In 1971, while Don Thomas was performing his first allogeneic transplants in Seattle, an eighteen-year-old high-school senior from the Bay Area named Carl June received news of his draft lottery. He had drawn the number fifty; deployment was virtually certain. So he turned down admission offers from Caltech and Stanford, and, as he likes to say, chose “the Naval Academy over the paddy fields of Vietnam.” June, who is rail-thin and lanky, with the physique of a long jumper, recalls his years at the academy with the ruefulness of an athlete forced to wait on the sidelines. After the Navy paid his way through medical school, at Baylor College, in Houston, he arrived at the Hutchinson Center, where he spent three years in the early nineteen-eighties as an oncology fellow, studying marrow transplants in Thomas’s research program. He was joining a high-powered group that included a tall, German-born rowing fanatic named Rainer Storb, who focussed on tissue typing and transplant therapy; a diminutive, Siberian-born soccer enthusiast named Alex Fefer, who had shown that immune systems could turn against tumors in mice; and Thomas’s wife, Dottie, who ran the day-to-day affairs of the lab and the clinic, and whom everyone called “the mother of bone-marrow transplantation.”
June became fascinated by early experiments in transferring T cells, but then spent a decade at the Naval Medical Research Institute, in Bethesda, studying infectious diseases, such as malaria and, later, H.I.V. Finally, in 1999, he moved his lab to the University of Pennsylvania. His personal life, meanwhile, was crosshatched with tragedy: in 1995, his wife, Cindy, was diagnosed with ovarian cancer, and she died six years later. Throughout these years—and especially after Cindy’s diagnosis—June kept imagining a new paradigm for cancer treatment, in which living immune cells, rather than drugs, would be mobilized against the disease.
Mature T cells normally come armed with proteins on their surface—called T-cell receptors—which allow them to recognize matching bits of foreign proteins that might be present on the surface of their target cells, such as human cells infected by a virus. These receptors are notably selective: they trigger only when a cell has mounted a protein fragment on its surface and “presented” it to the T cell in the context of certain other proteins—as if they can see a picture only when the frame is right.
Unlike antibodies—Y-shaped proteins that bind like Velcro to a wide range of targets, including free-floating viruses and proteins—T-cell receptors bind to their targets somewhat loosely. The T cell can thus inspect the surface of a cell, alert others, and move on, like a drug-sniffing dog at a security checkpoint, going from one suitcase to another, summoning help where necessary.
For decades, immunologists had reasoned that the T-cell surveillance system might be able to detect and kill cancer cells. But, unlike infected cells, cancerous ones tend to be so genetically similar to normal cells, with such a similar repertoire of proteins, that they’re hard for even T cells to pick out of a crowd. A cancer-specific T-cell response could arise only if a gene were mutated or incorrectly regulated in cancer, and if the protein encoded by that gene were fragmented in the right way, and if the fragments were channelled into the cell’s system for T-cell detection, and if there were a waiting T cell equipped to sense it as foreign: a graveyard of ifs.
June knew that two researchers at the Hutch—Stanley Riddell, an animated figure with blocky glasses and a mechanical pencil habitually clipped to his shirt pocket, and Philip Greenberg, a man with a dense shag of hair that he had kept since the sixties—had begun to identify T cells that could recognize cytomegalovirus (a major threat to immunocompromised patients), grow those cells in flasks, and transfuse the increased population of the cells into bone-marrow recipients. In Houston, Malcolm Brenner, Cliona Rooney, and Helen Heslop had done something similar with T cells that targeted tumor cells infected by another pathogen, Epstein-Barr virus. And at the National Cancer Institute, in Bethesda, a surgical oncologist named Steven Rosenberg tried yet another strategy: he drew native T cells out of malignant tumors, such as melanomas, positing that immune cells that had infiltrated a tumor must have the capacity to recognize and attack the tumor. Rosenberg’s team grew these tumor-infiltrating lymphocytes, expanding their numbers by a few orders of magnitude, and transferred them back into patients.