Immunotherapy: Why don't more patients respond?

Most physicians have been thrilled by the unprecedented success of the new treatments for some patients. Medical oncologist Thomas Gajewski, MD, PhD, and his team — early adopters— have been frustrated. They are focused on the failures.

 

“Oddly enough,” he said, “that focus — why doesn’t every patient respond — has been really useful for us, to identify new therapeutic strategies to expand efficacy further.” 

 

Nationally recognized as a leader in the field, Gajewski is an editor for Cancer, Cancer Discovery, the Journal of Experimental Medicine, and the Journal for ImmunoTherapy of Cancer, past president of the Society for Immunotherapy of Cancer, recipient of an Outstanding Investigator Award from the National Institutes of Health  and, according to OncLive, one of the 12 “Giants of Cancer Care” for 2017. 

 

Gajewski and colleagues showed that a large proportion of human cancers have activated T cells that have entered the tumor, but that inhibitory processes shut them back down.  One of these key pathways is the PD-1/PD-L1 (programmed cell death protein 1) interaction, which is broadly involved in many cancer types, hence the rapid FDA approvals of drugs targeting this pathway across multiple human cancers. 

The desirable anti-tumor T cells within the tumor site are held in check not just by PD-1 but by several other mechanisms.  Among them are Tregs, short for Foxp3+ regulatory T cells. These peacekeeper cells “suppress unruly immune responses,” said pathologist Peter Savage, PhD. “They prevent autoimmune diseases, like arthritis, but they are thought to be a major barrier to immunotherapy.” The difficulty is finding ways to tone down Tregs in the tumor setting without causing autoimmune mayhem somewhere else, a problem that is under active investigation.

 

Gajewski’s team recently identified another key component, the role of the host microbiome. In 2015, he and colleagues were surprised to discover that mice from one supplier tended to have a robust spontaneous immune response to melanoma tumors implanted under the skin. Mice from a different supplier had a much weaker response. 

 

When the researchers mixed the mice from both cages together, they found that both sets of mice had a robust response. Gajewski’s team traced the change to a strain of bacteria known as Bifidobacterium. The anti-cancer effects of the bacteria were comparable to treatment with checkpoint inhibitors -- drugs that take the ‘brakes’ off the immune system, helping it recognize and attack cancer cells. A similar human study from his group that relies on stool samples from patients is “quite compelling,” Gajewski said. The composition of microbes predicts treatment response.  “These results pave the way for the development of probiotics that could boost anti-tumor immunity in patients,” he said.   

One reason a minority of patients respond to a checkpoint blockade is an unfavorable local setting. A cellular neighborhood permeated with cytotoxic (or CD8+) T cells is a promising sign. Gajewski has labeled this the “T cell-inflamed tumor microenvironment.” But more often than not, the tumor settles in a gated community, in which T cells are not allowed to enter.  

 

High-profile studies from UChicago faculty have pointed to novel ways to extend the benefits of various immune-based therapies to help patients, by promoting better T cell entry.

 

In 2014, teams led by Gajewski and Melody Swartz, PhD, professor in the Institute for Molecular Engineering at the University of Chicago, found that lymphangiogenesis can determine which patients will benefit from treatment with checkpoint inhibitors. A simple blood test of vascular endothelial growth factor C (VEGF-C) levels before starting treatment may predict outcomes.

We thought that blocking lymphangiogenesis would boost immunotherapy by removing factors that suppress T cells,” she said. But her team’s studies in mice, supported by human data obtained from two clinical trials for melanoma patients, changed their thinking. “The difference was really striking,” Swartz said. “Almost all of the patients with higher than average VEGF-C levels in their blood responded to immunotherapy. This not only resulted in eradication of the primary tumors, it also encouraged T-cell infiltration into metastatic tumors and resulted in long-term protection.” 

Extending immune response