Exploiting the Immune System: Chimeric Antigen Receptor-T Cell Therapy for Hematologic Malignancies

Transcription

1 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

2 Disclosures I have the following disclosures Company Juno Therapeutics Jazz Pharmaceuticals Role Advisory Board 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

3 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

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

5 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:

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

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

8 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):

9 Dosing CAR-T Infusion 1 x 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: Lee DW, et al. Lancet 2015;385: Turtle CJ, et al. J Clin Invest 2016;126(6):

10 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

11 CAR-T cell Therapy for Hematologic Malignancies CLINICAL DATA

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

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

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

15 CAR-T Cell Therapy for ALL Study Davila ML, et al. Sci Transl Med 2014 Proceeded to transplant 44% overall 70% of eligible Comments No relapse in transplanted patients; Follow up: 2-24 months Maude S, et al. NEJM % overall Sustained responses for up to 2 years Lee DW, et al. Lancet % overall 83% of eligible No relapse in transplanted patients; 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: Lee DW, et al. Lancet 2015;385:

16 Chronic Lymphocytic Leukemia (CLL) Agent Response Rate Survival Comments Ibrutinib ORR: 63% CR: 0% 6-month PFS: 88% 1-yr OS: 90% Similar responses in high-risk patients Ibrutinib + Rituximab Idelalisib + Rituximab Venetoclax Venetoclax + Rituximab ORR: 95% CR: 8% ORR: 81% CR: 0% ORR: 79% CR: 20% ORR: 86% CR: 51% 18-month PFS: 78% 18-month OS: 84% 6-month PFS: 45% 1-year OS: 92% 15-month PFS: 69% High-risk population Median DOR: 15.4 months Frail population Similar responses in high-risk patients Similar responses in high-risk patients Median DOR: 24 months 2-year PFS: 82% 2-year ongoing response: 89% 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: Burger JA, et al. Lancet Oncol 2014;15: Furman RR, et al. N Engl J Med 2014;370: Roberts AW, et al. N Engl J Med 2016;374(4): Seymour JF, et al. Lancet Oncol 2017;18:

17 CAR-T cell Therapy for CLL Study N ORR N (%) CR N (%) DOR (months) Porter DL, et al. Sci Transl Med (57) 4 (29) 5-53 Porter DL, et al. Blood (39) 5 (22) NR Kalos, et al. Sci Transl Med (100) 2 (67) 7-11 Kochenderfer, et al. JCO (100) 3 (75) 4-23 Kochenderfer, et al. Blood (75) 1 (25) 7-15 Brentjens R, et al. Blood (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. Porter DL, et al. Blood 2014;124(21):1982. Kalos M, et al. Sci Transl Med 2011;3(95):95ra73. Kochenderfer, et al. J Clin Oncol 2015;33(6): Kochenderfer, et al. Blood 2012;119(12): Brentjens R, et al. Blood 2011;118(18):

18 CAR-T Therapy for Lymphoma Study Population CAR Response Rate N (%) Turtle, et al. Sci Transl Med 2016 N = 32 R/R NHL CD19 ORR: 19 (63) CR: 10 (33) Locke, et al. Mol Ther 2017 N = 7 R/R DLBCL CD19 ORR: 5 (71) CR: 4 (57) Wang C, et al. Clin Cancer Res 2017 N = 18 R/R HL CD30 ORR: 7 (39) 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): Wang C, et al. Clin Cancer Res 2017;23(5):

19 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): Blanc V, et al. Clin Cancer Res 2011;17(20);

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

21 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

22 CAR-T cell Therapy for Hematologic Malignancies MANAGING TOXICITIES

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

24 Grade Signs/Symptoms CRS: Grading 1 Constitutional symptoms; requires only symptomatic management Hypotension (responsive to fluids or low dose vasopressor) Oxygen requirement < 40% Grade 2 organ toxicity Hypotension (requiring high dose or > 1 vasopressor) Oxygen requirement 40% Grade 3 organ toxicity Grade 4 transaminitis Ventilator support required Grade 4 organ toxicity 5 Death Lee DW, et al. Blood 2014;124(2):

25 CAR-T cell dose Burden of disease CRS: Risk Factors Lee DW, et al. Lancet 2015;385:

26 Cytokine Elevations C-Reactive Protein (CRP) Interleukin-6 (IL-6) Association between CRP and IL-6 Lee DW, et al. Lancet 2015;385:

27 Neurotoxicity Spectrum of neurologic symptoms Confusion/delirium to obtundation Seizure activity Pathogenesis Direct CAR-T toxicity on CNS tissues vs. generalized T-cell mediated inflammatory state Lee DW, et al. Lancet 2015;385: Davila ML, et al. Sci Transl Med 2014;6(224);224ra25.

28 CRS and Response Response Rate Rate of CRS CRS in Responders CRS in non- Responders 14/21 16/21 14/14 2/7 Comments All 6 grade 3-4 CRS cases in responders Lee DW, et al. Lancet 2015;385:

29 Grade 1-2 Management of CRS Supportive measures Grade 3-4 Tocilizumab Inhibits soluble (sil-6r) and membrane-bound (mil-6r) IL-6 receptors Dosing 4-8 mg/kg (max 800 mg) IV over 1 hour x 1 Repeat if lack of response No CNS penetration Brundo JN, et al. Blood 2016;127(26):

30 Management of CRS Corticosteroids Indicated for: Tocilizumab refractory CRS Grade 3-4 neurotoxicity Methylprednisolone 1-2 mg/kg IV every 12 hours Dexamethasone 5-10 mg IV every 6-12 hours Brundo JN, et al. Blood 2016;127(26): Davila ML, et al. Sci Transl Med 2014;6(224);224ra25.

31 B-Cell Aplasia On-target off-tumor toxicity Potential measure of persistence of CD19- targeted CAR-T cells Prolonged B-cell aplasia in patients with sustained remissions Immunoglobulin deficiencies Intravenous immunoglobulin (IVIG) replacement Dai H, et al. J Natl Cancer Inst 2016;108(7):djv439.

32 Audience Response Question 3 JR is a 54 year-old male with ALL s/p CD19 CAR-T infusion. JR becomes hypoxic and hypotensive, ultimately requiring intubation and pressor support. He also has mild confusion. He is given tocilizumab 8 mg/kg IV x 1. Twelve hours later he continues to be hypotensive requiring an additional pressor, has progressive renal compromise, moderate reduction in alertness and inability to express speech.

33 Audience Response Question 3 What is the best approach for the management of JR s CRS at this time? a. Dexamethasone 10 mg IV every 12 hours b. Repeat tocilizumab 8 mg/kg IV x 1 c. Repeat tocilizumab 8 mg/kg IV x 1 and add dexamethasone 10 mg IV every 12 hours d. Methylprednisolone 1 mg/kg IV every 12 hours

34 Where Are We Now? Company/ CAR Trial Trial Population Response Rates Approval Status/ US Adopted Name (USAN) Novartis CTL019 Eliana N = 88 Age 3-23 B-ALL CR: 83% CRm: 83% Breakthrough status 7/2014 Granted FDA priority review 2017 tisagenlecleucel-t Novartis CTL019 Juliet N = 141 Adults DLBCL ORR: 59% CR: 43% Breakthrough status 4/2017 BLA filed 2017 tisagenlecleucel-t KITE KTE-C19 Zuma-1 N = 111 Adults NHL ORR: 82% CR: 54% Breakthrough status 7/2015 Granted FDA priority review 2017 axicabtagene ciloleucel KITE KTE-C19 Zuma-3 N = 11 Adults B-ALL CR: 75% CRm: 75% Trial ongoing Juno JCAR017 Transcend N = 39 Adults NHL ORR: 75% CR: 67% Trial ongoing Buechner J, et al. EHA Learning Center 2017; Schuster SJ, et al. EHA Learning Center 2017; Locke, FL, et al. AACR Abstract nr [CT019]. Shah BD, et al. J Clin Oncol 2017;35 (suppl; abstr 3024). Abramson JS, et al. Blood 2016;128:4192.

35 Summary Improvements in CAR-T engineering have enhanced clinical efficacy CAR-T therapy offers an effective treatment option in the relapsed/refractory setting for hematologic malignancies, particularly ALL Toxicities, such as CRS and neurotoxicity, can be fatal and warrant prompt management

36 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