Tumors are scrupulous recorders of their own life stories. The wreckage they acquire as a result of therapy, the stratagems they use to survive and dodge an immune attack are all inscribed in their DNA and the set of immune system cells within them.
Unfortunately for science, the autobiography of a tumor rarely consists of a single volume, especially if the tumor is a battle-hardened survivor of multiple therapies. Tumors that have spent years growing, or been subjected to treatment, may spawn different versions of themselves as they metastasize, each new growth having its own genetic quirks and capacity for survival. The tale of a tumor can take on the dimensions of a family history.
Scientists collect tumor samples from patients before and after treatment to analyze the genetic changes that occur in response to therapy — particularly the changes that enable to tumor to grow in spite of therapy. Such studies have revealed much about cancer’s evasive maneuvers, but these samples are challenging to collect and only a few are taken from each patient.
A new study led by researchers at Dana-Farber, Massachusetts General Hospital, and Harvard Medical School, takes a much deeper dive. Based on an analysis of 37 tumor samples collected over nine years from a patient with melanoma, the paper presents the largest, most in-depth account of a tumor’s evolution across all phases of its existence — from initial diagnosis, through treatment, and, finally, resistance to treatment. The analysis included not only the genetic twists and turns the tumor underwent over time but also the changes that occurred in its immune microenvironment, the mix of immune system cells in its midst.
The findings of the study, published in Nature Medicine, show with striking clarity this particular tumor’s capacity for deviousness — for altering itself to avoid being a uniform target — as well as its initial vulnerability to immunotherapy and its eventual imperviousness to that therapy. The results speak both to the power of immunotherapy against certain cancers and to the restless capacity for change that enables many tumors to circumvent that therapy.
Lazarus-like response
The course of the patient’s disease was far from ordinary. Diagnosed with a melanoma growth on his back, he developed metastases in his lungs and abdomen and on different parts of his skin — including his forearm, his face, scalp, ears, and neck — three and a half years later. He then began treatment with nivolumab, an immune checkpoint inhibitor that unleashes the immune system to attack cancer. Surgeons removed the original growth and the subsequent metastases; specimens were archived and later retrieved for analysis.
Treatment with nivolumab, and later with the checkpoint inhibitor ipilimumab and a brief course of radiation therapy, initially seemed to accelerate the disease rather than impede it. Over a four-and-a-half-month period, the patient would go on to develop numerous new skin metastases, on his scalp, arm, neck, face, wrist, finger, and groin. Because many of them were painful or disfiguring, they were removed and, as before, archived and retrieved for study.
“It looked like the disease was progressing, progressing, progressing. Each of the lesions continued to grow,” said the study’s first author, David Liu, MD, MPH, of Dana-Farber. “There seemed to be no response to therapy.”
Liu refers to what followed as a “Lazarus-like effect” after radiation therapy and ipilimumab: “All his lesions began disappearing. In a very brief time he had a clinical complete response,” a disappearance of all signs of cancer.
The patient continued to do well after stopping therapy. He did develop two small metastases — one in the small intestine and one in the brain — that were surgically removed. He was fine for the next year until several small metastases popped up and the cancer returned with a vengeance. When the patient died, more than five and a half years after his initial treatment with immunotherapy, he had metastatic growths in various parts of his body, including his skin, lungs, and brain. These, too, were collected and analyzed.
“Ninety percent of patients who have a great response after two years of treatment with a checkpoint inhibitor, as this patient did, have no progression of their disease two years later,” Liu remarks. “This patient was about three years out from stopping treatment when sustained resistance to therapy emerged.”
Analysis of the 37 tumor samples collected over the patient’s nine-year odyssey revealed several intriguing features. Researchers found that the original “parent” tumor begot seven separate lineages — genomically distinct knock-offs of the parent. Much like a beam of light diffracts into different colors in passing through a prism, the tumor took on slightly altered identities as it spread through the patient’s body.
“We saw a great deal of heterogeneity — different subclones of the tumor that became different metastatic lesions,” Liu observes.
A second major finding was that immunotherapy produced a “huge pruning” of these subclones, Liu remarks – wiping out all of them but one. The 13 metastatic growths that sprang up after the patient experienced a clinical complete response were all the offspring of that single subclone. “That escaping subclone seeded all the subsequent disease the patient experienced,” Liu remarks.
Because the study involved just one patient, its findings can’t be extrapolated to all other patients who become resistant to checkpoint inhibitor therapy. Still, the findings raise some provocative possibilities.
“The good news is that immunotherapy eliminated multiple lineages of the tumor,” Liu comments. “It didn’t target just a handful of lineages; it targeted all of them but one. This suggests that there may be a limited set of mechanisms by which melanoma can evade the effects of immunotherapy. Targeting those specific mechanisms might be a way to close off the cancer’s escape routes.”
When melanoma has metastasized, surgery to remove the individual metastases has not been thought to be very helpful. In the current study, though, after surgeons removed the brain metastasis that arose a few years after treatment, that tumor’s lineage did not arise again, suggesting that in certain situations, single-metastasis surgery may have a long-term benefit.