Recruiting the entire immune system to attack cancer

MIT scientists show that stimulating both major branches of the immune system simultaneously provides a more effective method of halting tumour growth in mice

Cancer cell and lymphocytes

The human immune system is poised to spring into action at the first sign of a foreign invader, but it often fails to eliminate tumours that arise from the body’s own cells. Cancer biologists are now looking to harness that untapped power using an approach known as cancer immunotherapy.

Orchestrating a successful immune attack against tumours has proved difficult in the past, but a new study from MIT suggests that such therapies could be improved by simultaneously activating both arms of the immune system. Until now, most researchers have focused on one of two strategies: attacking tumours with antibodies, which activate the innate immune system, or 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 antitumour 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 a faculty member in the Department of Biological Engineering, is senior author of a paper describing the work, published in the journal Cancer Cell. Lead authors are graduate students Eric Zhu and Cary Opel and recent PhD recipient Shuning Gai.

Antibody drugs for cancer are believed to work by binding to cancer proteins and blocking the signals that tell cancer cells to divide uncontrollably

Antibody drugs for cancer 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 natural killer cells innate in the immune system, which can destroy tumour cells. Adoptive T cell therapy, on the other hand, enlists the body’s T cells to attack tumours. However, many tumour proteins do not provoke T cells to attack, so T cells must be removed from the patient and programmed to attack a specific tumour molecule.

While experimenting with improving antibody drug performance with a signalling molecule called IL-2, which helps boost immune responses, Wittrup and his colleagues found they were able to generate both types of 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 realised that this failure might be caused by the timing of IL-2 delivery. When delivered to cells in a dish, IL-2 hangs around for a long time, amplifying the response of natural killer cells against cancer cells. But 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 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 tumour 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-tumour 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 tumour. In its absence, the tumour cells establish an environment where the T cells don’t work very well,’ Wittrup says.

Neutrophils, which are considered the immune system’s ‘first line of defence’ because they react strongly to foreign invaders that enter the skin through a cut or other injury, were also surprisingly important

People in immunotherapy don’t usually focus on neutrophils. They don’t really consider them as a viable tool

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

In a related paper that appeared recently in the Proceedings of the National Academy of Science, the MIT team also found that delivering IL-2 bound to any kind of antibody, even if the antibody did not target a protein on the tumour cell surface, would halt or slow tumour growth, especially if additional doses of the antibody alone were also given. Graduate student Alice Tzeng was the lead author of that study.

The researchers are now exploring additional proteins that could be added to the IL-2 and antibody combination to make immunotherapy more effective. In the meantime, simply giving patients more prolonged exposure to IL-2 could improve the effectiveness of existing antibody drugs, Wittrup says.

To read the full report visit http://newsoffice.mit.edu/ 2015/using-entire-immune-system-halts-tumor-growth-0414.