Tumor immunology takes off

Columnist
Graduate Division

Live from the Tumor Immunology Keystone Symposium in Banff, Canada

Tumors are not just solid masses of cancer cells. As those cancer cells grow and divide, they hijack all the normal cells around them for their own purposes. They coerce blood vessels to grow along with them, ensuring a continued supply of oxygen and nutrients from the blood stream as the tumor gets bigger. They stimulate the immune cells that are active in wound healing, mimicking a damaged tissue that needs growth stimulation. They also avoid and suppress the immune cells that would normally recognize and kill them. 

Basically, cancer cells have to use every trick in the genome—and a few new skills they’ve picked up from a mutated genome—in order to even begin to form a sizeable tumor, let alone invade other tissues and form distant secondary tumors known as metastases.

Tumor immunology is the study of the interactions between tumors and the immune system. This is arguably the hottest field of cancer research today because of the recent groundbreaking successes of cancer immunotherapy in the clinic—the therapeutic harnessing of the immune system to fight and cure cancer.

Immunotherapy took off in 2011, when the biologic drug ipilimumab (Yervoy) was approved by the FDA for treating patients with late-stage melanoma. The drug inhibits the protein CTLA4 and was developed on the basis of Matthew (Max) Krummel’s Ph.D. work in James Allison’s lab demonstrating that CTLA4 on the T cell surface acted as an immune checkpoint by inhibiting T cell activation (Krummel is now a professor at UCSF). Because T cells are the immune system’s snipers, blocking this checkpoint takes off their brakes and allows them to go nuts and kill the cancer cells.

The concept of immune checkpoint blockade has been expanded to another inhibitory system on T cells, PD1 and PDL1. Blocking CTLA4 and PD1 separately is effective, but blocking them in combination has been astounding when it comes to clinical responses. Ira Mellman and other speakers at the Keystone Symposium noted that targeting various proteins and signaling pathways within cancer cells can be transiently effective, but ultimately any number of resistance mechanisms can circumvent these targeted therapies and result in relapse. Unleashing the immune system’s might and wrath, on the other hand, can lead to durable responses that, many years later, appear to be permanent. For a patient with a late-stage metastatic cancer, such as melanoma—which a few short years ago had no treatment options—a sustained 10-year response (and counting) is nothing short of a miracle.

A key requirement for cancer immunotherapy to work is that the patient’s T cells already have an existing, albeit suppressed, response to the cancer cells via recognition of bits and pieces of the cancer cells (antigens) loaded onto a specialized protein called MHC–I and presented on the surface of the cancer cells. A major question tumor immunologists are working to answer is: What antigens do T cells recognize on cancer cells? Robert Schreiber and others employ sophisticated high-throughput techniques to sequence a patient’s cancer cell DNA, identify mutations, predict which ones might be presented on MHC–I, and then screen that same patient’s tumor-infiltrating T cells to determine how many recognize those predicted antigens. 

Early studies have suggested that T cells mostly recognize mutated proteins, because they are different from normal proteins and their novelty is recognized as a foreign entity, and in fact a cancer’s mutational load correlates to how much of an immune response can be unleashed by immunotherapy. Ton Schumacher called this the “neo-antigen lottery model”—each mutation has an equal chance of becoming a neo-antigen, an antigen not normally found in the body, and a large number of mutations increases the likelihood that neo-antigens will be presented to the immune system. Several labs are attempting to predict neo-antigens, identify neo-antigen-recognizing T cells, and study the dynamics of these interactions during immunotherapy.

Some clever techniques are being developed to expand the scope of immunotherapeutic approaches. Jay Berzofsky is developing a virus that carries a portion of the biologic drug trastuzumab (Herceptin), which is used to treat HER2-positive breast cancers. Both the drug and virus harness the immune system to target cancer cells. Steven Larson is using tumor-specific antibodies to deliver radioisotopes in a targeted way, an approach that aims to avoid toxic side effects and bring radiation therapy into the 21st century. Jonathan Powell reported that certain metabolic inhibitors that have been used to target cancer metabolism can differentially affect T cell subsets, allowing one to tweak which T cells are active within a tumor.

Several groups are studying the combination of standard chemotherapies or targeted therapies with immunotherapy, identifying situations in which the two can synergize. To this end, the FDA has at long last issued guidelines for the co-development of combinations of drugs that would only need to first demonstrate safety, but not efficacy, as monotherapies.

Of note, the microbiome—slowly but surely identified to interact with any and every aspect of human health and disease—is necessary for immunotherapies to work. Laurence Zitvogel demonstrated that while CTLA4 blockade failed to work in germ-free mouse models, its efficacy is rescued when a particular strain of bacteria is reintroduced. Such observations open doors for studying all aspects of the immune system’s dynamics in cancer patients.

These are just a few highlights from an exciting meeting in an exciting field of cancer research. We’re sure to have many exciting breakthroughs in the near future!