In January 2006, Daniel Barber and colleagues from Rafi Ahmed’s laboratory at Emory University published a seminal paper in the journal Nature describing the role of a protein called PD-1 in inhibiting virus-specific T cell responses. The study used a mouse model of chronic infection with the virus LCMV and showed that expression of PD-1 by LCMV-specific CD8 T cells was associated with a form of dysfunction called T cell exhaustion. Importantly, Barber discovered that targeting PD-1 with an anti-PD-1 antibody (described as PD-1 blockade) enhanced LCMV-specific CD8 T cell function and lowered LCMV viral load, leading to the suggestion that this approach might have potential as a therapy for chronic viral infections such as HIV and hepatitis C. However, the researchers also noted that PD-1 appears to play a role in inhibiting autoimmune T cell responses, raising concerns about the possible side effects of anti-PD-1 therapies. There was universal agreement that testing the approach in the SIV model would be a critical first step, and results from these studies have been eagerly anticipated.
Today, the results of the first SIV experiment have been published online, once again in the journal Nature. The study was led by Vijayakumar Velu from Emory. The results are strikingly reminiscent of the original findings in mice. A total of nine SIV-infected macaques (five infected for 10 weeks and four with advanced disease due to longer term infection for ~90 weeks) received four doses of an antibody targeting human PD-1 over a 10-day period. Five animals (three with early infection, two with advanced infection) received an irrelevant anti-RSV antibody and served as controls. In the treated group, average SIV viral load declined significantly overall (p=0.03) but individual responses were variable; some animals experienced transient increases in viremia followed by declines and two of the macaques with early infection showed a transient increase that subsequently returned to the pre-treatment baseline. Viral load reductions were not sustained beyond a few months in the majority of the animals, which is perhaps not surprising given the short course of blockade administration. All the treated macaques have survived (with follow up currently at seven months) while 4/5 animals in the control group had to be euthanized due to AIDS-related symptoms, a statistically significant difference. The salutary outcome in anti-PD-1 recipients was associated with increases in the magnitude and functionality of SIV-specific CD8 T cell responses, and the researchers also found that B cell and antibody responses were enhanced, a result not predicted by the mouse studies. Of note, granzyme B and perforin expression by SIV-specific CD8 T cells increased significantly (a very recent study of human elite controllers identified production of these proteins by CD8 T cells as a key correlate of viral load control). In terms of safety, no obvious untoward effects of PD-1 blockade were documented, although one macaque showed a transient 3-fold increase in anti-nuclear antibodies that returned to baseline by day 56.
While preliminary, the findings of Velu and colleagues are undoubtedly provocative and exciting. Anyone who has followed research on immune-based therapies over the years is painfully aware of how many supposedly promising basic research results have abjectly failed to pan out in vivo; in this context, the fact that PD-1 blockade performed even close to expectations in the SIV model (under the conditions of persisting viremia and advanced disease) is an extremely welcome surprise. The authors note that improved results may be achievable by combining the approach with transient antiretroviral therapy and/or therapeutic vaccination. Future studies will also explore the impact of different administration schedules. Additionally, the recent identification of other targets associated with T cell exhaustion, such as Tim-3, may open the door for combination blockade approaches. In terms of other chronic viral diseases, a collaboration between Rafi Ahmed's research group and Chris Miller at the University of California is investigating the therapeutic impact of PD-1 blockade in the chimpanzee model of hepatitis C infection.
More work will be needed before PD-1 blockade can be studied as a treatment for viral infections in human trials. So far there has only been one small phase I study in individuals with advanced cancers (a phase Ib follow-up has also recently been initiated). According to a Nature news story, Rama Rao Amara (Emory researcher and senior author on the paper) is in discussions with a company that produces an anti-PD-1 antibody regarding studies in HIV infection, with the hope of launching a phase I trial sometime next year.
Nature | doi:10.1038/nature07662
Received 14 October 2008; Accepted 21 November 2008; Published online 10 December 2008
Letters to Nature
Vijayakumar Velu1,2,6, Kehmia Titanji1,2,6, Baogong Zhu3,4, Sajid Husain1,2, Annette Pladevega1,2, Lilin Lai1,2, Thomas H. Vanderford5, Lakshmi Chennareddi1,2, Guido Silvestri5, Gordon J. Freeman3,4, Rafi Ahmed1 & Rama Rao Amara1,2
1. Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA
2. Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30329, USA
3. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
4. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
5. University of Pennsylvania School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
6. These authors contributed equally to this work.
Chronic immunodeficiency virus infections are characterized by dysfunctional cellular and humoral antiviral immune responses1, 2, 3. As such, immune modulatory therapies that enhance and/or restore the function of virus-specific immunity may protect from disease progression. Here we investigate the safety and immune restoration potential of blockade of the co-inhibitory receptor programmed death 1 (PD-1)4, 5 during chronic simian immunodeficiency virus (SIV) infection in macaques. We demonstrate that PD-1 blockade using an antibody to PD-1 is well tolerated and results in rapid expansion of virus-specific CD8 T cells with improved functional quality. This enhanced T-cell immunity was seen in the blood and also in the gut, a major reservoir of SIV infection. PD-1 blockade also resulted in proliferation of memory B cells and increases in SIV envelope-specific antibody. These improved immune responses were associated with significant reductions in plasma viral load and also prolonged the survival of SIV-infected macaques. Blockade was effective during the early (week 10) as well as late (week 90) phases of chronic infection even under conditions of severe lymphopenia. These results demonstrate enhancement of both cellular and humoral immune responses during a pathogenic immunodeficiency virus infection by blocking a single inhibitory pathway and identify a novel therapeutic approach for control of human immunodeficiency virus infections.