Attacking cancer by mobilising our entire immune system

Stimulating both immune system branches halts tumor growth more efficiently

T cells attack a cancer cell. Credit_Steve Gschmeissner_Science Source

Our human immune system is ready to spring into action at the first signs of foreign invaders however it often fails to eliminate tumors originating in the body’s own cells.

Orchestrating a successful immune attack against tumors has proven difficult so far, but a new study from MIT suggests that immune attack against tumors could be improved with cancer immunotherapy — simultaneously activating both arms of the immune system with antibodies (which activate the innate immune system) and stimulating T cells (which form the backbone of the adaptive immune system).

By combining these approaches, the MIT team was able to halt the growth of a very aggressive form of melanoma in mice.

“An anti-tumor antibody can improve adoptive T-cell therapy to a surprising extent,” says Dane Wittrup, the Carbon P. Dubbs Professor in Chemical Engineering at MIT. “These two different parts of the immune therapy are interdependent and synergistic.”

Wittrup, an associate director of MIT’s Koch Institute for Integrative Cancer Research and also a faculty member in the Department of Biological Engineering, is the senior author of a paper describing the work this week in the journal Cancer Cell.

Antibody drugs vs. T cells

Antibody drugs for cancer, which include rituximab and Herceptin, are believed to work by binding to cancer proteins and blocking the signals that tell cancer cells to divide uncontrollably. They may also draw the attention of cells belonging to the innate immune system, such as natural killer cells, which can destroy tumor cells.

Adoptive T cell therapy, on the other hand, enlists the body’s T cells to attack tumors. Billions of T cells flow through the average person’s bloodstream at any given time, each specialized to recognize different molecules.

The weak point with T cells is that many tumor proteins do not provoke T cells to attack, so T cells must be removed from the patient and programmed to attack a specific tumor molecule.

Timing is key to triggering both immune responses simultaneously

Instead of relying on that complicated process, Wittrup and his colleagues discovered that they could generate both types of immune responses — antibodies and T cells — while they were experimenting with improving antibody drug performance with a signaling molecule called IL-2, which helps boost immune responses.

Scientists have tried this strategy before, and about a dozen such therapies have gone through phase I clinical trials. However, most of these efforts failed, even though the antibody-IL-2 combination usually works very well against cancer cells grown in a lab dish.

The MIT team realized that this failure might be caused by the timing of IL-2 delivery. When delivered to cells in a dish, IL-2 sticks around for a long time, amplifying the response of natural killer cells against cancer cells. However, when IL-2 is injected into a patient’s bloodstream, the kidneys filter it out within an hour.

Wittrup and his colleagues overcame this by fusing IL-2 to part of an antibody molecule, which allows IL-2 to circulate in the bloodstream for much longer. In tests in mice with a very aggressive form of melanoma, the researchers found they could stop tumor growth by delivering this engineered form of IL-2, along with antibody drugs, once a week.

Immune synergy

The synergistic combination of immune response activation (Fc/IL-2, upper left), anti-tumor antibodies (IgC, near tumor), and neutrophils (PMN, purple) creates a massive assault on a tumor (credit: Eric F. Zhu et al./Cancer Cell)

To their surprise, the researchers found that T cells were the most important component of the anti-tumor response induced by the antibody-IL-2 combination.

They believe that the synergy of IL-2-induced cells and cytokines, along with the antibody treatment, creates an environment that lets T cells attack more effectively.

“The antibody-driven innate response creates an environment such that when the T cells come in, they can kill the tumor. In its absence, the tumor cells establish an environment where the T cells don’t work very well,” Wittrup says.

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