Harnessing the immune system is one of the major strategies in fighting cancer. And T cells are one of its most promising targets: They are as specific as monoclonal antibodies but theoretically can be directed against a broader range of targets.
That's only if they can be directed against a target at all. The problem with harnessing T cells is that they normally have strong regulatory mechanisms that make them unresponsive to their owner's own tissues. Tumor cells also do their best to foil T cells, both by masking themselves and by inactivating the T cells.
A worst-case scenario of what can happen when those mechanisms are disabled came to pass recently in the clinical trial of the molecule TGN1412, which sent six previously healthy volunteers into intensive care in a botched Phase I trial in March. (See BioWorld Today, March 16, 2006; March 30, 2006; and March 31, 2006.)
Despite the fact that TGN1412 made headlines for activating T cells too strongly, the more common problem is that they are not activated strongly enough - a problem that is exacerbated by the fact that there are both stimulatory T cells, and regulatory or inhibitory T cells that keep the stimulatory T-cell response from getting out of hand.
But two recent studies report progress in boosting stimulatory T-cell activity to combat cancer.
In a study published in the July 2006, issue of Journal of Clinical Investigation, now available online, researchers from New York City's Memorial Sloan-Kettering Cancer Center reported on using a combination therapy of a tumor cell vaccine and blockade of CTLA4, which down-regulates T-cell responses, to affect the balance of excitatory and inhibitory T cells within tumors.
The authors showed that when cancer develops in mouse skin cells, inhibitory T cells accumulate in tumors more than stimulatory T cells, and that is at least partly due to a direct effect on stimulatory T cells, rather than a boost for inhibitory T cells. Blockade of CTLA4 allowed both stimulatory and inhibitory T cells to proliferate.
Combination of CTLA4 blockade with the vaccine primed stimulatory T cells; this led to greater infiltration of stimulatory T cells into the tumor, and eventually to tumor rejection. Chronic exposure to anti-CTLA4 or to the vaccine/anti-CTLA4 combination therapy did not deplete the number of inhibitory T cells or their regulatory activity, suggesting that the combination therapy would not adversely effect the immune system's ability to control itself in the long run.
On June 16, Carlsbad, Calif.-based biotech company Micromet Inc. announced preliminary but favorable Phase I data from an ongoing trial at the Congress of the European Hematology Association in Amsterdam, the Netherlands. Micromet's approach uses an antibody-derived molecule, called BiTE, that has two binding sites: one binds CD3, which is expressed on killer T cells, and one for a target cell-specific protein, which could be either a tumor cell or another cell type. The drug is being developed with MedImmune Inc., of Gaithersburg, Md.
When target cells are present, the BiTE molecules will activate killer T cells, which will expand and attack the target cells. In the absence of target cells, BiTE molecules have no effect on killer T cells - an important difference to TGN1412, which had a mechanism of action based on being able to activate killer T cells in the absence of a co-stimulatory signal.
In the trial reported at EHA, 19 patients with indolent, relapsed non-Hodgkin's lymphoma received Micromet's MT103, which has a binding site for B cells in addition to its CD3 site. Of 19 treated patients, the majority showed depletion of malignant B cells as well as significant T-cell expansion. At the highest dose tested to date, one patient had a complete tumor response and two patients showed partial tumor responses.