects invaders. It’s the only way to develop truly effective cancer vaccines.” While overall, the immune system is very effective in protecting against viral, bacterial, and other infections, it is not very well developed for getting rid of cancer. One reason may be that cancer does not really threaten the existence of the human species, since most cancers occur after age 65. In any case, because cancer doesn’t present itself as an outside invader, the immune system’s cellular detection systems apparently don’t distinguish well between the normal tissue and tumor tissue and as a result cannot efficiently get rid of tumor cells.
Dr. Liu said that the existence of autoimmune diseases indicates that the immune system is capable of attacking self-tissues; the trick is learning how to get it to attack malignant tissue instead. By fully understanding how the immune system detects bacteria and viruses, we can develop ways to manipulate it to destroy cancerous cells as well.
 |
| "These dramatic responses happen in the minority of patients, but it shows that if we can stimulate the T-cells, we might have long-lasting effects against cancer." |
- Patrick Hwu, M.D.,
Chair, Department of Melanoma |
Eventually, immunotherapy could offer distinct advantages for cancer treatment. “Hypothetically, once the immune system has been sufficiently stimulated, it would be able to find and destroy every single tumor cell throughout the body,” said Dr. Liu.
Immunotherapy has potential not only for treatment of disease but also for prevention of recurrences as well because of the immune system’s ability to “remember” the antigen. Finally, it could be used as a preventative measure for healthy people who are at high risk of developing certain cancers.
Dr. Molldrem’s peptide vaccine, for example, has several potential clinical applications. “About two thirds of people with acute myelogenous leukemia go into a first remission with treatment, but most relapse and few survive,” said Dr. Molldrem. “We’re planning a study to look at whether administering the vaccine during that first remission can make the remission longer, or possibly even permanent.”
The vaccine also has potential use for prevention. “People who undergo chemotherapy are at increased risk of developing the leukemia-related blood disorder myelodysplastic syndrome,” he explained. “Eventually, the hope is that maybe that risk could be reduced or eliminated with a vaccination.”
Stimulating T-cells
M. D. Anderson currently has a number of immunotherapy studies under way, but efforts are primarily focused in three areas. “Right now, our vaccine development studies are concentrated in leukemia, lymphoma/myeloma, and melanoma,” said Dr. Liu. “That’s because we have very strong translational research programs in these areas at M. D. Anderson as well as very active immunotherapy programs.” Findings from these areas are likely to have applicability in other areas as well.
Dr. Molldrem developed the peptide vaccine for leukemia about 10 years ago, here at M. D. Anderson, whereas both Larry W. Kwak, M.D., Ph.D., and Patrick Hwu, M.D., recently were recruited from the National Cancer Institute to lead immunology development in the departments of Lymphoma/Myeloma and Melanoma, respectively. The two brought active programs and a wealth of research with them.
Research into vaccines for melanoma has produced limited but dramatic results, according to Dr. Hwu, who is chair of the Department of Melanoma. “We use interleukin 2 (IL-2) to stimulate T-cells, and it’s brought about long-term remissions in some of the patients, despite severe metastatic disease. Of course, these dramatic responses happen in the minority of patients, but it shows that if we can stimulate the T-cells, we might have long-lasting effects against cancer.”
Dr. Hwu explained that immunotherapy for melanoma can be done in one or more of the following ways:
Dr. Hwu’s previous studies demonstrated that the T-cell transfer method brought about objective clinical responses in 50% of patients with metastatic disease—which is a higher response rate than any other therapy for metastatic melanoma. More promising still are recent mouse models that suggest that combining these T-cells with dendritic cells may bring about an even greater clinical response.
“The fact that the treatment is individualized is what makes it challenging,” he said. “We have to come up with the best way to grow the cells sufficiently and easily in every patient. We are trying to develop a way to make this process easier and more widespread, just like bone marrow transplants.”
 |
| "It's the principle of breaking immunological tolerance." |
- Larry Kwak, M.D., Ph.D., Chair, Department of Lymphoma |
Amassing knowledge
Early vaccine research in lymphoma actually dates to initial studies begun in mice 30 years ago upon discovery of a very well-defined lymphoma tumor antigen, said Dr. Kwak, chair of the Department of Lymphoma. “The antigen truly distinguishes the tumor B cells from normal counterparts, making any immune response exquisitely specific to those cells.”
Dr. Kwak tested a “second-generation” lymphoma vaccine about 15 years ago in a successful and highly publicized human study. Since then, he has conducted a series of phase II trials of the vaccine, in which up to 75% of study participants with low-grade lymphoma achieved molecular remissions and long-term, disease-free survival. Currently, Dr. Kwak is involved in a national, multicenter phase III trial of the vaccine he pioneered.
He’s also investigating the use of a similar vaccine in another intriguing new area of immunotherapy research. “In collaboration with the Blood and Marrow Transplantation Department, we’re doing phase I testing of a similar vaccine in multiple myeloma in the setting of bone marrow transplantation,” he said. “Instead of vaccinating the patient, we actually vaccinate the bone marrow donor. It’s the principle of breaking immunological tolerance.Then we transfer the T-cells from the donor to the recipient. We’re really excited about that. That’s a new initiative that’s just coming out of the laboratory and is happening here.”
Dr. Kwak came to M. D. Anderson because of just this kind of opportunity—to advance immunology research in collaboration with researchers, scientists, and doctors across disciplines. As Dr. Liu explains it, the Center for Cancer Immunology Research is an important hub for collaborations that lead to the translation of findings from basic immunology research into clinical trials and, ultimately, new and better treatments. “Here, basic immunologists and clinical immunologists are together in one building, and the proximity provides an easy, natural opportunity for collaboration,” said Dr. Liu. “We have the critical mass here—that’s really exciting.”For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.
Other articles in OncoLog, April 2005 issue:
Home/Current Issue | Previous Issues | Articles by Topic | Patient Education
About Oncolog | Contact OncoLog | Sign Up for E-mail Alerts
©2008 The University of Texas M. D. Anderson Cancer Center
1515 Holcombe Blvd., Houston, TX 77030
1-877-MDA-6789 (USA) / 1-713-792-3245
Patient Referral Legal Statements Privacy Policy
TOP