BETHESDA, Md.—A new approach to stimulating immune cells enhances their anticancer activity, resulting in a powerful anti-tumor response in mice, according to a study by researchers at the National Cancer Institute, a part of the National Institutes of Health.
This work represents an advance in the development of immunotherapy for cancer and appears online in Nature Medicine.
"Our story of recent scientific efforts has very much to do with the discovery of novel drug candidates to treat cancer by altering the functions of tumor-specific T cells," says NCI lead author Dr. Nicholas P. Restifo, an investigator in the surgery branch at the Center for Cancer Research. "Specifically, our finding was about exploring the use of pharmacological methods to mimic Wnt/beta catenin signaling. The approach we took was to use inhibitors of glycogen synthase kinase-3 (GSK-3beta) to block the complex that degrades beta-catenin. This in turn has the effect of mimicking Wnt signaling."
Restifo's team found that a subset of immune cells, T lymphocytes called CD8+ memory stem cells, were capable of mediating strong anti-tumor immune response. These potent cells were generated in the laboratory by stimulating anti-tumor T cells in the presence of drugs designed to mimic an important signaling pathway called Wnt, which describes a complex network of proteins whose interactions are essential during development and stem cell maintenance.
Restifo points out that the surprising finding was that Wnt signals resulted in the generation of super-powerful anti-tumor T cells.
"An excellent consequence of this is that we might be able to treat large tumor burdens with very small numbers of anti-tumor T cells," he says. "That is because the T cells were able to proliferate robustly."
Under the influence of Wnt, T lymphocytes acquired stem cell-like properties of multipotency and self-renewal; that is, they generated differentiating daughter cells while regenerating themselves when transferred back to mice from the lab. These stem cell-like qualities enabled tiny numbers of T cells (about 40,000 cells) to trigger the destruction of large melanoma tumors (containing about one billion malignant cells).
This therapy, in which mice received CD8+ T memory stem cells together with a tumor vaccine and an immune system stimulant known as interleukin 2, improved the survival of treated mice compared with similar treatment using other types of memory T cells.
"This new category of lymphocytes is superior to T cells used in earlier experiments because they have the enhanced ability to renew themselves, to proliferate, to differentiate and ultimately to kill tumor cells," adds Restifo.
Current clinical immunotherapies based on the transfer of tumor-specific T cells generated and expanded in the laboratory rely on the use of large numbers of tumor-specific T cells and have had beneficial but sometimes limited success.
If confirmed in humans, the use of tumor-reactive CD8+ memory stem cells could reduce the numbers of tumor-specific T cells needed for successful immunotherapy, thus making this type of therapy easier to develop so that more patients could benefit.
These findings mark the latest advance in the field of cancer immunotherapy using tumor-specific T cells, which is moving from proof-of-concept to a promising treatment for patients with metastatic cancer.
According to Restifo, the next step for researchers is to test these ideas using human cells.
"All of the work was done using mice, but workers at the National Cancer Institute have the ability to do human clinical trials in patients with metastatic cancers," he notes.
A key component of that could be collaborations with drug companies could help push this work forward.
"Thus far, no company has successfully employed techniques using the adoptive transfer of tumor-specific T lymphocytes to treat patients with metastatic cancer," Restifo says.
This work represents an advance in the development of immunotherapy for cancer and appears online in Nature Medicine.
"Our story of recent scientific efforts has very much to do with the discovery of novel drug candidates to treat cancer by altering the functions of tumor-specific T cells," says NCI lead author Dr. Nicholas P. Restifo, an investigator in the surgery branch at the Center for Cancer Research. "Specifically, our finding was about exploring the use of pharmacological methods to mimic Wnt/beta catenin signaling. The approach we took was to use inhibitors of glycogen synthase kinase-3 (GSK-3beta) to block the complex that degrades beta-catenin. This in turn has the effect of mimicking Wnt signaling."
Restifo's team found that a subset of immune cells, T lymphocytes called CD8+ memory stem cells, were capable of mediating strong anti-tumor immune response. These potent cells were generated in the laboratory by stimulating anti-tumor T cells in the presence of drugs designed to mimic an important signaling pathway called Wnt, which describes a complex network of proteins whose interactions are essential during development and stem cell maintenance.
Restifo points out that the surprising finding was that Wnt signals resulted in the generation of super-powerful anti-tumor T cells.
"An excellent consequence of this is that we might be able to treat large tumor burdens with very small numbers of anti-tumor T cells," he says. "That is because the T cells were able to proliferate robustly."
Under the influence of Wnt, T lymphocytes acquired stem cell-like properties of multipotency and self-renewal; that is, they generated differentiating daughter cells while regenerating themselves when transferred back to mice from the lab. These stem cell-like qualities enabled tiny numbers of T cells (about 40,000 cells) to trigger the destruction of large melanoma tumors (containing about one billion malignant cells).
This therapy, in which mice received CD8+ T memory stem cells together with a tumor vaccine and an immune system stimulant known as interleukin 2, improved the survival of treated mice compared with similar treatment using other types of memory T cells.
"This new category of lymphocytes is superior to T cells used in earlier experiments because they have the enhanced ability to renew themselves, to proliferate, to differentiate and ultimately to kill tumor cells," adds Restifo.
Current clinical immunotherapies based on the transfer of tumor-specific T cells generated and expanded in the laboratory rely on the use of large numbers of tumor-specific T cells and have had beneficial but sometimes limited success.
If confirmed in humans, the use of tumor-reactive CD8+ memory stem cells could reduce the numbers of tumor-specific T cells needed for successful immunotherapy, thus making this type of therapy easier to develop so that more patients could benefit.
These findings mark the latest advance in the field of cancer immunotherapy using tumor-specific T cells, which is moving from proof-of-concept to a promising treatment for patients with metastatic cancer.
According to Restifo, the next step for researchers is to test these ideas using human cells.
"All of the work was done using mice, but workers at the National Cancer Institute have the ability to do human clinical trials in patients with metastatic cancers," he notes.
A key component of that could be collaborations with drug companies could help push this work forward.
"Thus far, no company has successfully employed techniques using the adoptive transfer of tumor-specific T lymphocytes to treat patients with metastatic cancer," Restifo says.
