Triggering T cells
NEW YORK—T cells have long been lauded for the role they play in immune function and their potential for treating cancer, but a recent study from researchers at the Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center (MSKCC) has shown that an even closer look—specifically at types of T cells and the molecules on them—could provide even greater results.
The Ludwig team, led by Dr. Jedd Wolchok, combined the cancer drug cyclophosphamide (CTX)—used to treat a variety of cancers, including Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma and certain kinds of leukemia, among others—and OX86, an antibody that activates the OX40 molecule on T cells, with adoptive T cell transfer to study their effects on melanoma tumors in mice.
The researchers had demonstrated in a previous study that treatment with CTX and OX86 led to tumor regression, and wanted to see if combining the compounds with T cell transfer would offer better results.
T cell transfer is an investigative immunotherapy that consists of isolating tumor-targeting T cells from patients, manipulating the cells, expanding them and then transfusing them back into the patients. Among T cells, there are several types that are particularly relevant in adoptive T cell transfer, including the CD8+ T cell, which can kill diseased or cancerous cells directly, and the CD4+ T cell, which coordinates the immune system's attack. The latter comes in subtypes of its own: T helper 1 (Th1) and T helper 2 (Th2), and the regulatory T cell manages the responses of the helper cells.
The activation of OX40 was found to cause CD4+ T cells to heighten the immune attack, which is what Wolchok and his colleagues tested in the most recent study. Melanoma tumors were transplanted into mouse models and allowed to grow to an advanced stage, at which pointed the mice were treated with CTX and OX86. The researchers waited a day, then transfused the mice with T helper cells that had been engineered to target the tumor antigen Trp1.
Following the combination therapy, tumors that expressed the Trp1 antigen were eliminated rapidly, as were tumors that consisted of cells that both did and did not express the antigen, a particularly notable result given that a majority of human tumors are composed of mixed cell populations.
"These T cells are so exquisitely tuned that they induce collateral damage to cells in the tumor that don't even express the targeted antigen," said Wolchok.
The work revealed that OX40 activation altered the transfused T helper cells, because while they remained CD4+ T cells, they also became capable of eradicating cancer cells as well (similar to the CD8+ T cells). Additionally, they presented traits similar to those of long-lived memory cells, which destroy future tumors that express their targeted antigen, and also had qualities of both Th1 and Th2 T helper cells.
Wolchok, who noted that most T cell transfer studies tend to focus on CD8+ T cells, pointed out that, "If these killer-memory CD4+ T cells are the ones that are really important to tumor killing, then they are the ones we should be trying to transfer." There is also a chance that combining OX40-stimulation with other immunotherapies could supplement T cell anti-tumor activity on its own, with Wolchok adding that "if one could make the endogenous immune response sufficiently robust, you might not need to do the adoptive transfer."
This study received support in grants from the National Cancer Institute, Swim Across America, the Lita Annenberg Hazen Foundation, the T.J. Martell Foundation, the Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Cancer Foundation for Research and the Experimental Therapeutics Center of MSKCC.