Gina Kolata has a section front story in Tuesday’s New York Times exploring the potential of a relatively new class of anticancer drugs. The drugs break through “shields” built by cancers to ward off the threat posed by the patient’s immune system. Many are based on blocking PD-1, an immune regulatory molecule whose importance in chronic infections was first defined by Emory’s Rafi Ahmed.
Of course, not every cancer research developmentÂ describedÂ as transformative inÂ the New York TimesÂ lives up to the hype. But the clinical trial results, reportedÂ in the New England Journal of Medicine, are solid enough that the researchers Kolata talks with think they are seeing “a moment in medical history when everything changed.”Â [Winship Cancer Institute’s John Kauh was a co-author on one of the 2012 NEJM papers.]
Let’s take a moment to examine some of the roots of this story.Â Rafi Ahmed didnâ€™t set out to study cancer. For the last two decades, he and his colleagues have been studying T cells, parts of the immune system that are critical for responding to infections. Along the way, his lab made a series of discoveries concerning immune exhaustion, when the immune system is worn out after fighting a chronic infection or a tumor.
Ahmed says his teamâ€™s discoveries emerged from an effort to figure out what happened to T cells during a chronic infection that apparently disables and silences the immune system. Did T cells wither away and disappear from the body? Or did they stick around?
Much of the Ahmed laboratoryâ€™s work on chronic infection and immune memory has taken advantage of the LCMV (lymphocytic choriomeningitis virus) model. LCMV has been a useful tool for investigating the immune system â€“ for example, Doherty and Zinkernagel used LCMV for their Nobel Prize-winning work in the 1970s. Conveniently, two varieties of LCMV (Armstrong and Clone 13) can be used to generate either an acute infection that is rapidly cleared by the hostâ€™s immune system, or a chronic infection that persists indefinitely.
To say what happens to T cells specific for a virus, scientists have to be able to label them and follow them. Until the 1990s, doing so was actually rather difficult. The type of T cells Ahmed and his colleagues were studying is a group of specially honed weapons, analogous to â€œspy detectors.â€ Cytotoxic T cells are Cheap Oakleys some of the immune systemâ€™s best tools for fighting viral infections, because they kill cells that have been taken over by a virus. If a virus has infected a cell, the peptides — fragments of proteins being produced inside the cell — reveal the infection.
However, the interactions between the tools T cells use to recognize their targets (T cell receptors) and MHC molecules, which display the peptides outside the target cell, are weak and generally last for only a few seconds. The â€œtetramerâ€ technique developed in part by Emory Vaccine Center colleague John Altman â€“ basically, lash four MHC molecules together to strengthen the interaction — made it possible to isolate and study particular populations of T cells in detail.
Soon after the tetramer technique was developed, the Ahmed lab put it to work. In a 1998 Journal of Experimental Medicine paper, postdoctoral fellow Allan Zajac showed that some virus-specific cytotoxic T cells remained in the body after a chronic infection. They stayed alive, but they didnâ€™t deploy their lethal weapons.
Once Ahmed and his colleagues could see the inactive T cells, they could tease apart what differences in gene activity they had, compared with other T cells. Graduate student Daniel Barber took on this task. He found that in a chronic infection, the inactive virus-specific T cells had high levels of a molecule called PD-1, while fresh T cells did not. PD-1 seems to be a way that the immune system slows things down so that its damaging attacks donâ€™t go on indefinitely. Critically, Barber and Ahmed showed that blocking PD-1 could allow the T cells to regain their antiviral functions. They worked with Gordon Freeman and Arlene Sharpe at Harvard, who had developed antibodies against PD-1. The results were published in a 2006 Nature paper.
The Ahmed lab did not discover PD-1 itself. The PD-1 gene was first identified and named by Tasuku Honjo and colleagues in Kyoto in 1992. But Ahmed and his colleagues were the first to demonstrate PD-1â€™s importance for the regulation of the immune system. After the publication appeared, similar observations of PD-1â€™s role were made in other systems of chronic infection. PD-1 was turned on in the T cells of patients with HIV and hepatitis C infections, for example.
Ahmed already had hints that his discoveries would be relevant for cancer. After one of the first talks he gave describing his results on exhausted T cells, several oncologists reported they had observed tumor-infiltrating T cells: similarly present, but inactive. Scientists studying cancer then observed Cheap Oakleys Sunglasses that the molecule that triggers PD-1â€™s effects (PD-L1) appears on many tumors. They reasoned that it could be one way a tumor disables the bodyâ€™s immune responses against it. Knowing that the T cells were still there, only sleeping, made the possibility of reviving them seem achievable.
Ahmed says that the efficacy of PD-1 drugs could be further increased by combining with other drugs that unlock the immune system, such as similar drugs targeting the molecule CTLA-4. Several research teams around the world are now examining which tumors are most vulnerable to PD-1 based immunotherapy (possibly, those that make lots of PD-L1), and what are markers that predict the best responses.
2 Responses to Cancer’s shield: PD-1