Regulating The Regulators: New Therapeutic Approach Against Cancer

First results will be presented during 2nd European Congress of Immunology 2009 in Berlin.

Tumors secrete immunosuppressive molecules that dampen the immune responses and recruit suppressor cells, called regulatory T cells (Treg cells). However, these Treg cells have a protective function in preventing immune responses against self antigens and normal host cells, which, if uncontrolled, can lead to autoimmune diseases. These immunosuppressive molecules and Treg cells make it very difficult for the immune system to kill the growing tumor, and this can lead to uncontrolled tumor growth and cancer.

Cancer is usually treated by surgery, chemotherapy, radiotherapy or a combination thereof. However, these approaches are not always effective and can have serious side effects. Alternative strategies are being developed, based on stimulating the body’s immune system to eliminate the tumor and prevent a recurrence. These include a range of biological therapies. Some of them activate dendritic cells, which direct the activation of the T lymphocytes that kill the tumor cells. Cell based therapies, involving infusion of cell culture expanded T lymphocytes or dendritic cells are also in development.

Some of these approaches are effective against a small range of tumors. For example, a Toll-like receptor (TLR) agonist, called imiquimod, which activates dendritic cells, is in clinical use as a topical application for basal cell carcinoma. In addition, a number of TLR agonists have been evaluated in clinical trials as an adjuvant for cancer vaccines. However there have also been disappointing results from clinical trials involving TLR agonists.

A problem with TLR agonists and other therapeutic and vaccine approaches against cancer that have not been fully appreciated is that they can generate suppressive as well as inflammatory responses in innate immune cells and can generate regulatory as well as protective T cells. This is part of a normal mechanism for limiting collateral damage during infection or inflammation, but can constrain their ability to induce protective anti-tumor immunity in the immune suppressed environment of the tumor.

Mills and co-workers have developed an approach to manipulate the TLR-activated innate immune responses to selectively block the suppressive arm. The scientists achieved this by manipulating intracellular signalling pathways in the dendritic cells, thereby blocking the induction of Treg cells and immunosuppressive responses and promoting the protective responses that eliminate the tumors. The new approach has proven very successful in prevent cancer in a tumor models in mice and may hold the key to enhancing the efficacy of tumor immunotherapeutics and vaccines against cancer in humans. The new technology has been licensed to a local start-up company, Opsona Therapeutics, who are planning to move it into clinical development in partnership with major pharmaceutical companies.