Conflict of Interest I have no professional/financial disclosures to - PDF document

9/21/2016 Conflict of Interest • I have no professional/financial disclosures to report A New Plan of Attack: Immunotherapy in Hematologic Malignancies Katie Culos, PharmD BCOP Adult Stem Cell Transplant Clinical Pharmacist Vanderbilt University Medical Center Immunogenicity of Cancer Objectives 1) Discuss the principles of immunotherapy use in hematologic Antigenic Tumors: Displayed: Tumor evasion: malignancies • Secrete antigens • Induction of immune • Spontaneous regression 2) Review the data supporting the current FDA ‐ approved agents recognized by host ‐ of primary lesions tolerance immune system • Resistance to • Histological evidence T ‐ to treat hematologic malignancies eliciting an immune cell infiltration in early immune effector response melanoma cells 3) Describe chimeric antigen receptor (CAR) T ‐ cell therapy • Increased incidence in immunosuppressed approaches under clinical development patients 4) Explain the common toxicities and management strategies of immunotherapy in hematologic malignancies Immunotherapy has eradicated hematologic malignancies with allogeneic hematopoietic cell • transplant (allo HCT) Use of alloreactive T ‐ cells to control recipient malignancy • Also target non malignant cells and cause graft versus host disease (GVHD) • Limitations to extending allo HCT to wider ranges of hematologic conditions • Guerry D et al. J Invest Dermatol. 1993 Mar;100(3):342S ‐ 345S. Welniak LA et al. Annu Rev Immunol. 2007;25:139 ‐ 170. Monoclonal Antibody (mAb) Therapy • Antibodies designed to bind with specific target tumor antigens ▫ Easy to produce as secreted proteins in mammalian cell culture ▫ Off ‐ the ‐ shelf reagents with high protein stability ▫ Used to treat a wide range of patients with hematologic cancers ▫ Offer a less toxic immune ‐ mediated treatment approach • Rituximab was the first U.S. Food and Drug Administration (FDA) approved mAb in 1997 ▫ Approval based on Phase II study (Maloney et al.)  37 relapsed low ‐ grade or Follicular Non Hodgkin Lymphoma (NHL) patients  Intent to treat response rate of 46%  17 responses (3 CR, 14 PR) Weiner LM et al. Nat Rev Immunol 2010;10:317 ‐ 327 CR: complete response, PR: partial response Maloney DG et al. Blood 1997;90:2188 ‐ 2195 1

9/21/2016 mAbs • 28% of Phase III cancer research pipeline • None shown to cure cancer as single agent due to limitations in their mechanisms of action including: ▫ Redundancy of molecular pathways leading to cancer cell survival ▫ Effects of the microenvironment ▫ Suboptimal interaction with effector cells due to alternative Fc glycosylation or Fc receptor polymorphism ▫ Activation of inhibitory receptors, and competition with circulating IgG http://www.antibodysociety.org Chames et el. Mabs. 2009 Nov ‐ Dec;1(6): 539 ‐ 547 BiTE Bispecific T ‐ Cell Engagers (BiTE) • Following activation, apoptosis occurs via perforin ‐ mediated membrane disruption of the cancer by the T cells • The BiTE antibody transiently • Granules containing granzymes and the pore ‐ forming protein, perforin, fuse with the T ‐ cell membrane and discharge their toxic content leading to the creates a cyto ‐ lytic synapse between death of the target cell a cytotoxic T ‐ cell and the cancer target cell • Can differ in size and specificity of antigens recognized • Most researcher use the CD3 complex on host T ‐ cells ▫ Expressed on all lymphocytes ▫ Engagement activates T ‐ cells https://upload.wikimedia.org/wikipedia/commons/4/40/BiTE_antibody_en.svg http://mutated ‐ unmuated.blogspot.com/2011_06_01_archive.html Dreier et al. Int J Cancer. 2002 Aug 20;100(6):690 ‐ 7. BiTE Blinatumomab (Blincyto™) • Sustained activation, proliferation, and cytotoxicity of T cells • BiTE antibody which links CD3 on T ‐ cells to CD19 on B ‐ cells as long as target cells are available resulting in a cyto ‐ lytic synapse and CD19 B ‐ cell death • Lack of cross resistance to commonly used forms of • CD19 is a B cell ‐ restricted cell surface antigen expressed on chemotherapy = effective in treatment refractory patients normal and malignant B cells with aggressive forms of leukemia and lymphomas ▫ Exception of hematopoietic stem cells (HSC) and terminally • Target cell ‐ dependent and mediated by polyclonal differentiated plasma cells lymphocytes • Granted Accelerated FDA Approval December 2014 ▫ Do not drive off ‐ target immune response to self • Indication: Treatment of patients with relapsed or refractory, ▫ T ‐ cell ‐ mediated autoimmune disorders have not been Philadelphia chromosome negative, precursor B ‐ cell acute observed lymphoblastic leukemia (ALL) Dreier et al. Int J Can 2002;100:690 ‐ 697 BLINCYTO [package insert]. Thousand Oaks, CA; Amgen, Inc. December, 2014. Handgretinger et al. Leukemia 2011;25:181 ‐ 184 2

9/21/2016 Blinatumomab Phase 2 Dose ‐ Finding Trial Inclusion Criteria Exclusion Criteria >5% bone marrow blasts Ph+ ALL eligible for dasatinib or imatinib Primary refractory disease or History or presence of CNS pathology relapse after induction and Active CNS leukemia consolidation chemo or after allo HCT GVHD or immunosuppression for GVHD within 1 week of start of therapy ECOG performance status ≤ 2 Active infections Life expectancy ≥ 12 weeks Immunotherapy within 4 weeks or chemo within 2 weeks of start Neutralizing human anti ‐ murine antibodies • Open ‐ label, multicenter, exploratory, single ‐ arm, phase II study that enrolled 36 patients from German centers • Step ‐ up dosing from 5 ‐ 30 mcg/m2 per day Topp MS, et al. J Clin Oncol. 2014;32(36): 4134 ‐ 4140. Results Results Cont. Response to Treatment • RFS (N=25) 7.6 months Response No. (N=36) % • Median OS 9.8 months CR/CRh 15/10 69 ▫ No prior allo HCT (N=21): 14.1 PR 2 6 months Hypocellular BM 3 8 ▫ Prior allo HCT (N=15): 8.8 months Refractory 4 11  P=0.201 Not evaluable 2 6 MRD Response No. (N=25) % • Of the 25 patients who achieved Across cycles 22 88 CR or CRh: End of cycle one 18 72 ▫ 13 proceeded to HSCT while still End of cycle two 3 12 in remission End of cycle three 1 4 No MRD response 3 12 CR: complete response, CRh: CR with partial hematologic recovery, PR: partial response, BM: bone marrow, MRD: minimal residual disease RFS: relapse free survival, OS: overall survival Topp MS, et al. J Clin Oncol.2014; 32(36): 4134 ‐ 4140. Topp MS, et al. J Clin Oncol. 2014;32(36): 4134 ‐ 4140. Inclusion Criteria Exclusion Criteria >10% bone marrow blasts Ph+ ALL, Burkitt’s leukemia, ALL in testes or CNS, history of malignant disease within 5 years Primary refractory disease after History or presence of CNS pathology induction or relapsed within 12 months after first CR or allo HCT, or Auto HSCT within 6 weeks; allo within 3 months not responded to or relapsed after Active infections, autoimmune disease, acute GVHD or first salvage or later chronic GVHD grade 2 ‐ 4 ECOG performance status ≤ 2 Chemo, radiotherapy, systemic GVHD treatment within 2 weeks Immunotherapy or investigational antileukemic drug within Ph ‐ B ‐ precursor ALL 4 weeks • Open ‐ label, multicenter, single ‐ arm, phase II study that enrolled 189 patients from European and US centers • Dosing: 9 mcg/day x 1 week, 28 mcg/day week 2 ‐ 4 Topp MS, et al. The Lancet. 2015;16:57 ‐ 66. 3