Immunotherapy - the enlisting of the immune system to fight cancer - is an exciting new field that has already led to early trials of new treatments. However, these often fail because promising results seen in petri dishes are not translating into successful attacks on real tumors.
Now, a new study from the Massachusetts Institute of Technology (MIT) suggests that one reason immunotherapy treatments appear to fail when they leave the lab may be because they are only enlisting one arm of the immune system. So far, immunotherapy developers have focused either on attacking tumors with antibodies, which enlists the innate immune response, or approaches like adoptive T cell therapy to boost numbers of T cells, which form the backbone of the adaptive immune response.In a report on their work in the journal Cancer Cell, senior author Dane Wittrup, a professor in chemical engineering, and colleagues describe how a combination of the two approaches successfully halted a very aggressive type of melanoma in mice. Their idea began as they were investigating how to improve the immune response of an antibody-based therapy using IL-2, a signaling molecule. Making IL-2 hang around longer boosts anti-tumor antibody therapy.
Other groups had already tried to use IL-2 to boost antibody-based immunotherapies, but found even though it appeared to work on lab-grown cancer cells, most efforts failed in trials against real tumors. The MIT researchers wondered if these failures were because patients' bodies were targeting IL-2 and eliminating it through their kidneys before it could do its job. In the petri dish, where it hangs around for a long time, IL-2 boosts the response of natural killer cells against cancer cells. Natural killer cells are part of the innate immune system.
So Prof. Wittrup and colleagues tried another approach - they fused IL-2 to part of an antibody molecule to make it less of a target and more likely to stay in the bloodstream for longer. The approach worked - giving mice this combination of tumor-fighting antibody and fused IL-2 once a week stoppedtumor growth in mice. But there was a surprise in store. They discovered the main reason the tumors stopped growing was because of a surge in T cells - which are part of the adaptive immune system. Prof. Wittrup explains what they believe happened:
"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."
The team found that another group of cells called neutrophils also played an important role. These cells are part of the immune system's first response to invasion and not normally considered in the development of immunotherapies. Anti-tumor antibody with fused IL-2 boosts adoptive T cell therapy. The researchers then tried a further experiment using a combination of the antibody therapy - the fused IL-2 and another therapy called adoptive T cell therapy. T cells are specialized killing agents in the adaptive immune system - each is programmed to recognize a particular "enemy" molecule, such as a tumor protein. However, for some reason, some tumor proteins do not feature on the enemy lists of T cells. In adoptive T cell therapy, T cells are taken from the patient, programmed to recognize tumor proteins, multiplied and then infused back into the patient.
The MIT team found the adoptive T cell therapy combined with antibody therapy supplemented with fused IL-2 was much more successful than using adoptive T cells on their own. In 80-90% of treated mice, the tumors disappeared completely. The team also found that the mice had developed "immunological memory;" when they injected them with tumor cells months later, their immune systems destroyed them.
Prof. Wittrup concludes: "An anti-tumor antibody can improve adoptive T cell therapy to a surprising extent. These two different parts of the immune therapy are interdependent and synergistic." The team is now investigating other ways to make this kind of immunotherapy more effective. In the meantime, Prof. Wittrup suggests simply giving patients prolonged exposure to IL-2 may boost some existing antibody therapies. Funds for the study came from the National Cancer Institute, the National Institute for General Medical Sciences and the National Science Foundation.
In December 2014, Medical News Today reported how researchers at the University of Southampton in the UK found that the shape of an antibody makes a difference in fighting cancer. For their study, also reported in Cancer Cell, they focused on a natural antibody called IgG2, and found that a version called IgG2B is particularly effective at stimulating anti-tumor immunity because it has what is known as a "locked B structure."
Written by Catharine Paddock PhD