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antigens relevant to immune response are in there, somewhere. However, another avenue of research has concentrated on the lack of signal 2 as the missing ingredient in immune response against tumors. There was evidence from earlier studies that one way to activate T-cells against tumor antigens was to provide signal 1 and signal 2 on the same cell, and that an important signal 2 for CTLs was IL-2 (or lymphokines made by helper T-cells).

Based on this paradigm, researchers began introducing cytokine genes into tumor cells, beginning with IL-2, in order to produce a whole-cell vaccine that contained all of the antigens and presented peptide as MHC signal 1 and signal 2 on the same cell. Aided by the use of defective retroviral vectors, they inserted a wide range of cytokine genes into a weakly immunogenic tumor, vaccinated animals, and compared the resulting protection against challenge with wild-type tumor cells. The most effective vaccine involved tumor cells transduced with a GM-CSF gene.

This was a surprise at the time, but other groups soon reported that GM-CSF has the unique and interesting function of inducing hematopoietic progenitors to differentiate not only into granulocytes and macrophages, but also into dendritic cells. It may be that these high-potency APCs, differentiating locally in the presence of GM-CSF, have something to do with the enhanced systemic immune response to GM-CSF-transduced tumor cells. Subsequent research has tried to explain how this process works.

Paracrine Cytokine Adjuvant. What turned out to be important physiologically, in addition to the particular cytokine, is the elaboration of that cytokine at the site of the antigen. In a sense, the GM-CSF-transduced tumor cell actually represents a timed-release depot for two sets of molecules: its own antigens, and GM-CSF. Importantly, it also replaces the complex “black boxes” of conventional adjuvants (BCG, C.parvum, mycobacterium, TB) with a single molecule, and in doing so generated a systemic antitumor immune response that was more potent than mixing irradiated tumor cells with conventional adjuvants.

Researchers have learned that APCs that differentiated at the site of the vaccine, under control of GM-CSF, actually ingest antigens from tumor cells and process them into both the Class I and Class II pathways, an example of crosspriming. As the APCs are ingesting and processing antigens, they are travelling to the draining lymph node, where one can first identify activated Class I- and Class II-restricted CTLs and helper cells. Once activated, these cells leave the draining lymph node and circulate systemically.

An important implication is that effector-phase CD4 is very important, in addition to CD8-positive cells. Consequently, the best vaccines will involve epitopes that actually represent tumor antigens. For this reason, there should be concern over the use of “universal helper epitopes,” which are not expressed by the tumor cell.

Clinical Trials. These results led researchers to initiate a Phase I trial in patients with metastatic renal cancer who had undergone nephrectomy to remove the primary tumor. They used a retroviral vector to transduce human GM-CSF gene into tumor cells, expanded these cells, irradiated them at doses that

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