A panel of researchers discussed ways to improve the performance of immunological therapies for metastatic melanoma at the annual American Society of Clinical Oncology meeting in Atlanta.
“The first vaccine clinical trials in the modern era started more than 10 years ago, but only a small percentage of patients respond with tumor shrinkage,” states Thomas Gajewski, M.D., Ph.D, Associate Professor at the University of Chicago, who presided over the presentations. “The cure rate for those treated with the most current vaccines is in the single-digit percentages,” he adds.
Yet according to Dr. Gajewski, immunological therapy may be the best hope for some patients with advanced melanoma.
“Even though biologic therapies cause a complete response in only a small percentage of those treated, in our experience this is the only kind of therapy that can cure a patient. We haven’t seen anybody we would call a cure with standard chemotherapy.”
To improve the so-far somewhat disappointing performance of these melanoma therapies, Dr. Gajewski and the other panelists discussed suggestions, including steering into immunological therapies those patients whose genetic make-up makes them most likely to benefit.
“We’ve been doing biopsies of tumor metastases and gene expression profiling. We should consider restricting eligibility to patients whose tumors can recruit the activated immune cells. Some patients have that capability and some don’t,” explains Dr. Gajewski.
Surprising Link to the Immune System
Another researcher, David H. Munn, M,D., detailed his exploration of another potential hindrance to successful vaccine treatment in some patients. The Medical College of Georgia Professor of Pediatric Oncology says indoleamine dioxygenase (IDO) has been shown to suppress human T cells in vitro. His research, which originated in a 1998 Science paper, showed that IDO functions in the human placenta.
“We were able to show that IDO participated in suppressing the immune response in the mother’s system against its fetus,” he claims, explaining that tumor behavior is conceptually analogous to that of the fetus in that the mother’s immune system tolerates its many antigens, although they are foreign to her. “We speculated that the tumor might hijack and use the same mechanism for pathological ends.”
Dr. Munn cites another paper published in Science in 2002 in which lymph nodes that drain melanoma tumors were examined. “We found in one-third of cases that cells expressing IDO were found in abnormal numbers,” he states.
That paper reported the results of a retrospective survey of 40 patients with non-metastasized melanoma who underwent lymph node biopsies. The survey used records archived at the Moffitt Cancer Center in Tampa, FL, of patients biopsied 10 years earlier. Groups included patient with increased IDO expression and patients without increased IDO expression.
“These were the patients who should have done the best. You would predict 80% of patients should have done well and survived,” says Dr. Munn. “About 75% of patients who had the increased IDO died by the end of the follow-up period, whereas only about 25% of patients died in the group that did not have increased IDO,” he notes.
Dr. Munn and his colleagues published these results in 2004 in the Journal of Clinical Investigation, and, with Newlink Genetics, are seeking an Investigational New Drug approval from the FDA for further trials of an inhibitor drug, 1-methyl-d-tryptophan, to be taken as a pill once daily.
Inhibitor Drug Combined with Chemotherapy
A paper in Nature Medicine last year found the drug to be synergistic when combined with chemotherapy, Dr. Munn states. An independent group collaborating with Dr. Munn and colleagues included Alexander Mueller, Ph.D., and George Prendergast, Ph.D., of the Lankenau Institute for Medical Research in Wynnewood, PA.
“We were very pleased they looked at a different tumor type — breast cancer — in studies in mice because our hypothesis is that this is a broadly expressed mechanism not peculiar to melanoma,” says Dr. Munn. The study researched 1-methyl-d-tryptophan taken in conjunction with conventional chemotherapies including paclitaxel, doxyrubicin, cyclophosphamide, and cysplatinum.
“It would be really nice if you didn’t have to deprive your patient of standard chemotherapy just because you used immunologic therapy as well,” Dr. Munn observes. “We would give 1-methyl-d-tryptophan in the period of time after chemotherapy while the patient was recovering from conventional chemotherapy, because that’s the time when the immune system recovers and can be more readily activated to respond to the tumor.”
Localized Immunotherapy
Other participants agree that immunotherapies have not worked optimally to date.
“We’re able to give people vaccines, but the problem is that the melanoma is smarter than our immunotherapies,” says panelist Benjamin Negin, M.D, a medical resident at Beth Israel Deaconness Hospital in Boston.
Dr. Negin and his colleagues performed a retrospective analysis of 37 adult melanoma patients from Beth Israel Deaconness Hospital, which has a lymph node bank. Using flow cytometry, they examined a marker called the T-cell receptor data subunit, which Dr. Negin calls “the business end of the T-cell.”
“This marker has the highest turnover, so it’s theoretically the first one to go down if the immune system goes down.”
The study reviewed data from the 37 patients organized into two categories: those who had undergone an excisional biopsy (leaving no tumor left on the skin) and those with a shaved biopsy (which still had some primary tumor left over), Dr. Negin explains. The group of lymph nodes that were downstream from the melanoma had statistically greater immunosuppression compared to those that were not downstream from remaining melanoma.
“The primary tumor is able to suppress the lymph node basin without actually being in the basin. That’s part of what causes the melanoma to spread,” he explains, adding that the average T-cell expression in patients with no melanoma upstream was about 85%, while the average expression in patients without tumor upstream was 70%. For patients with macroscopical involvement (where the tumor is visible), the expression was around 56%, he reports.
According to Dr. Negin, the discovery points to another possible way to improve the performance of melanoma vaccines: immunotherapy. “We could give that patient localized immunotherapy, applied directly to the affected area. When you give systemic immunotherapy, people get very sick; side effects are so nasty, people could die from them. A patient could get an injection in the arm instead of an infusion,” he asserts.
Differences in Genetic Expression
Dr. Gajewski maintains the relevance of a relatively small set of genes in determining patient response to melanoma vaccines or other immunotherapy. “We think we know what the genes are,” he says, noting that there are about seven controlling genes. “That has to be validated in a prospective study; but if true, we could at least exclude patients who have no chance of responding to a vaccine.”
Given the sheer volume of gene therapy trials and immunotherapy experiments, future developments appear likely. “Almost every center has its own favorite vaccination approach,” says Dr. Gajewski. “At any one time around the United States, there are dozens of different vaccine trials, with probably a couple dozen people in each trial. I’m sure there are hundreds of patients enrolled in vaccine trials, and if you expand the consideration to other immunotherapeutic interventions, there are probably thousands,” he concludes.
A panel of researchers discussed ways to improve the performance of immunological therapies for metastatic melanoma at the annual American Society of Clinical Oncology meeting in Atlanta.
“The first vaccine clinical trials in the modern era started more than 10 years ago, but only a small percentage of patients respond with tumor shrinkage,” states Thomas Gajewski, M.D., Ph.D, Associate Professor at the University of Chicago, who presided over the presentations. “The cure rate for those treated with the most current vaccines is in the single-digit percentages,” he adds.
Yet according to Dr. Gajewski, immunological therapy may be the best hope for some patients with advanced melanoma.
“Even though biologic therapies cause a complete response in only a small percentage of those treated, in our experience this is the only kind of therapy that can cure a patient. We haven’t seen anybody we would call a cure with standard chemotherapy.”
To improve the so-far somewhat disappointing performance of these melanoma therapies, Dr. Gajewski and the other panelists discussed suggestions, including steering into immunological therapies those patients whose genetic make-up makes them most likely to benefit.
“We’ve been doing biopsies of tumor metastases and gene expression profiling. We should consider restricting eligibility to patients whose tumors can recruit the activated immune cells. Some patients have that capability and some don’t,” explains Dr. Gajewski.
Surprising Link to the Immune System
Another researcher, David H. Munn, M,D., detailed his exploration of another potential hindrance to successful vaccine treatment in some patients. The Medical College of Georgia Professor of Pediatric Oncology says indoleamine dioxygenase (IDO) has been shown to suppress human T cells in vitro. His research, which originated in a 1998 Science paper, showed that IDO functions in the human placenta.
“We were able to show that IDO participated in suppressing the immune response in the mother’s system against its fetus,” he claims, explaining that tumor behavior is conceptually analogous to that of the fetus in that the mother’s immune system tolerates its many antigens, although they are foreign to her. “We speculated that the tumor might hijack and use the same mechanism for pathological ends.”
Dr. Munn cites another paper published in Science in 2002 in which lymph nodes that drain melanoma tumors were examined. “We found in one-third of cases that cells expressing IDO were found in abnormal numbers,” he states.
That paper reported the results of a retrospective survey of 40 patients with non-metastasized melanoma who underwent lymph node biopsies. The survey used records archived at the Moffitt Cancer Center in Tampa, FL, of patients biopsied 10 years earlier. Groups included patient with increased IDO expression and patients without increased IDO expression.
“These were the patients who should have done the best. You would predict 80% of patients should have done well and survived,” says Dr. Munn. “About 75% of patients who had the increased IDO died by the end of the follow-up period, whereas only about 25% of patients died in the group that did not have increased IDO,” he notes.
Dr. Munn and his colleagues published these results in 2004 in the Journal of Clinical Investigation, and, with Newlink Genetics, are seeking an Investigational New Drug approval from the FDA for further trials of an inhibitor drug, 1-methyl-d-tryptophan, to be taken as a pill once daily.
Inhibitor Drug Combined with Chemotherapy
A paper in Nature Medicine last year found the drug to be synergistic when combined with chemotherapy, Dr. Munn states. An independent group collaborating with Dr. Munn and colleagues included Alexander Mueller, Ph.D., and George Prendergast, Ph.D., of the Lankenau Institute for Medical Research in Wynnewood, PA.
“We were very pleased they looked at a different tumor type — breast cancer — in studies in mice because our hypothesis is that this is a broadly expressed mechanism not peculiar to melanoma,” says Dr. Munn. The study researched 1-methyl-d-tryptophan taken in conjunction with conventional chemotherapies including paclitaxel, doxyrubicin, cyclophosphamide, and cysplatinum.
“It would be really nice if you didn’t have to deprive your patient of standard chemotherapy just because you used immunologic therapy as well,” Dr. Munn observes. “We would give 1-methyl-d-tryptophan in the period of time after chemotherapy while the patient was recovering from conventional chemotherapy, because that’s the time when the immune system recovers and can be more readily activated to respond to the tumor.”
Localized Immunotherapy
Other participants agree that immunotherapies have not worked optimally to date.
“We’re able to give people vaccines, but the problem is that the melanoma is smarter than our immunotherapies,” says panelist Benjamin Negin, M.D, a medical resident at Beth Israel Deaconness Hospital in Boston.
Dr. Negin and his colleagues performed a retrospective analysis of 37 adult melanoma patients from Beth Israel Deaconness Hospital, which has a lymph node bank. Using flow cytometry, they examined a marker called the T-cell receptor data subunit, which Dr. Negin calls “the business end of the T-cell.”
“This marker has the highest turnover, so it’s theoretically the first one to go down if the immune system goes down.”
The study reviewed data from the 37 patients organized into two categories: those who had undergone an excisional biopsy (leaving no tumor left on the skin) and those with a shaved biopsy (which still had some primary tumor left over), Dr. Negin explains. The group of lymph nodes that were downstream from the melanoma had statistically greater immunosuppression compared to those that were not downstream from remaining melanoma.
“The primary tumor is able to suppress the lymph node basin without actually being in the basin. That’s part of what causes the melanoma to spread,” he explains, adding that the average T-cell expression in patients with no melanoma upstream was about 85%, while the average expression in patients without tumor upstream was 70%. For patients with macroscopical involvement (where the tumor is visible), the expression was around 56%, he reports.
According to Dr. Negin, the discovery points to another possible way to improve the performance of melanoma vaccines: immunotherapy. “We could give that patient localized immunotherapy, applied directly to the affected area. When you give systemic immunotherapy, people get very sick; side effects are so nasty, people could die from them. A patient could get an injection in the arm instead of an infusion,” he asserts.
Differences in Genetic Expression
Dr. Gajewski maintains the relevance of a relatively small set of genes in determining patient response to melanoma vaccines or other immunotherapy. “We think we know what the genes are,” he says, noting that there are about seven controlling genes. “That has to be validated in a prospective study; but if true, we could at least exclude patients who have no chance of responding to a vaccine.”
Given the sheer volume of gene therapy trials and immunotherapy experiments, future developments appear likely. “Almost every center has its own favorite vaccination approach,” says Dr. Gajewski. “At any one time around the United States, there are dozens of different vaccine trials, with probably a couple dozen people in each trial. I’m sure there are hundreds of patients enrolled in vaccine trials, and if you expand the consideration to other immunotherapeutic interventions, there are probably thousands,” he concludes.
A panel of researchers discussed ways to improve the performance of immunological therapies for metastatic melanoma at the annual American Society of Clinical Oncology meeting in Atlanta.
“The first vaccine clinical trials in the modern era started more than 10 years ago, but only a small percentage of patients respond with tumor shrinkage,” states Thomas Gajewski, M.D., Ph.D, Associate Professor at the University of Chicago, who presided over the presentations. “The cure rate for those treated with the most current vaccines is in the single-digit percentages,” he adds.
Yet according to Dr. Gajewski, immunological therapy may be the best hope for some patients with advanced melanoma.
“Even though biologic therapies cause a complete response in only a small percentage of those treated, in our experience this is the only kind of therapy that can cure a patient. We haven’t seen anybody we would call a cure with standard chemotherapy.”
To improve the so-far somewhat disappointing performance of these melanoma therapies, Dr. Gajewski and the other panelists discussed suggestions, including steering into immunological therapies those patients whose genetic make-up makes them most likely to benefit.
“We’ve been doing biopsies of tumor metastases and gene expression profiling. We should consider restricting eligibility to patients whose tumors can recruit the activated immune cells. Some patients have that capability and some don’t,” explains Dr. Gajewski.
Surprising Link to the Immune System
Another researcher, David H. Munn, M,D., detailed his exploration of another potential hindrance to successful vaccine treatment in some patients. The Medical College of Georgia Professor of Pediatric Oncology says indoleamine dioxygenase (IDO) has been shown to suppress human T cells in vitro. His research, which originated in a 1998 Science paper, showed that IDO functions in the human placenta.
“We were able to show that IDO participated in suppressing the immune response in the mother’s system against its fetus,” he claims, explaining that tumor behavior is conceptually analogous to that of the fetus in that the mother’s immune system tolerates its many antigens, although they are foreign to her. “We speculated that the tumor might hijack and use the same mechanism for pathological ends.”
Dr. Munn cites another paper published in Science in 2002 in which lymph nodes that drain melanoma tumors were examined. “We found in one-third of cases that cells expressing IDO were found in abnormal numbers,” he states.
That paper reported the results of a retrospective survey of 40 patients with non-metastasized melanoma who underwent lymph node biopsies. The survey used records archived at the Moffitt Cancer Center in Tampa, FL, of patients biopsied 10 years earlier. Groups included patient with increased IDO expression and patients without increased IDO expression.
“These were the patients who should have done the best. You would predict 80% of patients should have done well and survived,” says Dr. Munn. “About 75% of patients who had the increased IDO died by the end of the follow-up period, whereas only about 25% of patients died in the group that did not have increased IDO,” he notes.
Dr. Munn and his colleagues published these results in 2004 in the Journal of Clinical Investigation, and, with Newlink Genetics, are seeking an Investigational New Drug approval from the FDA for further trials of an inhibitor drug, 1-methyl-d-tryptophan, to be taken as a pill once daily.
Inhibitor Drug Combined with Chemotherapy
A paper in Nature Medicine last year found the drug to be synergistic when combined with chemotherapy, Dr. Munn states. An independent group collaborating with Dr. Munn and colleagues included Alexander Mueller, Ph.D., and George Prendergast, Ph.D., of the Lankenau Institute for Medical Research in Wynnewood, PA.
“We were very pleased they looked at a different tumor type — breast cancer — in studies in mice because our hypothesis is that this is a broadly expressed mechanism not peculiar to melanoma,” says Dr. Munn. The study researched 1-methyl-d-tryptophan taken in conjunction with conventional chemotherapies including paclitaxel, doxyrubicin, cyclophosphamide, and cysplatinum.
“It would be really nice if you didn’t have to deprive your patient of standard chemotherapy just because you used immunologic therapy as well,” Dr. Munn observes. “We would give 1-methyl-d-tryptophan in the period of time after chemotherapy while the patient was recovering from conventional chemotherapy, because that’s the time when the immune system recovers and can be more readily activated to respond to the tumor.”
Localized Immunotherapy
Other participants agree that immunotherapies have not worked optimally to date.
“We’re able to give people vaccines, but the problem is that the melanoma is smarter than our immunotherapies,” says panelist Benjamin Negin, M.D, a medical resident at Beth Israel Deaconness Hospital in Boston.
Dr. Negin and his colleagues performed a retrospective analysis of 37 adult melanoma patients from Beth Israel Deaconness Hospital, which has a lymph node bank. Using flow cytometry, they examined a marker called the T-cell receptor data subunit, which Dr. Negin calls “the business end of the T-cell.”
“This marker has the highest turnover, so it’s theoretically the first one to go down if the immune system goes down.”
The study reviewed data from the 37 patients organized into two categories: those who had undergone an excisional biopsy (leaving no tumor left on the skin) and those with a shaved biopsy (which still had some primary tumor left over), Dr. Negin explains. The group of lymph nodes that were downstream from the melanoma had statistically greater immunosuppression compared to those that were not downstream from remaining melanoma.
“The primary tumor is able to suppress the lymph node basin without actually being in the basin. That’s part of what causes the melanoma to spread,” he explains, adding that the average T-cell expression in patients with no melanoma upstream was about 85%, while the average expression in patients without tumor upstream was 70%. For patients with macroscopical involvement (where the tumor is visible), the expression was around 56%, he reports.
According to Dr. Negin, the discovery points to another possible way to improve the performance of melanoma vaccines: immunotherapy. “We could give that patient localized immunotherapy, applied directly to the affected area. When you give systemic immunotherapy, people get very sick; side effects are so nasty, people could die from them. A patient could get an injection in the arm instead of an infusion,” he asserts.
Differences in Genetic Expression
Dr. Gajewski maintains the relevance of a relatively small set of genes in determining patient response to melanoma vaccines or other immunotherapy. “We think we know what the genes are,” he says, noting that there are about seven controlling genes. “That has to be validated in a prospective study; but if true, we could at least exclude patients who have no chance of responding to a vaccine.”
Given the sheer volume of gene therapy trials and immunotherapy experiments, future developments appear likely. “Almost every center has its own favorite vaccination approach,” says Dr. Gajewski. “At any one time around the United States, there are dozens of different vaccine trials, with probably a couple dozen people in each trial. I’m sure there are hundreds of patients enrolled in vaccine trials, and if you expand the consideration to other immunotherapeutic interventions, there are probably thousands,” he concludes.
