Making the most of lymphopenia

July 10, 2002

A study undertaken by investigators at The Scripps Research Institute (TSRI) suggests a new, potentially more effective way to battle cancer--hit the immune system with cancer vaccines or cancer cells when it's down and it will bounce back swinging harder than ever against those cancer cells.

The technique involves administering an injection of fresh immune cells to replace the ones that die immediately after chemotherapy or irradiation. An injection of cancer cells at the same time serves as a form of "immunotherapy," which induces a person's immune system to attack existing colonies of those cancer cells. In the technique, the fresh immune cells immediately begin to multiply and, because they see the cancer cells, they are rapidly activated to kill them.

"The treatment has utility on the basis of its simplicity," says TSRI immunology Professor Argyrios N. Theofilopoulos, M.D., who led the study.

Theofilopoulos's study, which is published in the latest issue of the Journal of Clinical Investigation, suggests that immunotherapy should be initiated immediately after chemotherapy or irradiation because the reduction in the body's T cells is actually an advantage.

"If you have only a small number of T cells," says Theofilopoulos, "It is very likely that, during their subsequent expansion, you will develop a strong T cell response [to the cancer]."

For years, the main treatment for various sorts of cancers has been systemic chemotherapeutics--drugs that have a cytotoxic effect on rapidly dividing cancer cells--or irradiation, the use of x-rays or some other sort of ionizing radiation that is also lethal to cancer cells. However, they both cause collateral damage, killing non-cancerous cells as well. Like innocent bystanders, T cells and other cells of the immune system are killed along with the tumor cells during chemotherapy and irradiation--a state referred to as "lymphopenia."

Immunotherapy is another approach to cancer therapy that has evolved over the last few decades to give the immune system a push to start doing what it should be doing in the first place--killing cancer cells. Immunotherapy involves helping the T lymphocytes and other cells of the immune system to attack and kill cancer cells. It is best at killing small colonies of cancer cells before they grow into tumors.

One way in which this is accomplished is by injecting tumor cells, which carry tumor-specific antigens. Antigens are markers--proteins on the surface of a cancer cell, for instance--that are used by the immune system to distinguish one cell from another. After recognizing the antigens presented by the antigen presenting cells, the immune cells become activated and mount an immune defense, selectively attacking any cells displaying the antigens. Once the immune system is activated, it will go about killing these cancer cells in a discriminate fashion.

Now, the study by Theofilopoulos and his colleagues suggests the anti-tumor effect of immunotherapy could be increased if it were coupled with an injection of fresh T cells after chemotherapy or irradiation.

Traditional thinking had been that it did not make sense to initiate immunotherapy until some time after chemotherapy or irradiation, because these techniques induce lymphopenia. However, the body responds to lymphopenia via a "homeostatic" mechanism that induces proliferation in the T cells and other lymphocytes that survive the chemotherapy or irradiation. The body detects when there is less than a certain desirable number--usually a few million lymphocytes per milliliter--and causes them to expand and return the body's pool of lymphocytes to its former levels.

But one can give the immune system a head-start by injecting T cells that were obtained from blood samples prior to irradiation. These T cells, detecting the lymphopenia, will immediately begin homeostatic expansion. What Theofilopoulos and his colleagues found was that if these T cells see the cancer antigen when they proliferate, they will have a marked bias towards the cancer antigen, seek out cancer cells, and kill them.

In in vivo studies with murine models, Theofilopoulos and his colleagues were able to establish protection against tumor formation and strong regression of existing tumors. They performed their studies with melanoma and carcinoma tumors and found that they could be inhibited from growth by the one-two punch of tumor and T cell injections following lymphopenia.

The article "T cell homeostatic proliferation elicits effective antitumor autoimmunity" is authored by Wolfgang Dummer, Andreas G. Niethammer, Roberto Baccala, Brian R. Lawson, Ralph A Reisfeld, and Argyrios N. Theofilopoulos and appears in the July 15, 2002 issue of The Journal of Clinical Investigation.
The research was supported by the National Institutes of Health.

Scripps Research Institute

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