Lani
04-20-2007, 01:05 PM
removing NK cells and expanding them ex vivo (outside the body), then injecting them back in with herceptin increases herceptin's efficacy it seems
Jefferson Researchers Boost Immune "Killer Cells," Increase Antibody Effectiveness Against Cancer [Thomas Jefferson University Hospital]
Researchers at the Kimmel Cancer Center at Jefferson in Philadelphia have devised a novel method to expand the number of immune system "natural killer (NK)" cells from blood cells outside the body. They have found that adding such cells to anti-cancer therapies involving monoclonal antibody drugs is more effective in killing cancer cells, and perhaps someday may improve treatments.
Reporting April 18, 2007 at the annual meeting of the American Association for Cancer Research in Los Angeles, scientists led by Takami Sato, M.D., K. Hasumi Associate Professor of Medical Oncology at Jefferson Medical College of Thomas Jefferson University showed in laboratory studies that adding such NK cells to a monoclonal antibody, Herceptin, which targets the HER2/neu protein on breast cancer cells, was more efficient at killing the cancer cells. The HER2/neu protein is expressed in approximately one-quarter of all breast cancers.
According to Dr. Sato, monoclonal antibodies help kill cancer cells by attaching to the cancer cell surface, in turn stimulating an outpouring of "effector" cells such as NK cells that attempt to neutralize the cancer. NK cells alone are often powerful cancer fighters, he notes, but NK cell function in cancer patients can be diminished, and chemotherapy can make things even worse.
Dr. Sato, international research study coordinator Mizue Terai, M.S., and their co-workers decided to try a different approach. They cultured peripheral blood mononuclear cells, which are a mixture of immune cells, including NK cells, for three weeks in the test tube with their novel technique. The resulting population of NK cells increased 500 to 1,000-fold. In subsequent experiments, they showed that the combination of NK cells and Herceptin was effective in killing HER2/neu-expressing breast cancer cells, though the effect depended on the amount of antibody.
They found that the expanded group of NK cells and antibody had little effect against breast cancer cells that did not express the HER2/neu protein.
"It [the results] doesn't mean that the antibody and the NK cells will cure the cancer," Dr. Sato notes, "but it shows that using an antibody that recognizes the cancer cell along with added NK cells can be very effective against the tumor."
The researchers also found that the monoclonal antibody Rituxan greatly enhanced the cancer cell-killing ability of the expanded NK cells against another cancer cell line, B-cell lymphoma cell line. Rituxan is typically used in combination with chemotherapy to treat patients with B-cell non-Hodgkin's lymphoma.
Dr. Sato says that the technique can be applied to "any cancer that has a monoclonal antibody available."
The team's next step is to test the effectiveness of the added NK cells in an animal model. The group is also in the process of starting an early phase clinical study.
AACR 2007: ABSTRACT #5119: Ex-vivo expanded natural killer cells enhance antibody-dependent cellular cytotoxicity against cancer cells [American Association for Cancer Research]
Monoclonal antibodies such as trastuzumab and rituximab have significantly improved the outcome of cancer patients when combined with chemotherapeutic drugs. One of the key functions of monoclonal antibody in anti-cancer treatment is to mediate antibody-dependent cellular cytotoxicity (ADCC). Binding of monoclonal antibody to the surface of cancer cells facilitates the accumulation of effector cells such as natural killer (NK) cells in tumor sites and induces ADCC via Fc gamma receptor III (CD16) on the effector cells. However, it has been reported that NK cell function in cancer patients is impaired and that chemotherapy itself can decrease the number of circulating NK cells. To overcome these limitations, we have developed a novel method to selectively expand CD3-/CD56+ NK cells from peripheral blood mononuclear cells (PMBC). In this method, PBMC are cultured in a complete medium with rhIL-2 for 21 days after they are stimulated. After 3 weeks of culture, the proportion of expanded cells was 50-90% CD3-/CD56+ NK cells. NK cells were expanded 500-1,000 fold and more than 10E9 NK cells were obtained from 20 ml of peripheral blood. In this study, we investigated the functions of these ex-vivo expanded cells. The ex-vivo expanded cells demonstrated strong cytotoxic activity against K-562 (75-90% killing at 5:1 E/T ratio, chromium release assay). They demonstrated significant cytotoxicity against HER2/neu-expressing breast cancer cells (SKBR-3) in combination with anti-HER2/neu monoclonal antibody (trastuzumab). The cytotoxic activity was dependent on the concentration of trastuzumab (38% killing with 15 mcg/ml of trastuzumab, 8% without trastuzumab, 1:10 E/T ratio, LDH assay). On the other hand, ex-vivo expanded cells did not show cytotoxic activity against HER2/neu non-expressing cells (MDA-MB-468) even with trastuzumab (<5% killing). Furthermore, we confirmed that anti-CD20 monoclonal antibody, rituximab, significantly enhanced the cytotoxicic activity of ex-vivo expanded cells against autologous Epstein-Barr virus-transformed B-lymphoblastoid cell line (LCL) in a dose-dependent manner (55% killing with 1 mcg/ml of rituximab, 7% without rituximab, 1:10 E/T ratio, LDH assay). The killing of LCL was significantly inhibited by anti-CD16 antibody (>80% blocking). These results indicate that ex-vivo expanded NK cells might have significant anti-tumor effects in combination with monoclonal antibodies that bind to tumor cells.
Jefferson Researchers Boost Immune "Killer Cells," Increase Antibody Effectiveness Against Cancer [Thomas Jefferson University Hospital]
Researchers at the Kimmel Cancer Center at Jefferson in Philadelphia have devised a novel method to expand the number of immune system "natural killer (NK)" cells from blood cells outside the body. They have found that adding such cells to anti-cancer therapies involving monoclonal antibody drugs is more effective in killing cancer cells, and perhaps someday may improve treatments.
Reporting April 18, 2007 at the annual meeting of the American Association for Cancer Research in Los Angeles, scientists led by Takami Sato, M.D., K. Hasumi Associate Professor of Medical Oncology at Jefferson Medical College of Thomas Jefferson University showed in laboratory studies that adding such NK cells to a monoclonal antibody, Herceptin, which targets the HER2/neu protein on breast cancer cells, was more efficient at killing the cancer cells. The HER2/neu protein is expressed in approximately one-quarter of all breast cancers.
According to Dr. Sato, monoclonal antibodies help kill cancer cells by attaching to the cancer cell surface, in turn stimulating an outpouring of "effector" cells such as NK cells that attempt to neutralize the cancer. NK cells alone are often powerful cancer fighters, he notes, but NK cell function in cancer patients can be diminished, and chemotherapy can make things even worse.
Dr. Sato, international research study coordinator Mizue Terai, M.S., and their co-workers decided to try a different approach. They cultured peripheral blood mononuclear cells, which are a mixture of immune cells, including NK cells, for three weeks in the test tube with their novel technique. The resulting population of NK cells increased 500 to 1,000-fold. In subsequent experiments, they showed that the combination of NK cells and Herceptin was effective in killing HER2/neu-expressing breast cancer cells, though the effect depended on the amount of antibody.
They found that the expanded group of NK cells and antibody had little effect against breast cancer cells that did not express the HER2/neu protein.
"It [the results] doesn't mean that the antibody and the NK cells will cure the cancer," Dr. Sato notes, "but it shows that using an antibody that recognizes the cancer cell along with added NK cells can be very effective against the tumor."
The researchers also found that the monoclonal antibody Rituxan greatly enhanced the cancer cell-killing ability of the expanded NK cells against another cancer cell line, B-cell lymphoma cell line. Rituxan is typically used in combination with chemotherapy to treat patients with B-cell non-Hodgkin's lymphoma.
Dr. Sato says that the technique can be applied to "any cancer that has a monoclonal antibody available."
The team's next step is to test the effectiveness of the added NK cells in an animal model. The group is also in the process of starting an early phase clinical study.
AACR 2007: ABSTRACT #5119: Ex-vivo expanded natural killer cells enhance antibody-dependent cellular cytotoxicity against cancer cells [American Association for Cancer Research]
Monoclonal antibodies such as trastuzumab and rituximab have significantly improved the outcome of cancer patients when combined with chemotherapeutic drugs. One of the key functions of monoclonal antibody in anti-cancer treatment is to mediate antibody-dependent cellular cytotoxicity (ADCC). Binding of monoclonal antibody to the surface of cancer cells facilitates the accumulation of effector cells such as natural killer (NK) cells in tumor sites and induces ADCC via Fc gamma receptor III (CD16) on the effector cells. However, it has been reported that NK cell function in cancer patients is impaired and that chemotherapy itself can decrease the number of circulating NK cells. To overcome these limitations, we have developed a novel method to selectively expand CD3-/CD56+ NK cells from peripheral blood mononuclear cells (PMBC). In this method, PBMC are cultured in a complete medium with rhIL-2 for 21 days after they are stimulated. After 3 weeks of culture, the proportion of expanded cells was 50-90% CD3-/CD56+ NK cells. NK cells were expanded 500-1,000 fold and more than 10E9 NK cells were obtained from 20 ml of peripheral blood. In this study, we investigated the functions of these ex-vivo expanded cells. The ex-vivo expanded cells demonstrated strong cytotoxic activity against K-562 (75-90% killing at 5:1 E/T ratio, chromium release assay). They demonstrated significant cytotoxicity against HER2/neu-expressing breast cancer cells (SKBR-3) in combination with anti-HER2/neu monoclonal antibody (trastuzumab). The cytotoxic activity was dependent on the concentration of trastuzumab (38% killing with 15 mcg/ml of trastuzumab, 8% without trastuzumab, 1:10 E/T ratio, LDH assay). On the other hand, ex-vivo expanded cells did not show cytotoxic activity against HER2/neu non-expressing cells (MDA-MB-468) even with trastuzumab (<5% killing). Furthermore, we confirmed that anti-CD20 monoclonal antibody, rituximab, significantly enhanced the cytotoxicic activity of ex-vivo expanded cells against autologous Epstein-Barr virus-transformed B-lymphoblastoid cell line (LCL) in a dose-dependent manner (55% killing with 1 mcg/ml of rituximab, 7% without rituximab, 1:10 E/T ratio, LDH assay). The killing of LCL was significantly inhibited by anti-CD16 antibody (>80% blocking). These results indicate that ex-vivo expanded NK cells might have significant anti-tumor effects in combination with monoclonal antibodies that bind to tumor cells.