Toll-like receptors that activate immune cells being developed as alternative cure to cancer

Sep 16 2009

The development of cancer involves the uncontrolled growth of normal cells of the body. Our immune system can sense the growth of the tumor cells and can usually eliminate them using direct killing mechanisms, mediated by natural killer cells and cytotoxic T lymphocytes. However, the tumor has an arsenal of strategies to counteract the immune response that seeks to eliminate it. Professor Kingston Mills, Trinity College Dublin, has developed a new strategy to selectively block the tumor induced immunosuppression and thereby enhance the efficacy of tumor immunotherapeutics. First results will be presented during 2^nd 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.

EFIS is an umbrella organization that represents more than 12,000 individual members from 28 member societies in 31 European countries (all European Union member states and all other European states) and reaches beyond the European boundaries to Israel.

"Immunity for Life - Immunology for Health": with this as their motto, all National European Societies of Immunology will convene from the 13^th to 16^th   September, 2009, in Berlin, Germany.  This Congress offers a four day comprehensive program on the state of the art in Immunology. More than 30 symposia and 60 workshops will cover topics from basic research to applied Immunology. The foci of this meeting are newly acquired knowledge about innate and adaptive immunity, the various aspects of immunological diseases, as well as new options for immune interventions. Professor Reinhold E. Schmidt, the president of the Congress and Director of the Clinic for Immunology and Rheumatology at Hanover Medical School, is pleased to invite journalists to attend this event.