We need to embrace the biology of the tumor and recognize that all of the cells in the mass communicate and that they all regulate each other's activity. Unless we can grasp that communication, I think we're missing the boat.
Greater understanding of the tumor microenvironment may lead to more-durable responses to therapy
“I do not characterize myself as an immunologist,” says Lisa Coussens, PhD. “I am a cancer biologist. We need to embrace the biology of the tumor and recognize that all of the cells in the mass communicate and that they all regulate each other's activity. Unless we can grasp that communication, I think we're missing the boat.”
Associate director of basic research for the Knight Cancer Institute at Oregon Health and Science University in Portland, OR, Coussens is well known for her studies of inflammation and cancer, as well as immune cell–mediated regulation of breast and squamous cancers. Her recent work includes findings about how the immune microenvironment of tumors can be reprogrammed to improve response to cytotoxic therapy (Cancer Discov 2011;1:54–67). She spoke with Cancer Discovery's Suzanne Rose about her field.
What are we learning about immune system cells and the tumor microenvironment?
For the last 10 years, biologists have been documenting the pro-tumorigenic roles of infiltrating immune cells across all organ types and across all tumor types. Within the past 5 years, studies have examined how pro-tumor immune cells can be programmed. We recognize now that when you attenuate pro-tumor signaling, you can reprogram infiltrating immune cells to act in a more tumor-repressive manner.
How do we achieve that? What are the best targets to go after? Can we achieve durable antitumor immunity by using reprogramming agents in combination with chemotherapies? By reprogramming the immune microenvironment, will adoptive transfer of antigen-specific T-cells or cell-based therapies like dendritic cell vaccines provide a more-durable or more broad-based response?
How would that reprogramming improve vaccines?
Tumors are very TH2 [T-helper type 2] polarized, and cytotoxic T cells and dendritic cell–based vaccines theoretically can't provide durable antitumor immunity in that environment. It stands to reason that if you could reprogram that immune microenvironment to instead favor a TH1-type state, then you could achieve a more durable response. This approach is being pursued by several investigators with second-generation targets that have evolved out of the anti-CTLA4 work: PD1 and the B7 family, for example, as well as directly reprogramming myeloid cells.
How is research on immune cells and the tumor microenvironment impacting drug development?
I know of very few biotech or pharmaceutical companies that don't have drugs in their pipeline to target an immune response pathway. Since we reported that macrophages could be differentially regulated to retard metastasis in mammary cancer models (Cancer Cell 2009;16:91–102), I've been approached by at least 50 biotechs and pharmaceutical companies with various CSF1 [colony-stimulating factor 1] receptor antagonists.
If the immune microenvironment couldn't be reprogrammed, I don't believe we would be seeing this explosion in drug development. But the data argue that we can reprogram it, and that provides us with an opportunity to think about layering therapies, such as kinase inhibitors that target cell-intrinsic pathways downstream of oncogenes, as well as antiangiogenic drugs in combination with cytotoxic approaches.
What drugs target immune response pathways?
Two immune therapies have recently been approved: ipilimumab and sipuleucel-T. I anticipate more-durable responses from these once they are combined with chemotherapy or with therapies that reprogram local tumor immune microenvironments that blunt TH2-based pathways, but those are in the future.
That said, probably a half dozen CSF1 receptor antagonists are in phase I testing. Some are in phase Ib. One or 2 are in phase II for selected malignancies. We're going into phase Ib–phase II testing of a CSF1 receptor antagonist in breast cancer, and we're working on opening trials in mesothelioma and pancreatic cancer—and we're not alone.
“Explosion” is a good word to describe what's happening. It's analogous to what happened with the explosion of receptor tyrosine kinase inhibitors 10 to 15 years ago.
Will these agents be used in combination treatments?
I do not anticipate that we will see significant efficacy with any of these approaches as monotherapy. I anticipate improved efficacy in slowing time-to-progression when we are able to combine them with cytotoxic agents. I anticipate seeing durable tumor repression and long-term extension of survival when we start layering in immunotherapeutics that span the gamut of these reprogramming approaches with traditional immunotherapeutic approaches like adoptive T-cell transfer, along with cytotoxics, and perhaps relevant kinase inhibitors.
What's the focus of your research now?
We are digging in to understand the in vivo mechanisms that we see being reprogrammed. We're looking ahead, using mouse models to anticipate acquired resistance. We're collaborating with tumor immunologists to combine adoptive T-cell transfer and dendritic cell–based vaccine approaches. We're collaborating with medical oncologists so that we treat and monitor the mouse models like patients and appropriately dose them with standard cytotoxics. If our work doesn't mirror what's happening in the clinic, it's irrelevant.
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