Abstract IA17: PD-1 blockade therapy for cancer
Authors: Ribas Antoni 
Published: October 2015

Abstract
PD-1 and PD-L1 blockade therapy with therapeutic antibodies is providing unprecedented rates of durable tumor responses in a variety of cancers, including melanoma, lung, renal, bladder and ovarian cancers (1-5). A key question is defining in which settings blocking the PD-1/PD-L1 interaction will lead to tumor responses. PD-L1 expressed by cells in the tumor microenvironment engages PD-1 on T cells and triggers inhibitory signaling downstream of the TCR, blocking effector functions and reducing T-cell killing capacity. PD-L1 can be constitutively expressed on the surface of cancer cells through poorly characterized oncogenic signaling pathways, or more frequently alternatively, expressed in response to the presence of T cells producing immune-stimulating cytokines such as interferons (6, 7). The inducible process has been termed “adaptive immune resistance”, and represents a mechanism by which cancer cells attempt to protect themselves from immune-cell mediated cell killing. Based on this conceptual framework, we sought to determine whether pre-existing tumor-associated CD8+ T-cells with associated PD-1/PD-L1 engagement within tumors represented a key factor in determining clinical response to PD-1 blocking therapy.
Our emerging data suggests that responses to PD-1 blockade indeed happen when PD-1/PD-L1 is the limiting step preventing a pre-existing clonal CD8 infiltrate from attacking the melanoma. The same process could be limiting T cell responses to many other cancer histologies in a significant proportion of patients. Releasing the PD-1 block would lead to durable tumor responses in them the same way that it happens in melanoma. Therefore, it is likely that in the near future, instead of relying on the status of estrogen receptor or Her2/neu in breast cancer, EGFR in lung cancer or BRAF in melanoma, for example, to decide on the front line therapy, oncologists will want to know if a patient is predisposed to respond to anti-PD-1/L1 antibody therapy as the initial decision point to select oncologic therapy. Such a predictive assay will likely need to take into account PD-L1 expression as well as other variables that quantitate tumor antigen-specific T cell infiltration leading to a dominant role of PD-1/L1 negative signaling in the cancer of a particular patient (8).
References:
1. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. The New England journal of medicine. 2012;366:2455-65.
2. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. The New England journal of medicine. 2012;366:2443-54.
3. Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence DP, Atkins MB, Powderly JD, Leming PD, Lipson EJ, Puzanov I, Smith DC, Taube JM, Wigginton JM, Kollia GD, Gupta A, Pardoll DM, Sosman JA, Hodi FS. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32:1020-30.
4. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134-44.
5. Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, Chmielowski B, Mateus C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone R, Ebbinghaus SW, Kang SP, Daud A. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014.
6. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature reviews Cancer. 2012;12:252-64.
7. Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med. 2012;366:2517-9.
8. Ribas A, Tumeh PC. The future of cancer therapy: Selecting patients who respond to PD-1/L1 blockade. Clin Cancer Res. 2014.
Citation Format: Antoni Ribas. PD-1 blockade therapy for cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA17.