Hematologic Malignancies Maurice Alexander, PharmD, BCOP, CPP - PowerPoint PPT Presentation

Exploiting the Immune System: Chimeric Antigen Receptor-T Cell Therapy for Hematologic Malignancies Maurice Alexander, PharmD, BCOP, CPP Clinical Specialist, Blood and Marrow Transplant UNC Bone Marrow Transplant and Cellular Therapy Program

Disclosures • I have the following disclosures Company Role Juno Therapeutics Advisory Board Jazz Pharmaceuticals Advisory Board • Off-label use disclosure – This session will include a discussion of off-label treatment and investigational agents not approved by the FDA for use in the US

Objectives • Understand the engineering process and administration of chimeric antigen receptor-T (CAR-T) cells • Interpret clinical data for the use of CAR-T cells in the management of hematologic malignancies • Describe the management of toxicities associated with CAR-T therapy

CAR-T cell Therapy for Hematologic Malignancies CAR-T ENGINEERING AND ADMINISTRATION STRATEGIES

Chimeric Antigen Receptor-T (CAR-T) Cells • Chimeric Antigen Receptors (CARs) – Recombinant molecules that target a specific antigen – Mediate cell activation • T-cells – Activated after CAR exposure to the cancer antigen – Destruction of tumor cells and proliferation of CAR-Ts Kulemzin SV, et al. Acta Naturae 2017;9(1):6-14. Ramos CA, et al. Annu Rev Med 2016;67:165-183.

CAR-T Engineering Process Mato A, et al. Blood 2015;126:478-485.

CAR-T Engineering Batlevi CL, et al. Nat Rev Clin Oncol 2016;13(1):25-40.

Lymphodepletion • Depletes endogenous lymphocytes • Elimination of regulatory T cells • Removal of competing targets • Prevents T-cell mediated responses against CARs • Improves CAR-T persistence • May include disease-targeted agents . Gattinoni L, et al. J Exp Med 2015;202(7):907-912.

CAR-T Infusion • Dosing – 1 x 10 5 – 1 x 10 8 cells/kg – Dose level associated with both response and toxicity – No uniform/standard dose • Infusion strategies – Single infusions – Fractionated/multiple infusions Davila ML, et al. Sci Transl Med 2014;6(224):224ra25. Maude L, et al. N Engl J Med 2014;371:1507-1517. Lee DW, et al. Lancet 2015;385:517-28. Turtle CJ, et al. J Clin Invest 2016;126(6):2123-2138.

Audience Response Question 1 Which of the following components of CAR-T cells have been modified for enhancement of activity in newer generation CAR-Ts? a. Antigen recognition domain b. Hinge/Spacer c. Transmembrane domain d. Signaling/Costimulatory domain

CAR-T cell Therapy for Hematologic Malignancies CLINICAL DATA

CD19 Expression Blanc V, et al. Clin Cancer Res 2011;17(20);6448-6458.

Acute Lymphoblastic Leukemia (ALL) • Relapsed/refractory disease remains a challenge – Initial CR: > 80% – Refractory: ~20% – Relapse: > 50% • Responses to salvage therapies are poor Salvage treatment Relapse number Previous therapy CR Rate number 1 st 1 st Chemotherapy ~40% 2 nd 2 nd Chemotherapy ~30% 1 st 1 st Stem Cell Transplant ~20% CR: Complete Remission Fielding AK, et al. Blood 2007;109:944-950. Gokbuget N, et al. Blood 2012;120(10):2032-2041.

CAR-T Cell Therapy for ALL Lympho- Costimulation/ Response Rate Study Population depletion Cell dose (cells/kg) N (%) Davila ML, et al. N = 16 CD28 CR: 14 (88) Cy 3 x 10 6 Sci Transl Med 2014 Adults CRm: 12 (75) N = 30 Maude S, et al. 4-1BB CR: 27 (90) Peds (25) Various 8 x 10 5 – 2 x 10 7 NEJM 2014 CRm: 23 (77) Adults (5) N = 21 Lee DW, et al. CD28 CR: 14 (70) Peds (16) Cy/Flu 1 x 10 6 – 3 x 10 6 Lancet 2015 CRm: 12 (60) Adults (5) Cy Turtle CJ, et al. N = 32 4-1BB CR: 27 (93) Cy/Etop 2 x 10 5 – 2 x 10 7 J Clin Invest 2016 Adults CRm: 25 (86) Cy/Flu Cy: Cyclophosphamide; Flu: Fludarabine; Etop: Etoposide; CR: Complete remission; CRm: Complete molecular remission Davila ML, et al. Sci Transl Med 2014;6(224):224ra25. Lee DW, et al. Lancet 2015;385:517-28. Maude L, et al. N Engl J Med 2014;371:1507-1517. Turtle CJ, et al. J Clin Invest 2016;126(6):2123-2138.

CAR-T Cell Therapy for ALL Proceeded to Study Comments transplant Davila ML, et al. 44% overall No relapse in transplanted patients; Sci Transl Med 2014 70% of eligible Follow up: 2 -24 months Maude S, et al. 10% overall Sustained responses for up to 2 years NEJM 2014 Lee DW, et al. 48% overall No relapse in transplanted patients; Lancet 2015 83% of eligible Median follow up: 10 months Davila ML, et al. Sci Transl Med 2014;6(224):224ra25. Maude L, et al. N Engl J Med 2014;371:1507-1517. Lee DW, et al. Lancet 2015;385:517-28.

Chronic Lymphocytic Leukemia (CLL) Response Agent Survival Comments Rate ORR: 63% 6-month PFS: 88% Ibrutinib Similar responses in high-risk patients CR: 0% 1-yr OS: 90% Ibrutinib + ORR: 95% 18-month PFS: 78% High-risk population Rituximab CR: 8% 18-month OS: 84% Median DOR: 15.4 months Idelalisib + ORR: 81% 6-month PFS: 45% Frail population Rituximab CR: 0% 1-year OS: 92% Similar responses in high-risk patients ORR: 79% Similar responses in high-risk patients Venetoclax 15-month PFS: 69% CR: 20% Median DOR: 24 months Venetoclax + ORR: 86% 2-year PFS: 82% 2-year ongoing response: 89% Rituximab CR: 51% ORR: Objective response rate; CR: Complete response; PFS: Progression-free survival; OS: Overall survival; DOR: Duration of response Byrd JC, et al. N Engl J Med 2014;321:213-223. Burger JA, et al. Lancet Oncol 2014;15:1090-1099. Roberts AW, et al. N Engl J Med 2016;374(4):311-322. Furman RR, et al. N Engl J Med 2014;370:997-1007. Seymour JF, et al. Lancet Oncol 2017;18:230-40.

CAR-T cell Therapy for CLL ORR CR DOR Study N N (%) N (%) (months) Porter DL, et al. Sci Transl Med 2015 14 8 (57) 4 (29) 5-53 Porter DL, et al. Blood 2014 23 9 (39) 5 (22) NR Kalos, et al. Sci Transl Med 2011 3 3 (100) 2 (67) 7-11 Kochenderfer, et al. JCO 2015 4 4 (100) 3 (75) 4-23 Kochenderfer, et al. Blood 2012 4 3 (75) 1 (25) 7-15 Brentjens R, et al. Blood 2011 8 1 (13) 0 (0) 6 ORR: Objective response rate; CR: Complete response; DOR: Duration of response Porter DL, et al. Sci Transl Med 2015;7(303):303ra139. Kochenderfer, et al. J Clin Oncol 2015;33(6):540-549. Porter DL, et al. Blood 2014;124(21):1982. Kochenderfer, et al. Blood 2012;119(12):2709-2720. Kalos M, et al. Sci Transl Med 2011;3(95):95ra73. Brentjens R, et al. Blood 2011;118(18):4817-4828.

CAR-T Therapy for Lymphoma Response Rate Study Population CAR N (%) Turtle, et al. N = 32 ORR: 19 (63) CD19 Sci Transl Med 2016 R/R NHL CR: 10 (33) Locke, et al. N = 7 ORR: 5 (71) CD19 Mol Ther 2017 R/R DLBCL CR: 4 (57) Wang C, et al. N = 18 ORR: 7 (39) CD30 Clin Cancer Res 2017 R/R HL CR: 0 (0) R/R: Relapsed/refractory; NHL: Non-Hodgkin lymphoma; DLBCL: Diffuse large B-cell lymphoma; HL: Hodgkin lymphoma; ORR: Objective response rate; CR: Complete response Turtle CJ, et al. Sci Transl Med 2016;8(355):355ra116. Locke FL, et al. Mol Ther 2017;25(1):285-295. Wang C, et al. Clin Cancer Res 2017;23(5):1156-1166.

Multiple Myeloma (MM) • CD19 expression in MM – Minor component of the MM clone – CD19 CAR-T activity despite low level expression Garfall AL, et al. N Engl J Med 2015;373(11):1040-1047. Blanc V, et al. Clin Cancer Res 2011;17(20);6448-6458.

CAR-T Therapy for MM • Alternative targets: CD38, CD56, CD138, BCMA Responses Study N CAR N (%) Guo, B, et al. 5 CD138 SD: 4 (80) J Cell Immunother 2016 sCR: 1 (9) Ali SA, et al. 11 BCMA VGPR: 2 (18) Blood 2015 PR: 1 (9) Cohen AD, et al. sCR: 1 (17) 6 BCMA Blood 2016 VGPR: 1 (17) sCR: 14 (74) Fan F, et al. 19 BCMA VGPR: 4 (21) J Clin Oncol 2017 PR: 1 (11) BCMA: B-cell maturation antigen; SD: Stable Guo B, et al. J Cell Immonther 2016;2:28-35. disease; sCR: Stringent complete response; Ali SA, et al. Blood 2015;126:LBA-1. VGPR: Very good partial response; PR: Partial Cohen AD, et al. Blood 2016;128:1147. Fan F, et al. J Clin Oncol 2017;35 (suppl; abstr LBA3001). response

Audience Response Question 2 Clinical data for CAR-T therapy in hematologic malignancies suggest which of the following? a. CAR-T responses in ALL are typically transient, requiring additional therapy b. Complete remissions have been reported in up to 90% of patients with ALL c. Patients with ALL are unlikely to be able to proceed to stem cell transplant after receiving CD19 CAR-T therapy d. CD19 is the ideal CAR-T target antigen for multiple myeloma and has resulted in high CR rates

CAR-T cell Therapy for Hematologic Malignancies MANAGING TOXICITIES

Cytokine Release Syndrome (CRS) • Non-antigen specific toxicity • Results from widespread immune activation – Elevation of systemic cytokines • Reversible, but potentially fatal Organ System Signs/Symptoms Fevers, rigors, malaise, myalgias/arthralgias Constitutional Nausea, vomiting, diarrhea Gastrointestinal Tachycardia, hypotension Cardiovascular Azotemia, renal failure Renal Transaminitis, hyperbilirubinemia Hepatic Altered mental status, confusion, delirium, seizures, etc. Neurologic Tachypnea, hypoxia Respiratory Lee DW, et al. Blood 2014;124(2):188-195. Brundo JN, et al. Blood 2016;127(26):3321-3330.