Translation of cancer immunotherapies

Abstract

To the editor: Following mechanical or chemical damage of the vessel or monocyte stimulation, tissue factor is exposed to the blood and binds plasma factor VIIa (FVIIa) forming the FVIIa–tissue factor enzyme complex. During the last several years, a number of studies have reported that physiologically active tissue factor is found circulating in blood of healthy individuals either as a component of blood cells and microparticles or as a soluble plasma protein1. Reports of the presence, source and activity of tissue factor in blood are controversial, with reported concentrations of physiologically active tissue factor varying from undetectable (<60 fM) in whole blood2 to as high as 37 pM in the plasma of healthy individuals3. Blood or plasma activated with (sub)picomolar concentrations of functional tissue factor clots within several minutes (Fig. 1), suggesting that such concentrations of functional tissue factor cannot be present in blood or plasma in vivo. We titrated tissue factor into fresh nonanticoagulated blood from healthy individuals in the presence of the corn trypsin inhibitor (CTI). CTI suppresses the contact pathway initiation of coagulation by inhibiting factor XIIa4. In the absence of exogenous tissue factor, CTI-blood kept at 37 οC with mixing does not clot for >1,200 s (Fig. 1). The addition of as little as 20 fM of tissue factor to blood treated with CTI resulted in clot formation in 1,000 s. Titrations of tissue factor resulted in shortening of the blood clotting time in a tissue factor concentration–dependent manner. The coagulation response observed at a concentration of tissue factor as low as 20 fM leads to the conclusion that this concentration of functional tissue factor must be well beyond that present in blood from healthy individuals. Over the past 9 years, we have performed >300 tissue factor–initiated whole blood clotting experiments using many donors, multiple phlebotomists and different CTI and tissue factor preparations. In virtually all of these experiments, the clotting time in the absence of added tissue factor was 20 min or greater (extending up to 40 min)4,5. The potential origins of discrepancies in the detection of active blood tissue factor are of interest. The most commonly used tissue factor activity assay evaluates factor Xa generation in the presence of FVIIa. In this assay, supraphysiologic concentrations of FVIIa are used, frequently exceeding those circulating in vivo (∼0.1 nM) by two orders of magnitude6. At these FVIIa concentrations, the soluble form of tissue factor (an extracellular domain of tissue factor) can bind FVIIa and display limited proteolytic activity. At the physiologic FVIIa concentration, however, soluble tissue factor displays negligible activity7 and is not likely to trigger blood coagulation; as a competitor, it would most likely inhibit coagulation. In a recent study, the authors used physiologically irrelevant conditions to 10158, USA. 2Cancer Research Institute, 681 Fifth Avenue, New York, New York 10022, USA. e-mail: jskipper@licr.org

DOI: 10.1038/nm1104-1155a

Cite this paper

@article{Pardoll2004TranslationOC, title={Translation of cancer immunotherapies}, author={Drew M . Pardoll and James Patrick Allison}, journal={Nature Medicine}, year={2004}, volume={10}, pages={1153-1154} }