I. Speculative science
Lloyd Old of Memorial Sloan Kettering (MSK), one of the founding figures of cancer immunology, once submitted a grant. The reviewer, an eminent scientist, dismissed more than the proposal and labeled the entire field speculative science.
Jedd Wolchok, now Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, told me this story when he joined me on Precision Signals. He was a fellow at MSK in the late 1990s, a period he describes as the epitome of nihilism around cancer immunology. People spoke about the field the way they spoke about mysticism. “You either believed in it or you didn’t,” he said.
What struck me is that Jedd never described his career as an act of belief. He described it as an inability to let go of what he had seen.
Early in his training, he worked in the laboratory of Alan Houghton, a physician-scientist in Old’s group who was testing antibodies as cancer therapeutics. There he watched patients with metastatic melanoma receive R24, a mouse antibody against the GD3 ganglioside, a molecule abundant on the surface of melanoma cells. It was one of the first clinical trials of a monoclonal antibody in a solid tumor. Patients soon developed antibodies against the mouse protein, and the window of activity closed quickly. But in the first published report, three of 12 patients had major tumor regressions. An immune product, not a cytotoxic drug, had made cancer shrink.
Years later, as a fellow, he immunized mice against tyrosinase and related proteins shared by melanoma and the normal pigment cells it arises from. The vaccinated mice resisted an intravenous melanoma challenge. The immune system could be taught to recognize a cancer as foreign, even when its targets were the body’s own proteins. He resists calling these moments anecdotes. They were, in his words, singular observations, and for him they were enough.
II. Bigger before smaller
Those observations carried him into the early clinical studies of CTLA-4 blockade. CTLA-4 is an inhibitory receptor on T cells, one of the molecular brakes that keep immune responses in check. Ipilimumab, an antibody that blocks it, was designed to release that brake. The patients who enrolled had advanced melanoma, a median survival of about six and a half months, and often one, two, or three failed therapies behind them. Ipilimumab produced striking responses in 10% to 15% of them, and those responses tended to last.
The pattern of response, however, looked nothing like chemotherapy. With chemotherapy, a response usually appears early or not at all. With ipilimumab, some patients’ tumors grew dramatically for weeks, sometimes a couple of months, before shrinking rapidly. Under the WHO and RECIST criteria, the “gold standard” for tumor response assessments, a growing tumor meant the drug had failed and the patient should come off study.
Jedd and his fellow investigators began to notice a discordance. Some patients whose scans looked terrible were feeling better. They brought these observations to Bristol Myers Squibb, the company developing ipilimumab, and colleagues there agreed to let them keep such patients on study as long as no better therapy was available. “And of course, there were no better therapies for those people to receive,” Jedd said. The investigators continued to follow these patients, and about a quarter of those with overt radiographic progression eventually responded or stabilized with no additional therapy.
The scans were not wrong. The rules for reading them were. In 2009, Jedd and his colleagues published the immune-related response criteria, which measured total tumor burden and allowed for growth before shrinkage. Under the new criteria, a single new lesion no longer erased the disappearance of many others.
When ipilimumab was approved in 2011, the evidence that carried it was overall survival, because response rates and progression-free survival had proven unreliable measures of what the drug was doing. PD-1 blockade followed. Because CTLA-4 and PD-1 restrain T cells through non-redundant mechanisms, Jedd went on to lead the clinical development of their combination, which made immunotherapy a standard of care in melanoma.
III. The problem was always there
I came to the same problem from the regulatory side. In 2016, at FDA, we compared two readings of the same scans across registrational trials: the investigators’ assessments and those of blinded independent radiologists. Across 13,677 paired assessments, they disagreed about 30% of the time. In tumors that are hard to measure, such as pancreatic and ovarian cancers, the disagreement exceeded 40%.
Some of that disagreement is built into the criteria. RECIST reduces a tumor to the summed diameters of a few selected lesions. The sum must shrink 30% to count as a response, and it must grow 20% from its smallest value to count as progression. Everything in between is called stable disease, whether or not anything about it is stable.
Immunotherapy did not create this measurement problem. It exposed it. As Jedd put it, an imaging study holds far more information than a binary of bigger or smaller, including the shape and density of each lesion, the features radiomics tries to capture. Cell-free DNA shed by tumors into the blood may offer an earlier read while the images lag. Both point toward measuring the disease as it changes over time, rather than as a single size at a single moment.
IV. How much
Fifteen years after the first checkpoint inhibitor approval, there is still no gold-standard biomarker to predict who will benefit. Tumor mutational burden comes closest in principle. The more mutations a tumor carries, the more neoantigens it may display, the mutated protein fragments that make it look foreign to T cells. Jedd calls it a good but not great biomarker. What the field needs, he argues, is a precise measure of the fitness of individual neoantigens: how well each is presented on the tumor surface, how widely it is shared across tumor cells, and how likely T cells are to recognize it. He sees this as a natural use case for AI.
Better prediction leads to the question he keeps returning to. It is no longer whether immunotherapy works, but “when and how much immunotherapy an individual patient needs.” The neoadjuvant trials have already supplied part of the answer. The older sequence was surgery first, then immunotherapy to eliminate residual disease. It has been outperformed by treating while gross disease is still present, resecting what remains, and letting the pathologic response guide whether more therapy is needed.
Near the end of our conversation, I offered a version of the principle in surgical terms: the more we know, the less we cut.
“That’s right,” he said.
V. On us
Answering these questions depends on who participates in the trials that ask them. At Weill Cornell, Jedd is opening trials at sites in Brooklyn and Queens and choosing studies whose eligibility criteria reflect the communities those sites serve. “People are interested in clinical research,” he told me. “We just have to make it much more convenient for them.” Then he added, “That’s really on us.”
Cancer immunology has rarely looked like progress at first. It looked like mysticism, and then it looked like a failed scan. The work now is to measure well enough that we recognize progress when it arrives, and to make sure more patients are in the trials where it does.