Immunotherapy Approaches in Lymphoma John Kuruvilla MD FRCPC 1
Disclosures for John Kuruvilla MD Research Support Employee Leukemia and Lymphoma Society US, Rasch Foundation Roche, N/A Consultant Abbvie, BMS, Gilead, Janssen, Roche Major Stockholder N/A Speakers Bureau Honoraria Scientific Advisory Board N/A Abbvie Amgen, BMS, Celgene, Gilead, Roche, Janssen, Lundbeck, Merck Seattle Genetics, Lymphoma Canada (Chair) I will likely discuss all sorts of off-label use of agents as well as investigational agents 2
The old era of immunotherapy A few examples in lymphoma of immunotherapy Allogeneic stem cell transplantation Interferon-a Anti-idiotype vaccination 3
Objectives Immunotherapy Approaches in Lymphoma Assess the new era of immunotherapies Review checkpoint inhibitors and adoptive immunotherapies Recognize how immunotherapies should be used in lymphoma therapy. Create some controversy 4
First example of GVLY Johns Hopkins Comparison of ASCT and ALLO ALLO ASCT N=118 ASCT 80 (purged) ALLO 38 Pre-SCT status predicts outcome No OS difference Reduced REL suggestive of antitumour effect Jones Blood 1991 5
DLI and wist in NHL From Porter et al BBMT 2010 6
IFN- 2 in FL Meta-Analysis Shows Benefit Meta-analysis performed of 10 randomized trials in newly diagnosed FL (1922 patients) trial heterogeneity re: Timing and dose of IFN Type of chemotherapy given (anthracycline or not) Survival advantage demonstrated when: In conjunction with relatively intensive chemo Dose 5 million units Cumulative dose 36 million units per month IFN given with chemotherapy as opposed to as maintenance Rohatiner et al. JCO Vol. 23 No. 10, 2005 7
OS Advantage with maintenance IFN Rohatiner et al. JCO Vol. 23 No. 10, 2005 8
PFS Advantage with Immune Response (not vaccine) in FL Immune response assessed by development of humoral anti-id antibody Levy JCO 2014 9
Mayo Clinic Lymphocyte recovery post ASCT NHL OS post ASCT HL OS post ASCT Multiple studies, but effectors or specific subsets not identified Porrata Blood 2002; Porrata BJH 2002 10
Summary of the old era Therapies are non-specific Allogeneic transplant may be the ultimate adoptive immunotherapy But it comes with a potential price Other therapies (IFN, vaccines etc.) have more modest benefit Immune responsiveness may be an important concept Disease specific (FL different than DLBCL which is different than HL) 11
Immunotherapy a problem of definition Think of all of the therapy you give as standard of care chemotherapy How much of it may be immune active? Rituximab Brentuximab Lenalidomide Autologous transplantation 12
So in the new era Checkpoint inhibitors A host of other antibody approaches Cell-based therapies Combination strategies Signaling pathway inhibitors (PI3K, BTK as examples) What s ready for prime time? 13
Role of the Immune Checkpoint We need the immune system to fight pathogens and help eliminate abnormal cells We also need to have controls on this system Maintain tolerance and prevent injury to self tissue The immune checkpoint is the series of inhibitory signals for this system While designed for self control, these signals can be exploited by cancer cells Cancer Cell T cell Pardoll, 2012, Nat Rev Can, 5, 252 265 14
Immune Checkpoint Blockade Cancer Cell T cell Pardoll, 2012, Nat Rev Can, 5, 252 265 15
Relevance of the Immune Checkpoint in Classical HL Pathology of chl: rare malignant Reed Sternberg cells within an extensive inflammatory/immune cell infiltrate. Genetic analyses: frequent 9p24.1 amplification with upregulation of PD 1 ligands and JAK2. Hypothesis: chl may have a genetically driven dependence on PD 1. Juszczynski et al PNAS 2007; 104: 13134 Green et al Blood 2010; 116: 3268; Chen et al. Clin Cancer Res 2013; 19:3462 16
Ready for prime time 17
Nivolumab in Patients (Pts) With Relapsed or Refractory Classical Hodgkin Lymphoma (R/R chl): Clinical Outcomes From Extended Follow up of a Phase 1 Study (CA209 039) Stephen M. Ansell, MD, PhD, 1 Philippe Armand, MD, PhD, 2 John Timmerman, MD, 3 Margaret A. Shipp, MD, 2 M. Brigid Bradley Garelick, MD, 4 Lili Zhu, MS, 5 Alexander M. Lesokhin, MD 6 1 Mayo Clinic, Rochester, MN, USA; 2 Dana Farber Cancer Institute, Boston, MA, USA; 3 Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA; 4 Bristol Myers Squibb, Wallingford, CT, USA; 5 Bristol Myers Squibb, Princeton, NJ, USA; 6 Memorial Sloan Kettering Cancer Center, New York, NY, USA Presented at ASH 2015 18
19
Compare and Contrast 2 different Phase II trials (at your peril) Nivo Pembro Schedule Q2Weekly Q2Weekly Toxicity 22% Grade 3 AE No Grade 4 10% Grade 3 AE No Grade 4 ORR 87% 66% Time to Response 12W 12W PFS / DOR Median NR Median NR Difficult to assess any differences at this point Nivolumab further ahead in development at this time (and has a published manuscript) 20
Nivolumab in Relapsed or Refractory Lymphoid Malignancies and Classical Hodgkin Lymphoma: Updated Results of a Phase 1 Study Philippe Armand 1, John Timmerman 2, Alexander M. Lesokhin 3, Ahmad Halwani 4, Michael M. Millenson 5, Stephen J. Schuster 6, Martin Gutierrez 7, Emma C. Scott 8, Deepika Cattry 3, Gordon J. Freeman 1, Bjoern Chapuy 1, Azra H. Ligon 9, Scott J. Rodig 9, Lili Zhu 10, Joseph F. Grosso 10, Jason Simon 10, Margaret A. Shipp 1, Adam D. Cohen 6, Daniel Lebovic 11,Madhav Dhodapkar 12, David Avigan 13, Stephen M. Ansell 14, Ivan Borrello 15 1 Dana Farber Cancer Institute, Boston, MA; 2 Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA; 3 Memorial Sloan Kettering Cancer Center, New York, NY; 4 University of Utah Huntsman Cancer Institute, Salt Lake City, UT; 5 Fox Chase Cancer Center, Philadelphia, PA; 6 Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; 7 John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; 8 Oregon Health and Science University, Portland, Oregon; 9 Brigham and Women s Hospital, Boston, MA; 10 Bristol Myers Squibb, Princeton, NJ; 11 University of Michigan Hematology, Ann Arbor, MI; 12 Yale Cancer Center, New Haven, CT; 13 Beth Israel Deaconess Medical Center, Boston, MA; 14 Mayo Clinic, Rochester, MN; 15 Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD EHA 20 TH CONGRESS JUNE 2015 VIENNA, AUSTRIA 21
22
Summary of anti-pd1 Ab Activity in Lymphoma Agent Histology N ORR (%) Nivo HL 23 87 Pembro HL 31 66 Nivo TCL 23 17 Nivo FL 10 40 Nivo DLBCL 11 36 Nivo PMBL 2 0 (2SD) Pembro PMBL 10 40 Ansell ASH 2015, Armand ASH 2015, Armand EHA 2015, Zinzani ASH 2015 23
Immunotherapy in Lymphoma - Summary Long history of usage of immune-based therapy in lymphoma Frequently employed non-specifically Checkpoint inhibition is a specific targeted strategy that appears safe with promising activity Development in NHL is less clear Biologic insights are needed HL is an excellent paradigm 24
Immunotherapy in Lymphoma Conclusions PD1 inhibition is a new paradigm in the treatment of REL/REF HL Appears to be new standard post brentuximab failure PD1 inhibition requires further development in NHL Biology and biomarkers needed Multiple new immunotherapies in development 25