Thema: Presse: Immunotherapy with CD8+ RTE T Cells
Presse: Immunotherapy with CD8+ RTE T Cells
Katja[a]
26.08.2003 11:49:17
Immunotherapy: CD8+ RTE T Cells Hold Great Promise in Fighting Gliomas
By Christopher Wheeler, PhD
Many clinical vaccine trials for cancer patients, including those with malignant brain tumors (gliomas), have been completed with intriguing results. Nevertheless, immune-based therapies for human cancer have thus far been applied with limited success in counteracting tumor progression. This has led some scientists to doubt whether cancer vaccines - or the anti-tumor immune responses they are supposed to enhance - have any place in the future of cancer treatment. This is a justifiable view because the concept that enhancing anti-tumor immune responses slows the growth of human tumors remains unproven.
Skepticism directed toward cancer vaccines has arisen and, in fact, has increased for at least three reasons. First, tumors whose growth is unquestionably impacted by immune activity have not been identified. Second, although cancer vaccines appear to both enhance anti-tumor immune activity and clinically benefit some patients, these two effects almost never completely coincide with each other. This leaves researchers confused as to how vaccines work and, therefore, how to improve them. Third, it is still not clear what is most important in making an immune cell recognize and kill tumors and what prevents this in cancer patients. To move beyond this skepticism, as well as to improve cancer vaccines, tumors susceptible to immune activity must be identified, the particular immune parameters responsible for clinical benefits (if any) determined and the discrete influences on tumor recognition and killing by cells of the immune system elucidated.
These requirements are accentuated for malignant brain tumors. This is because these tumors reside within an organ without normal access to immune components, because immune activity in the brain can be different than that in the rest of the body and because a large variety of immune-suppressing properties has been ascribed to these tumors. It would seem that studying malignant brain tumors might be an unlikely way to try to validate and improve cancer vaccines in general and a long shot for attempting to develop clinically effective cancer vaccination. There is, however, one parallel between malignant brain tumor growth and immunity that is intriguing. Malignant gliomas grow substantially faster in older patients who, incidentally, usually have defects in the kind of immune cells able to recognize and kill tumors. In addition, individuals with immune systems that are so hyperactive they attack certain portions of their own bodies (autoimmune patients) have a significantly reduced risk of acquiring a brain tumor, suggesting that hyperimmunity might prevent brain tumors. Thus, investigators within Cedars-Sinai´s Maxine Dunitz Neurosurgical Institute´s (MDNSI) Immunology Program sought to determine if malignant brain tumors were sensitive to immune activity and to identify the specific immune parameter that might contribute to age-dependent brain tumor progression.
T cells, special types of white blood cells, constitute the main source of anti-tumor immune activity, and cancer vaccines are designed to enhance T cell activity. Almost all T cells, including the major type responsible for anti-tumor responses, are produced in the thymus. Although its role in tumor progression is unknown, the thymus is exquisitely sensitive to aging, and the decreased thymus activity that accompanies aging could potentially impair anti-tumor immunity and contribute to age-dependent tumor progression. Using an extremely sensitive molecular test, Immunology Program investigators at the MDNSI determined the precise amounts of each of the two major types of T cells (potentially tumor-killing CD8+ and non-tumor-killing CD4+) recently produced by the thymus of malignant brain tumor patients. They found that the amount of CD8+ T cells recently produced by the thymus predicted GBM progression even in patient groups with identical age ranges, whereas patient age itself failed to predict this progression in patient groups with very similar levels of these T cells. This implied that the amount of CD8+ T cells recently produced by the thymus fully accounted for the influence of patient age on malignant brain tumor progression. This was surprising because normally only a tiny proportion of more mature CD8+ T cells can actually kill tumors, and it was not immediately clear why the levels of less mature (newly produced) CD8+ T cells would predict GBM recurrence times. Indirect data suggested that many more of the recently produced CD8+ T cells than we would expect could respond to vaccination. Something appeared to be different about these newly produced T cells that made them more responsive to proteins on GBM tumors.
To directly test this, a way to directly look at the kind of T cells stimulated by GBM vaccines was needed. T cells do not recognize free tumor proteins but rather see fragments of those proteins bound to special immune presentation molecules (HLA) expressed by most of the body´s own cells. Engineered versions of these HLA molecules have been invented and used to directly identify and count reactive T cells from cancer and other disease patients. This is done by first loading the engineered HLA with tumor protein fragments, allowing them to bind to patients´ blood cells and then counting the number of T cells bound to them. After identifying some of the particular protein fragments to which brain tumor patients were responding, engineered HLA molecules were loaded with them to see what kind of T cells and how many of them were responding after vaccination in malignant brain tumor patients. Surprisingly, almost all of the T cells responding to the specific HLA/protein fragments after vaccination looked like recently produced CD8+ T cells (CD8+ recent thymic emigrants or RTE), and this population of cells appeared to contain many more tumor-recognizing cells compared to more mature CD8+ T cells.
These results meant that CD8+ RTE were preferentially responding to vaccination, so the number of responding CD8+ RTE in brain tumor patients was estimated and compared with other prognostic and immune factors for its ability to predict recurrence times. Only the number of responding CD8+ RTE significantly predicted malignant brain tumor progression, whereas patient age and distinct measures of anti-tumor immunity did not. These findings suggest that malignant brain tumors are strongly immune sensitive and reveal a unique ability of recently produced CD8+ T cells to recognize and respond to protein fragments present on a variety human cancers.
Having identified the particular aspects of immunity important for GBM progression, as well as the particular immune cells that predominantly respond to GBM, MDNSI Immunology Program investigators are in a unique position to meaningfully monitor the efficacy of and, therefore, improve their cancer vaccines. Perhaps even more important for brain tumor patients, those individuals most likely to respond immunologically and clinically to vaccination, as well as those with inherently slow-growing tumors that may benefit from other treatment regimens, can be accurately predicted. Ways that vaccination might be used most effectively in combination with other treatments are currently being investigated. Finally, an idea about how the normally tiny population of CD8+ RTE T cells responds so dominantly to tumor protein fragments is being actively tested in hopes of using this knowledge to render much larger populations of T cells similarly responsive in brain tumor patients.
Christopher Wheeler, PhD, is a Research Scientist I and head of the Immunology Program at the Maxine Dunitz Neurosurgical Institute at Cedars-Sinai Medical Center in Los Angeles.
© Copyright 2000-2003 Cedars-Sinai Health System. All rights reserved.
By Christopher Wheeler, PhD
Many clinical vaccine trials for cancer patients, including those with malignant brain tumors (gliomas), have been completed with intriguing results. Nevertheless, immune-based therapies for human cancer have thus far been applied with limited success in counteracting tumor progression. This has led some scientists to doubt whether cancer vaccines - or the anti-tumor immune responses they are supposed to enhance - have any place in the future of cancer treatment. This is a justifiable view because the concept that enhancing anti-tumor immune responses slows the growth of human tumors remains unproven.
Skepticism directed toward cancer vaccines has arisen and, in fact, has increased for at least three reasons. First, tumors whose growth is unquestionably impacted by immune activity have not been identified. Second, although cancer vaccines appear to both enhance anti-tumor immune activity and clinically benefit some patients, these two effects almost never completely coincide with each other. This leaves researchers confused as to how vaccines work and, therefore, how to improve them. Third, it is still not clear what is most important in making an immune cell recognize and kill tumors and what prevents this in cancer patients. To move beyond this skepticism, as well as to improve cancer vaccines, tumors susceptible to immune activity must be identified, the particular immune parameters responsible for clinical benefits (if any) determined and the discrete influences on tumor recognition and killing by cells of the immune system elucidated.
These requirements are accentuated for malignant brain tumors. This is because these tumors reside within an organ without normal access to immune components, because immune activity in the brain can be different than that in the rest of the body and because a large variety of immune-suppressing properties has been ascribed to these tumors. It would seem that studying malignant brain tumors might be an unlikely way to try to validate and improve cancer vaccines in general and a long shot for attempting to develop clinically effective cancer vaccination. There is, however, one parallel between malignant brain tumor growth and immunity that is intriguing. Malignant gliomas grow substantially faster in older patients who, incidentally, usually have defects in the kind of immune cells able to recognize and kill tumors. In addition, individuals with immune systems that are so hyperactive they attack certain portions of their own bodies (autoimmune patients) have a significantly reduced risk of acquiring a brain tumor, suggesting that hyperimmunity might prevent brain tumors. Thus, investigators within Cedars-Sinai´s Maxine Dunitz Neurosurgical Institute´s (MDNSI) Immunology Program sought to determine if malignant brain tumors were sensitive to immune activity and to identify the specific immune parameter that might contribute to age-dependent brain tumor progression.
T cells, special types of white blood cells, constitute the main source of anti-tumor immune activity, and cancer vaccines are designed to enhance T cell activity. Almost all T cells, including the major type responsible for anti-tumor responses, are produced in the thymus. Although its role in tumor progression is unknown, the thymus is exquisitely sensitive to aging, and the decreased thymus activity that accompanies aging could potentially impair anti-tumor immunity and contribute to age-dependent tumor progression. Using an extremely sensitive molecular test, Immunology Program investigators at the MDNSI determined the precise amounts of each of the two major types of T cells (potentially tumor-killing CD8+ and non-tumor-killing CD4+) recently produced by the thymus of malignant brain tumor patients. They found that the amount of CD8+ T cells recently produced by the thymus predicted GBM progression even in patient groups with identical age ranges, whereas patient age itself failed to predict this progression in patient groups with very similar levels of these T cells. This implied that the amount of CD8+ T cells recently produced by the thymus fully accounted for the influence of patient age on malignant brain tumor progression. This was surprising because normally only a tiny proportion of more mature CD8+ T cells can actually kill tumors, and it was not immediately clear why the levels of less mature (newly produced) CD8+ T cells would predict GBM recurrence times. Indirect data suggested that many more of the recently produced CD8+ T cells than we would expect could respond to vaccination. Something appeared to be different about these newly produced T cells that made them more responsive to proteins on GBM tumors.
To directly test this, a way to directly look at the kind of T cells stimulated by GBM vaccines was needed. T cells do not recognize free tumor proteins but rather see fragments of those proteins bound to special immune presentation molecules (HLA) expressed by most of the body´s own cells. Engineered versions of these HLA molecules have been invented and used to directly identify and count reactive T cells from cancer and other disease patients. This is done by first loading the engineered HLA with tumor protein fragments, allowing them to bind to patients´ blood cells and then counting the number of T cells bound to them. After identifying some of the particular protein fragments to which brain tumor patients were responding, engineered HLA molecules were loaded with them to see what kind of T cells and how many of them were responding after vaccination in malignant brain tumor patients. Surprisingly, almost all of the T cells responding to the specific HLA/protein fragments after vaccination looked like recently produced CD8+ T cells (CD8+ recent thymic emigrants or RTE), and this population of cells appeared to contain many more tumor-recognizing cells compared to more mature CD8+ T cells.
These results meant that CD8+ RTE were preferentially responding to vaccination, so the number of responding CD8+ RTE in brain tumor patients was estimated and compared with other prognostic and immune factors for its ability to predict recurrence times. Only the number of responding CD8+ RTE significantly predicted malignant brain tumor progression, whereas patient age and distinct measures of anti-tumor immunity did not. These findings suggest that malignant brain tumors are strongly immune sensitive and reveal a unique ability of recently produced CD8+ T cells to recognize and respond to protein fragments present on a variety human cancers.
Having identified the particular aspects of immunity important for GBM progression, as well as the particular immune cells that predominantly respond to GBM, MDNSI Immunology Program investigators are in a unique position to meaningfully monitor the efficacy of and, therefore, improve their cancer vaccines. Perhaps even more important for brain tumor patients, those individuals most likely to respond immunologically and clinically to vaccination, as well as those with inherently slow-growing tumors that may benefit from other treatment regimens, can be accurately predicted. Ways that vaccination might be used most effectively in combination with other treatments are currently being investigated. Finally, an idea about how the normally tiny population of CD8+ RTE T cells responds so dominantly to tumor protein fragments is being actively tested in hopes of using this knowledge to render much larger populations of T cells similarly responsive in brain tumor patients.
Christopher Wheeler, PhD, is a Research Scientist I and head of the Immunology Program at the Maxine Dunitz Neurosurgical Institute at Cedars-Sinai Medical Center in Los Angeles.
© Copyright 2000-2003 Cedars-Sinai Health System. All rights reserved.
Katja[a]
