Immunotherapy: Why don't more patients respond?

Thomas Gajewski, MD, PhD, in lab
This is part two of a two-part feature on the latest advances in immunotherapy for cancer. Read part one: Immunotherapy: Using the body's immune system to fight cancer

UChicago Medicine researchers are tackling the big challenge with immunotherapy: Why doesn’t it work for everyone?


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. 
High-profile studies from UChicago faculty have pointed to novel ways to extend the benefits of various immune-based therapies to help patients.
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.   

Making cold tumors hot

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 labelled 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 Ralph Weichselbaum, MD, chair of radiation and cellular oncology and co-director of the Ludwig Center for Metastasis Research at the University of Chicago, showed, in back-to-back papers in the journal Immunity, how the protein complex known as STING, short for stimulator of interferon genes, might help warm up cold tumors. This complex, first described by Gajewski, reacts to DNA that is damaged or in the wrong place, inside the cell but outside the nucleus. Detection of this cytosolic DNA, in the cell but outside the nucleus, alerts the immune system to a threat, helps detect cancerous or infected cells, and ultimately sends activated T cells into battle. Injection of STING agonists showed remarkable efficacy in mouse cancer models, and a clinical trial of the first human STING agonist is ongoing at UChicago.
 
The following year, Gajewski’s lab showed how cold tumors shield themselves from T cells by producing high levels of beta-catenin, an intracellular messenger. Tumors that don’t activate beta-catenin allow dendritic cell entry, leading to an immune response and ultimate tumor cell death. But tumors that activate beta-catenin use it to shield themselves. The study was published in Nature.
 
A 2016 study by Weichselbaum found that the combination of local radiation therapy, anti-cancer vaccines and checkpoint inhibitors could increase response rate for new immunotherapy agents. “By promoting T-cell infiltration, radiation therapy improved the efficacy of tumor vaccines and checkpoint inhibitors,” Weichselbaum said. The results, in a mouse model of pancreatic cancer, suggest that radiation therapy could “synergize with immunotherapy to convert cancers with an unfavorable cold phenotype to a more favorable hot phenotype. 
 
“Radiation's effects may include release of cell fragments and other signals that stimulate the immune system,” he added, “as well as elimination of some of the immunosuppressive factors.”
 
And earlier this year, in Cancer Cell, Gajewski and colleagues showed that dendritic cells, part of the innate immune system, are responsible for recruiting battle-ready T cells into the tumor microenvironment. The absence of these dendritic cells from the tumor site appears to be a “dominant mechanism of resistance to multiple immunotherapies, including cancer vaccines and adoptive T cell therapy.”
 
Other high-profile studies from UChicago researchers:
  • Onco-immunologist Hans Schreiber, MD, PhD, an authority on tumor-specific antigens, found that adoptively transferred immune T cells could eliminate well-established tumors by destroying tumor blood vessels. His team’s results, published in 2014, indicate that these transferred T cells can overcome local and system immunosuppression caused by myeloid cells. In 2016, he and colleagues were the first to demonstrate the potential efficacy of mutation-specific T-cell-receptor gene therapy to eradicate established solid tumors, in mice. 
  • While treatments that mobilize the body's own immune system to help fight cancer have shown considerable success in many tumor types, prostate cancer rarely responds. Medical oncologist Akash Patnaik, MD, PhD, and colleagues found that cabozantinib, an FDA-approved drug for treatment of certain thyroid and kidney cancers, could within days, eradicate difficult-to-treat types of prostate cancer in mice. Patnaik's lab found that the drug induced neutrophils – first-responders of the innate immune system – to infiltrate the tumor, where they triggered an innate immune response that led to tumor clearance. He has launched two first-in-human clinical trials based on these studies.
  • And a surprise finding from an international team led by 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 

UChicago Medicine clinicians have also probed the current limits of immunotherapy. In a 2015 study, oncologist Tanguy Seiwert, MD, the associate program leader for head and neck cancer, showed that treatment with the checkpoint blocker pembrolizumab decreased the size of tumors by 30 percent or more in one out of four patients with recurrent or metastatic head and neck cancer. 
 
“The efficacy was roughly twice as good as any drug combination in our arsenal,” he said at a press conference at the annual American Society of Clinical Oncology meeting. “Overall, 57 percent of patients experienced a measurable decrease in the size of their tumors.”
 
Researchers led by hematologist/oncologist Justin Kline, MD, showed that injecting STING agonists could provoke a life-extending immune response in mice with acute myeloid leukemia, the most common type of acute leukemia seen in adults. This was the first demonstration that activating the STING pathway could be effective not only in solid, localized tumors, but also in blood cancers.
 
At the 2017 annual meeting of the American Society of Clinical Oncology in Chicago, breast cancer specialist Rita Nanda, MD, presented data from the I-SPY 2 clinical trial that added pembrolizumab to standard therapy. The treatment dramatically improved response rates for patients with invasive triple-negative breast cancer. Sixty percent of the women who received pembrolizumab had a pathological complete response — no evidence of cancer in the breast or lymph nodes — compared to 20 percent of the women who received standard chemotherapy alone. For women with hormone-receptor positive, HER2-negative disease, the complete response nearly tripled, from 13 percent to 34 percent. 
 
Everett Vokes, MD, an internationally renowned expert in the treatment of head and neck and lung cancer and chair of the Department of Medicine, reported results from the CheckMate 017/057 trial of the immunotherapy nivolumab compared to the chemotherapy drug docetaxel at the ESMO Congress earlier this year in Barcelona. After at least three years of treatment, patients taking nivolumab had an overall survival rate nearly three times as high as those taking docetaxel; 71 of the 427 patients (17 percent) taking nivolumab survived for more than three years.
 
Earlier this year, the FDA gave pembrolizumab a green light for use in any solid tumor that has a specific genomic signature, the first such approval in cancer medicine.
 
Oncologist Rita Nanda, MD, meets with a patient

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