A concerted innate and adaptive attack involving neutrophils, NK cells, macrophages, and CD8+ T cells beat back cancer in isogenic tumor models. [© kniazev_iv/Fotolia]
A concerted innate and adaptive attack involving neutrophils, NK cells, macrophages, and CD8+ T cells beat back cancer in isogenic tumor models. [© kniazev_iv/Fotolia]

Staging the immunological equivalent of a two-front war, MIT scientists simultaneously activated both arms of the immune system to halt the growth of a very aggressive form of melanoma in mice. The MIT scientists, like many other researchers, decided to use an approach called cancer immunotherapy. Ordinarily, this approach involves either the activation of the innate immune system or the stimulation of T cells. The MIT researchers, however, mustered both innate and adaptive immune forces.

“An antitumor antibody can improve adoptive T-cell therapy to a surprising extent,” said K. Dane Wittrup, Ph.D., a professor of chemical engineering at MIT. “These two different parts of the immune therapy are interdependent and synergistic.”

To date, immunotherapeutic campaigns against cancer have proven difficult. The immune system often fails to recognize the appearance of tumors as a call to arms. And it often seems a reluctant recruit, whether the “I want you” is issued to raise antibodies or enlist T cells. Dr. Wittrup and his colleagues, however, made the discovery that they could generate both types of immune responses while they were experimenting with improving antibody drug performance with a signaling molecule called IL-2, which helps boost immune responses.

The scientists described their work April 13 in the journal Cancer Cell, in an article entitled, “Synergistic Innate and Adaptive Immune Response to Combination Immunotherapy with Anti-Tumor Antigen Antibodies and Extended Serum Half-Life IL-2.”

“We find that a combination of an anti-tumor antigen antibody and an untargeted IL-2 fusion protein with delayed systemic clearance induces significant tumor control in aggressive isogenic tumor models via a concerted innate and adaptive response involving neutrophils, NK cells, macrophages, and CD8+ T cells,” they wrote. “This combination therapy induces an intratumoral ‘cytokine storm’ and extensive lymphocyte infiltration.”

About a dozen IL-2-enhanced antibody 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.

Dr. Wittrup and his colleagues overcame this by fusing IL-2 to part of an antibody molecule, which allows it 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.

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, and 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,” Dr. Wittrup said.

Cells called neutrophils, which are considered the immune system's first line of defense because they react strongly to foreign invaders that enter the skin through a cut or other injury, were also surprisingly important.

The researchers also found that when they delivered an antibody, IL-2, and T cells targeted to the tumor, the adoptively transferred T cells killed cancer cells much more successfully than when only T cells were delivered. In 80–90% of the mice, tumors disappeared completely; even when tumor cells were reinjected into the mice months after the original treatment, their immune systems destroyed the cells, preventing new tumors from forming.

“Adoptive transfer of antitumor T cells together with this combination therapy,” the authors of the Cancer Cell article concluded, “leads to robust cures of established tumors and development of immunological memory.”

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