The Ludwig team, led by Dr. Jedd Wolchok, combinedthe cancer drug cyclophosphamide (CTX)—used to treat a variety of cancers,including Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma andcertain kinds of leukemia, among others—and OX86, an antibody that activatesthe OX40 molecule on T cells, with adoptive T cell transfer to study theireffects on melanoma tumors in mice.
The researchers had demonstrated in a previous study thattreatment with CTX and OX86 led to tumor regression, and wanted to see ifcombining the compounds with T cell transfer would offer better results.
T cell transfer is an investigative immunotherapy thatconsists of isolating tumor-targeting T cells from patients, manipulating thecells, expanding them and then transfusing them back into the patients. Among Tcells, there are several types that are particularly relevant in adoptive Tcell transfer, including the CD8+ T cell, which can kill diseased or cancerouscells directly, and the CD4+ T cell, which coordinates the immune system'sattack. The latter comes in subtypes of its own: T helper 1 (Th1) and T helper2 (Th2), and the regulatory T cell manages the responses of the helper cells.
The activation of OX40 was found to cause CD4+ T cells toheighten the immune attack, which is what Wolchok and his colleagues tested inthe most recent study. Melanoma tumors were transplanted into mouse models andallowed to grow to an advanced stage, at which pointed the mice were treatedwith CTX and OX86. The researchers waited a day, then transfused the mice withT helper cells that had been engineered to target the tumor antigen Trp1.
Following the combination therapy, tumors that expressed theTrp1 antigen were eliminated rapidly, as were tumors that consisted of cellsthat both did and did not express the antigen, a particularly notable resultgiven that a majority of human tumors are composed of mixed cell populations.
"These T cells are so exquisitely tuned that they inducecollateral damage to cells in the tumor that don't even express the targetedantigen," said Wolchok.
The work revealed that OX40 activation altered thetransfused T helper cells, because while they remained CD4+ T cells, they alsobecame capable of eradicating cancer cells as well (similar to the CD8+ Tcells). Additionally, they presented traits similar to those of long-livedmemory 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 tofocus on CD8+ T cells, pointed out that, "If these killer-memory CD4+ T cellsare the ones that are really important to tumor killing, then they are the oneswe should be trying to transfer." There is also a chance that combining OX40-stimulationwith other immunotherapies could supplement T cell anti-tumor activity on itsown, with Wolchok adding that "if one could make the endogenous immune responsesufficiently robust, you might not need to do the adoptive transfer."
Thisstudy received support in grants from the National Cancer Institute, SwimAcross America, the Lita Annenberg Hazen Foundation, the T.J. MartellFoundation, the Mr. William H. Goodwin and Mrs. Alice Goodwin and theCommonwealth Cancer Foundation for Research and the Experimental TherapeuticsCenter of MSKCC.
