To the best of my knowledge, these are the first data to be published on the use of the anti-PD1 approach in humans. The goal is to revive exhausted and dysfunctional T cell responses, in this case against cancer. This was a Phase I, single dose (in most cases) study involving people with a variety of very advanced cancers, and I'm not knowledgeable enough about these conditions to be able to evaluate the authors claims regarding clinical benefit. It will also require much more work to establish the safety and tolerability of the approach in other settings. Anti-PD1 antibodies are being studied in animal models as potential immunotherapies for both HIV and HCV.
Clinical Cancer Research 14, 3044-3051, May 15, 2008.
doi: 10.1158/1078-0432.CCR-07-4079
Raanan Berger1, Rinat Rotem-Yehudar3, Gideon Slama3, Shimon Landes3, Abraham Kneller2, Merav Leiba2, Maya Koren-Michowitz2, Avichai Shimoni2 and Arnon Nagler2
Authors' Affiliation: 1 Institute of Oncology and Radiotherapy and 2 Hematology Division, Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer, Israel; and 3 Curetech Ltd., Yavne, Israel
Requests for reprints: Arnon Nagler, Hematology Division, Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer, Israel.
Purpose: CT-011 is a humanized IgG1 monoclonal antibody that modulates the immune response through interaction with PD-1, a protein belonging to the B7 receptor family present on lymphocytes. The objectives of this phase I study were to assess the dose-limiting toxicities, to determine the maximum tolerated dose, and to study the pharmacokinetics of CT-011 administered once to patients with advanced hematologic malignancies.
Experimental Design: Seventeen patients were treated with escalating doses of CT-011 ranging from 0.2 to 6 mg/kg. For pharmacokinetic analysis, blood samples were withdrawn from the patients before and immediately after treatment and at 24 hours, 48 hours, and on days 7, 14, and 21. CT-011 blood levels were assessed with a specific ELISA and derived concentrations were used to calculate pharmacokinetic parameters. Activation of the immune system was assessed by measuring peripheral blood CD4+, CD8+, and CD69+ lymphocytes.
Results: The study showed the antibody to be safe and well tolerated in this patient population. No single maximum tolerated dose was defined in this study. Clinical benefit was observed in 33% of the patients with one complete remission. Pharmacokinetic analyses show that serum Cmax and the AUC of CT-011 increased proportionally with dose. The median t1/2 of CT-011 ranged from 217 to 410 hours. Sustained elevation in the percentage of peripheral blood CD4+ lymphocytes was observed up to 21 days following CT-011 treatment.
Conclusions: A single administration of 0.2 to 6.0 mg/kg of CT-011 is safe and well tolerated in patients with advanced hematologic malignancies.
That's interesting .... I have been considering PD-1 to be a marker of CD8 exhaustion, as described by Ahmed's group last year (Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, Kalia V, Subramaniam S, Blattman JN, Barber DL, Ahmed R (2007) Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27:670–684.) If that was the case, then blocking PD-1 wouldn't do much, because there are still presumably other defects in the exhausted cell ("functional exhaustion is probably due to both active suppression and passive defects in signaling and metabolism").
But I see that there's evidence for a dominant, active suppression role for PD-1; for example, the latest J Immunol has this paper from Cao's group:
Mohamed Elrefaei, Chris A. R. Baker, Norman G. Jones, David R. Bangsberg and Huyen Cao. Presence of Suppressor HIV-Specific CD8+ T Cells Is Associated with Increased PD-1 Expression on Effector CD8+ T Cells. The Journal of Immunology, 2008, 180: 7757-7763
that links active suppression to PD-1.
Posted by: iayork | May 20, 2008 at 09:31 AM