3 min readResearch Shows How Antibodies Produce Vaccine-Like Effect Against Tumours

New York, NY — The problem with traditional cancer treatments is that their effects don’t always last: Stop the therapy and the disease may return.

That’s why antibody therapy — which not only kills tumours, but also appears to train the body’s own defences to recognize them — has such promise. New research at Rockefeller University, published May 11 in Cell, shows how this happens, with the destruction of tumour cells prompting a patient’s immune system to form immunological memory that can suppress the same tumour should it try to return.

“Our experiments using lymphoma, a type of blood cell cancer, uncovered a two-step process that revolves around two receptors found on different types of immune cells, linking those cells to antibodies. In this way, these so-called Fc receptors act as crucial intermediaries,” says Jeffrey Ravetch, Theresa and Eugene M. Lang Professor and head of the Leonard Wagner Laboratory of Molecular Genetics and Immunology.

“These findings suggests ways current anticancer antibody treatments might be improved, as well as combined with other immune system stimulating therapies to help cancer patients,” Ravetch says.

Antibody-based therapies, in which patients receive immune proteins that target specific proteins, called antigens, produced by their tumours, have been available for about two decades. Previous work in the lab has shown that these antitumour antibodies bind to Fc receptors on activated immune cells, prompting those immune cells to kill the tumour. However, it was unknown which Fc receptor was involved, or how the tumour killing led the immune system to generate memory T cells against these same antigens, in case the tumour producing them should return.

Ravetch and first author David DiLillo, a postdoc in the lab, broke down the process by injecting lymphoma cells that expressed the antigen CD20 into mice with immune systems engineered to contain human Fc receptors. When these mice received antibodies that targeted CD20, they all survived. Three months later, most of the same mice survived being challenged again with the same lymphoma or a different one that also expressed CD20. Mice not treated with antibodies, or those that received non-CD20 lymphoma the second time around, did not fare well.

Different types of immune cells can express different Fc receptors. So, based on the cells Ravetch and DiLillo thought were involved, they looked to the Fc receptors expressed by cytotoxic, or cell killing, immune cells, that carried out the initial attack on tumours, and the Fc receptors found on dendritic cells, which are crucial to formation of memory T cells.

To test the involvement of these receptors, the researchers altered the therapeutic antibodies delivered to the lymphoma-infected mice so as to change their affinity for these Fc receptors. Then, they looked for changes in the survival rate of the mice after the first challenge with lymphoma, and then again after a second.

When they dissected this process, they found two steps: One Fc receptor, known as FcRIIIA, found on a Pac-Man-like immune cell known as a macrophage, responds to the antibodies, and prompts the macrophage to engulf and destroy the antibody-laden tumour cell. These same antibodies, still attached to tumour antigens, activate a second receptor, FcRIIA, on dendritic cells, which use the antigen to prime T cells. The result was the generation of a T cell memory response that protected the mice against future tumours expressing CD20.

“By engineering the antibodies so as to increase their affinity for both FcRIIIA and FcRIIA, we were able to optimize both steps in this process,” DiLillo says. “Current antibody therapies are only engineered to improve the immediate killing of tumour cells, but not the formation of immunological memory. We are proposing that an ideal antibody therapy would be engineered to take full advantage of both steps.”

It is important to note that the immunological memory at the centre of this study had a significant limitation: It protects only against tumours that express the specific antigen targeted by the antibodies that are administered.

“Because cancer can be highly unpredictable, and can reoccur in altered forms, we think an important next step may be boosting the antitumour immunity by combining antibody therapy with other, new immunological therapies that can, for example, enhance T cell responses,” Ravetch says.

Article adapted from a Rockefeller University news release.

Publication: Differential Fc-Receptor Engagement Drives an Anti-tumor Vaccinal Effect. David J. DiLillo and Jeffrey V. Ravetch. Cell (May 11, 2015): Click here to view.

Cancer Immunotherapy

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