Researchers at British biotechnology firm Immunocore Ltd., with academic colleagues, have come up with a method to break T-cell tolerance to cancer cells and target tumor-specific proteins, even when those proteins are expressed at very low levels.

The approach, which they have named ImmTAC and described in a paper published in the May 6, 2012, advance online edition of Nature Medicine, allows the targeting of cancer-specific proteins whose surface expression is more or less at needle-in-a-haystack levels.

Antibodies and regular T cells are normally effective against target proteins that are present anywhere from 1,000 to 10,000 times per cell. In the work published in Nature Medicine, Immunocore chief scientific officer Bent Jakobsen and his team were able to target cells that typically had 30 to 150 copies of the target protein on their surface. The lower limit appears to be on the order of 10 copies, or two to three orders of magnitude lower than what unadulterated immune system cells need.

"Cancer cells are very similar to our healthy normal cells," Jakobsen told BioWorld Today. "But they do activate a number of genes that our normal cells have stopped using and will never use again."

Most of the proteins produced by those genes, however, cannot be used as targets with currently available methods. Antibodies cannot get at them because by and large, they are found in the nucleus or cytoplasm: "very few indeed are actually presented on the cell surface," Jakobsen said.

Small molecules, of course, can go after intracellular targets. But in that case, the target protein needs to be essential for the cancer cell's survival – which most of them aren't.

Those intracellular proteins do sooner or later make their way onto the cell surface – they are presented, in fragments, by major histocompatibility complex or MHC proteins. In that form, they can and do activate killer T cells. But most often, a given cell will have few copies of the protein on its cell surface – so few, in fact, that it fails to stimulate a T-cell response.

Jakobsen and his team addressed this issue by creating what they have termed immune-mobilizing monoclonal TCRs against cancer, or ImmTACs.

One part of the ImmTAC is an engineered T-cell receptor that binds to MHC-presented tumor antigens on cell surfaces with much higher affinity than normal T-cell receptors. That receptor is coupled to an antibody fragment that recognizes the CD3 receptor, which is a potent T-cell activator.

The T-cell receptor part of the ImmTAC essentially clings to the cancer cell and draws in T cells – in practice, mainly previously activated T cells, but it could be any T cell. "It's very different from the normal T-cell response, which is clonal" – that is, one T cell whose receptor is specific to the antigen at hand expands as it encounters its target.

In the experiments now published in Nature Medicine, senior author Jakobsen and his team tested four different ImmTACs, two that are specific to melanoma and two that are expressed by several types of solid tumors. ImmTACs were able to activate both killer and helper T cells, with the strength of the activation increasing with the binding strength of the T-cell receptor to its target.

Comparing the method to other immune-based approaches, Jakobsen said it is most similar to the Bispecific T-cell engager or BiTE method developed by Micromet AG, which is now part of Amgen Inc.

"Micromet has reported, I think it is fair to say, some of the most spectacular clinical results ever," Jakobsen said. (See BioWorld Today, Aug. 15, 2008.)

But the BiTE technology has also grappled with toxicity. Micromet has been successful in addressing those issues, and blinatumomab, the lead BiTE antibody, is now in Phase II trials. But Jakobsen hopes that Immunocore's approach will be less-beset with toxicity problems to begin with, because the ImmTAC technology opens up a wider range of targets: "We can be pickier" about which of those targets to go for, he said.

Immunocore is in clinical trials with the first of its therapies, which targets the gp100 protein for the treatment of melanoma. A second program, targeting MAGE antigen, is slated for starting trials by the middle of the year. The initial indication for that program will be multiple myeloma.

Beyond that, Jakobsen said, the company has a "deep pipeline" of ImmTACs in preclinical development. Because of the novelty of the approach, Immunocore expects a fairly high attrition rate in preclinical development. But the company hopes to have at least half a dozen programs targeting various cancers within the next few years. And ultimately, Jakobsen said, "I think one could envisage 50-100 suitable candidates, if resources allow."