Searching the Human Immune System for Clues to Cancer

After a young man with acute leukemia was treated successfully with traditional chemotherapy, he found himself facing a tough decision. He could stay on chemo and face the high risk of relapse associated with his particular disease, or he could undergo a blood or bone marrow transplant, which would offer the best chance of a cure but put him at risk for severe complications.

To help guide the decision, Frederick Appelbaum, director of the clinical research division at the Fred Hutchinson Cancer Research Center in Seattle, and other doctors there used a new diagnostic test that analyzed the patient’s own cancer DNA, as well as the genetic makeup of his immune cells, and then used that information to detect whether trace amounts of the disease remained after his treatment. That’s something standard diagnostic tests can’t do well.

The new test revealed leukemia cells still lurking in the patient’s body, so he opted for the transplant, despite the additional risk. He’s now in remission, says Appelbaum.

A T cell from the immune system of a person in good health.

The diagnostic test, called ClonoSEQ, is the first product introduced by Adaptive Biotechnologies, which was founded in 2009 by brothers Chad and Harlan Robins. (Appelbaum is an advisor to Adaptive.) Harlan originally came up with the concept for the test at Hutchinson, where he holds a faculty position. His idea was to use DNA sequencing to scrutinize the genes of T and B cells, which are the building blocks of the immune system. Unlike other cells in the body, T and B cells constantly reshuffle their DNA in response to pathogens in their environment. Adaptive’s technology is designed to detect those changes—essentially tracking the immune responses of individual patients over time.

The idea of sequencing the DNA of immune cells is still in its infancy and pursued mostly by academics and a handful of companies, so Adaptive must establish demand for a whole new category of test. In the past seven years, working with his brother Chad, a Wharton MBA and experienced executive, Robins has raised more than $400 million from a cadre of A-list investors including Matrix Capital Management, biotechnology giant Celgene, and Illumina, the leading maker of gene-sequencing technology.

Understanding the immune system has become a priority in oncology research, particularly with the recent success of a class of drugs called checkpoint inhibitors, which block proteins in the body that would normally prevent the immune system from recognizing and fighting cancer. Two leading examples are Merck’s Keytruda and Bristol-Myers Squibb’s Opdivo, used to treat melanoma, lung cancer, and other tumor types. Many more checkpoint inhibitors are being developed, as are other immune approaches, such as removing T cells from patients and engineering them to attack their specific cancers (see 10 Breakthrough Technologies 2016: Immune Engineering).

Such immune-based treatments have improved the prognosis for some cancer patients, but others don’t respond to them at all—and scientists have not yet figured out why.

“Oncologists had been trying to figure out how to coöpt the immune system to help kill cancer for 40 years, and finally they’re finding success,” Robins says. For treatments like checkpoint inhibitors to be effective, he explains, there must first be an existing immune response in the tumor. Adaptive’s technology measures that response.

Illumina sees Adaptive’s approach as the next frontier in gene sequencing, says John Leite, vice president of marketing for Illumina’s oncology business, in addition to looking for genetic mutations in cancer cells that may help patients respond to particular therapies.

Adaptive has shown that its test can be much more sensitive to disease than other tools, such as the cell-counting technology called flow cytometry.

The insights gained from sequencing immune cells may include identifying which patients are most likely to respond to a particular immuno-oncology drug, pinpointing other drugs that might be effectively used in combination with that treatment, and suggesting what order the drugs should be taken in for best results, says Chad Robins. In January Adaptive formed a partnership with Pfizer aimed at identifying patients who are most likely to benefit from the immuno-oncology drugs the company is developing. And it is working with other large pharmaceutical companies as well.

Beyond cancer, the technology could be useful in treating other diseases with a strong immune component, including autoimmune disorders such as rheumatoid arthritis, the Robinses say. It could be helpful in controlling infectious diseases, too.

The brothers won’t reveal their pricing strategy for ClonoSEQ or future products, but they believe they’ll ultimately be able to prove that immuno-sequencing lowers costs by reducing the risk of disease recurrence and helping patients avoid expensive treatments that are unlikely to work for them.

To prove the value of its test to oncologists, Adaptive has worked with scientists at the University of California, Los Angeles, to study its use in patients with melanoma, myeloma, leukemia, and lymphoma. Last year the company opened a research center in San Diego that’s using its system to generate ideas for new drugs.

The ability to genetically profile immune cells is part of a larger push in oncology to scrutinize the cells and tissues that coexist with cancer and affect its ability to persist, says Jill O’Donnell-Tormey, chief executive officer and director of scientific affairs at the Cancer Research Institute in New York. Surviving cancer, she says, “is about what is happening not just in the tumor, but in the immune cells.”