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J. Brahmer

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    MS09 - Immune Therapies for Lung Cancer (ID 26)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Medical Oncology
    • Presentations: 1
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      MS09.2 - Treatment Targeting PD1/PDL1 and Toxicity (ID 497)

      14:00 - 15:30  |  Author(s): J. Brahmer

      • Abstract
      • Presentation
      • Slides

      Tumors evade immune system attack through various different mechanisms. One such mechanism is through coopting inhibitory immune checkpoints.(1) These inhibitory checkpoints cause compromised T cell activation and effector function. The two immune checkpoints best known are CTLA-4 and PD-1.(2) CTLA-4 is the receptor that is expressed earlier on in T cell activation and whose ligands are B7.1 and B7.2. Tumor cells have not been known to express the CTLA-4 ligands which are only known to be expressed on antigen presenting cells (APC). CTLA-4 deficient mice die early on of massive lymphoproliferative disorders.(3) Alternatively, the PD-1 receptor is expressed later on in T cell activation in the periphery and binds to two ligands, PD-L1(B7-H1) and PD-L2 (B7-DC). Both ligands are known to be expressed in peripheral tissues on APCs as well as tumor cells. Both ligands are upregulated by type 1 and 2 interferons, particularly gamma interferon.(4) PD-1 deficient mice develop strain specific autoimmune diseases later on in life.(5) Antibodies developed to block the binding between co-inhibitory receptor and its ligands cause T cell activation. While CTLA-4 blockade via the antibody, ipilimumab, has yielded an improvement in survival in patients with melanoma, PD-1 blockade is earlier on its development.(6,7) Several antibodies are in various stages of development. Of the antibodies designed to bind to the PD-1 receptor, Nivolumab (BMS-936558) is furthest along in development. In the first in human, single dose study of nivolumab, no maximum tolerated dose was found.(8) The pharmacokinetics of the antibody revealed a 14 day half-life, but the antibody was found to occupy T cell receptors for up to 3 months after treatment leading to prolonged pharmacodynamic effects. The toxicities were relatively mild and consistent with the immune mechanism of action. Early signs of clinical activity were seen in patients with melanoma, colon cancer, non-small cell lung cancer (NSCLC), and renal cell cancer (RCC).(9) Two patients remain in a complete response even up to almost 5 years after their last treatment. One patient’s response was maintained up to 18 months after stopping treatment and when the cancer progressed, the patient was retreated with nivolumab resulting again in a response. More recently, a multidose phase I study of Nivolumab was performed.(10) Again, no maximum tolerated dose was found up to 10 mg/kg every two weeks. Toxicities again tended to be manageable and consistent with the immune mechanism of action. Because of initial signs of significant clinical activity, expansion cohorts in NSCCLC, RCC, and melanoma were enrolled. Exciting responses in NSCLC (17%) were seen. These responses were durable with a median duration of response of 17 months. Based on these results, two phase III trials have been initiated in the second line treatment setting comparing nivolumab to docetaxel in both squamous cell and non-squamous cell carcinomas. Another anti-PD-1 antibody, MK-3475, recently reported similar toxicities consistent with the immune mechanism of action as well as initial clinical activity in melanoma (47% response rate).(11) Further expansion cohorts were enrolled in NSCLC and information is forthcoming. Antibodies blocking the ligand, PD-L1, have also been developed. Theoretically there may be differences in activity and toxicities between the two groups of antibodies. By blocking the PD-L1, the interaction between PD-1 and PD-L2 remains intact. It remains to be seen if this is meaningful, clinically. The first in human study of once every two week dosing of BMS-936559 reported initial tumor activity in several tumor types including NSCLC (10%) as well as a tolerable safety profile.(12) Another PD-L1 antibody, MPDL3280A, initial phase I trial was reported at ASCO in 2013. Toxicities were mild, no MTD was reached, and initial clinical activity was seen in multiple tumor type including NSCLC (22%).(13) These trials demonstrate that the PD-1 pathway is important in tumor immune evasion, and by blocking this pathway, immune activation occurs which in turn can cause durable tumor control. References 1. Zou W: Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 5:263-74, 2005 2. Chen L: Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol 4:336-47, 2004 3. Waterhouse P, Penninger JM, Timms E, et al: Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270:985-8, 1995 4. Keir ME, Butte MJ, Freeman GJ, et al: PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677-704, 2008 5. Nishimura H, Nose M, Hiai H, et al: Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141-51, 1999 6. Hodi FS, O'Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711-23, 2010 7. Robert C, Thomas L, Bondarenko I, et al: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517-26, 2011 8. Brahmer JR, Drake CG, Wollner I, et al: Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 28:3167-75, 2010 9. Lipson EJ, Sharfman WH, Drake CG, et al: Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res 19:462-8, 2013 10. Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443-54, 2012 11. Iannone R, Gergick K, Cong C, et al: Efficacy and safety of MK-3475 in patients with advanced melanoma, 9th International Congress of the Society for Melanoma Research. Los Angeles. California, 2012 12. Brahmer JR, Tykodi SS, Chow LQ, et al: Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455-65, 2012 13. Herbst R, Gordon M, Fine J, et al: A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors, ASCO Annual Meeting 2013. Chicago, I.L., 2013

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