Current Applications and Future Directions of CAR-T cell therapies for B-cell Malignancies

Transcription

1 Current Applications and Future Directions of CAR-T cell therapies for B-cell Malignancies Nirav Shah, MD MSHP Assistant Professor of Medicine Medical College of Wisconsin 1

2 Financial Disclosure I currently have or have had the following relevant financial relations to disclose: Consultant: Juno Pharmaceuticals, Kite Pharmaceuticals Contracted Research: Lentigen Technology

3 Off Label Use Disclosure I do intend to discuss an off label use of a product during this activity, the following products will be discussed: 1. BB2121 (Myeloma CAR-T under development) 2. JCAR017 (CAR-T in development for NHL 3. CTL019 (CAR-T in development for adults) 4. CAR20-19 T Cell

4 Objectives 1) Updates in CAR-T cell technologies for treatment of ALL, NHL, and MM 2) Review of clinical outcomes to date with CAR-T cell therapies 3) Future directions of CAR-T cells: Dual targeted CAR-T therapies, Novel Targets, NK CARs, Armored CARs 4

5 CAR-T Technology Chimeric Antigen Receptor Modified T- cells Utilizes a viral vector to insert a gene into T-cells to target malignant conditions with co-stimulatory signaling domains, generally CD3z with either 4-1BB or CD28 This technology is most advanced in B-cell malignancies with known targets such as CD19, CD22, BCMA Incredible outcomes in Phase 1/2 studies for patients with relapsed, refractory B-cell ALL, B-cell NHL, & MM which has led to two FDA approvals for CAR-T products 5

6 CAR-T cell production T cell CAR-T cell Lentiviral vector Native TCR Anti-CD 19 or CD20 CAR-T construct CD20 or CD19 Dead tumor cell Tumor cell Figures courtesy of Dr. Porter and UPenn

7 Cytokine Release Syndrome (CRS) A newly defined, potentially lethal complication of CAR-T cell infusion CRS is a non-antigen specific toxicity that occurs as a result of high-level immune activation and can lead to hypotension, renal failure, shock, and death. Syndrome with similarities to HLH (elevated ferritin>100 K, high grade fevers) Lee, D.W., et al., Current concepts in the diagnosis and management of cytokine release syndrome. Blood, (2): p

8 Treatment of CRS Tocilizumab, a monoclonal antibody against the IL-6 receptor, is the FDA approved and standard approach for severe CRS Can see improvement within hours of administration Dose 8 mg/kg, max dose 800 mg Refractory CRS: corticosteroids, siltuximab, etarnacept are used Despite treatment patients have died from refractory CRS 8

9 CAR-T Constructs - First generation CAR-T cells had minimal in vivo activity - CD3z+41BB and CD3z+CD28 are the most commonly used constructs - CD28 CARs have greater anti-tumor activity and more rapid tumor clearance (correlates with increased and earlier CRS). - 41BB CARs have slower tumor elimination but achieve similar elimination due to greater persistence. 41BB can last years vs <1 month with CD28 - This is felt to be due to increased memory T- cell development with 41BB CAR-T cells Zhao, Z., M. Condomines, S.J.C. van der Stegen, F. Perna, C.C. Kloss, G. Gunset, J. Plotkin, and M. Sadelain, Structural Design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T Cells. Cancer Cell, (4): p

10 Determinants of CAR-T Efficacy and Toxicity Construct: CD28 vs 41BB Disease: NHL vs ALL vs MM NHL: Nodal disease ALL: Blood/marrow MM: Marrow/Bone Disease Burden at Treatment High burden disease, higher LDH correlates with worse CRS. 10

11 Determinants of CAR-T Efficacy and Toxicity Lymphodepletion (intensity) Elimination of T-regulatory cells and depleting cellular elements that utilize cytokines enhances adoptive T-cell function (Gattinoni et al. 2005) CAR-T Dose (Frey et al. 2016) Higher dose, more toxicity Presence of Concurrent Infection Viral Vector (lentiviral vs retroviral) Lentivirus can integrate into dividing and non-dividing cells, can accommodate a larger DNA sequence with greater stability, and are less susceptible to silencing (Kenderian et al. 2014) 11

12 CLINICAL OUTCOMES TO DATE 12

13 CD19 CAR-T cells in ALL Phase 2, global, 25 center study of CTL019 in pediatric and young adults with relapsed/refractory B-cell ALL (CD3z & 41BB) 75 patients treated (92 enrolled) 61% relapsed post allo-hct for ALL Overall Remission Rate within 3 months=81% (all MRD negative) 6 months=90% months=76% CRS occurred in 77% of patients, 48% received tocilizumab Neurotoxicity in 40%, all managed with supportive care Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in Children and Young Adults with B- Cell Lymphoblastic Leukemia. New England Journal of Medicine. 2018;378(5):

14 Overall Survival and Toxicities Median OS 19.1 months 19 deaths: 1 PD, 1 cerebral hemorrhage, 12 relapsed/progression, 2 infections due to prolonged neutropenia (mucor/hhv6), 3 other 14

15 FDA Approval: Kymriah Indicated for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. First FDA CAR-T product approved in the United States (August 2017) 15

16 ALL and CAR-T cells Phase 1, dose-escalation CD3z-CD28 CAR-T trial in children and young adults with B-cell ALL 21 patients enrolled, 20 with ALL 6 patients with ALL had primary refractory disease 8 patients had undergone prior allogeneic transplant for ALL 70% complete response rate in ALL and 60% were MRD- 51% alive at 10 months post-infusion CD19 CAR-T cells trafficked to CNS and cleared disease in 2 pts CRS occurred in 16/21 patients (Grade 3-4 CRS 6/21) Lee, D.W., et al., T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet, (9967): p

17 Phase 1, CD19 CAR-T cell (CD28 and CD3z) 53 patients treated with relapsed/refractory B-cell ALL Severe CRS in 14/53 patients CR rate: 83% Median Event Free Survival: 6.1 months ADULT B-Cell ALL Park JH, et al. Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. New England Journal of Medicine 378: ,

18 ALL CD22 CAR-T cells CD22 is a marker of mature and immature B-cells. It normally functions to prevent overactivation of the immune system. Phase 1 Study of anti-cd22 CAR-T cells for B-cell malignancies at NIH 21 patients, all with CD22+ B-cell ALL 17 of these patients had prior anti-cd19 directed immunotherapy 12 patient (57%) achieved CR, 9 were MRD negative, response was dependent on dose level Only 3 patients maintained CR at time of publication 16/21 experienced cytokine release syndrome Results prove CAR-T activity at targets outside CD19 Fry, T.J., N.N. Shah, R.J. Orentas, M. Stetler-Stevenson, C.M. Yuan, S. Ramakrishna, P. Wolters, S. Martin, C. Delbrook, B. Yates, H. Shalabi, T.J. Fountaine, J.F. Shern, R.G. Majzner, D.F. Stroncek, M. Sabatino, Y. Feng, D.S. Dimitrov, L. Zhang, S. Nguyen, H. Qin, B. Dropulic, D.W. Lee, and C.L. Mackall, CD22-CAR T Cells Induce Remissions in CD19-CAR Naïve and Resistant B-ALL. Nature medicine, (1): p

19 To Transplant or Not To Transplant May be dependent on CAR-T construct 41BB CAR-T (Maude et al. NEJM 2018) only 9% of patients proceeded to allogeneic transplant after CAR-T treatment with relapse free survival of 59% at 12 months CD28 CAR-T cell (Lee et al. Blood 2016), improved leukemia free survival in patients after allo-hct 19

20 CAR-T cells in NHL 20

21 CTL019: Tisagenlecleucel Juliet Trial, Phase II, Global Trial of anti-cd19 CAR-T cell therapy. 41BB/CD3ζ lentiviral CAR-T cell Inclusion Criteria 18 years with relapsed, refractory DLBCL 2 lines of therapy or failed/ineligible for autologous transplant 27 centers, 10 countries, 4 continents Cryopreserved apheresis & central production either in Germany or US 21

22 Novartis: CTL019 q Cell Dose: Median 3 x 10 8 total transduced cells q Lymphodepletion: Flu/Cy (25 mg/m 2 & Cytoxan 250 mg/m 2 /day x 3 days) q 99 infused patients (142 enrolled) q43 discontinued before infusion (34 patient related/9 production failure) q ORR: 53% (40% CR and 14% PR) q At 6 months, CR rate 30% and PR 7%. q In responders, 73% remained in remission at 6 months Schuster S, et al. Blood.2017;130: Abstract

23 Novartis: CTL019 Toxicity 15% received tocilizumab and 11% corticosteroids 23

24 JCAR017 TRANSCEND NHL Trial Anti-CD19 CAR-T cell administered in a defined composition of CD8:CD4 cells. Lymphodepletion: Flu 30 mg/m2 and Cy 300 mg/m2 x 3 days 41BB/CD3ζ lentiviral CAR-T cell with truncated EGFR receptor (EGFRt allows for rapid killing of CAR-T cells in setting of toxicity by administration of cetuximab) Inclusion - Relapsed, refractory DLBCL, PMBCL, FL Grade 3B or MCL - No minimum ALC Two does levels 5 x 10 7 CAR T cells or 1 x 10 8 CAR T cells 24

25 Juno: JCAR017 TRANSCEND Outcomes q DLBCL after 2 lines of therapy: DLBCL, NOS (de novo or transformed FL) High-grade B-cell lymphoma (double/triple hit) DLBCL transformed from CLL or MZL PMBCL FL3B q patients in DLBCL cohort, Median age 61 years q Best Overall Response: 75% q 3 month CR rates 40% and 6 month CR rates 37% q Adverse Events CRS: 21/69 patients approx. 30% Grade 3-4 Neurotoxicity 10/69 approx. 14% 25

26 Axi-Cel ZUMA-1 Trial CD28/CD3ζ Retroviral CAR-T cell 111 patients enrolled, 101 administered Median age 58 years Inclusion: Refractory aggressive large cell lymphoma DLBCL, PMBCL, or transformed FL Centralized processing 26

27 ORR: 82% and CR 52% Median Follow-up Time of 15.4 months, 40% with ongoing complete response Overall Survival at 18 months: 52% Median duration of response 11.1 months Kite: Axi-Cel Outcomes 27

28 FDA Approved Indications Kymriah (tisagenlecleucel) is approved for treatment of adult patients with relapsed or refractory (r/r) large B cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Yescarta (axicabtagene ciloleucel) is approved for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. 28

29 Current Products in NHL Construct Juno Kite (AT MCW) Novartis 4-1BB, CD3z, FMC63 (CD19) binding domain CD28, CD3z, FMC63 binding domain 4-1BB, CD3z, FMC63 binding domain Vector lentiviral retrovirus lentiviral ORR 74% (CORE) 82% 59% Lymphodepletion Flu: 30 mg/m2 x 3D Cy: 300 mg/m2 x 3D Flu: 30 mg/m2 x 3D Cy: 500 mg/m2 x 3D CR 50% (6 months) 42% CR at 15 months) Median Day--CRS Day +5 CRS (1-14 days) Day +2 (1-12 days) Flu: 25 mg/m2 x 3D Cy: 250 mg/m2 x 3D 40% (3 months) Day +3 (1-51) only 2 pts after Day 10 Approval No FDA approval to date DLBCL Pediatric ALL and adult DLBCL 29

30 CAR-T cells in Multiple Myeloma 30

31 CAR-T in MM B-cell maturation antigen (BCMA) is a protein universally expressed on the surface of malignant plasma cells and limited to mature B-cells and plasma cells. Curr. Hematol. Malig. Rep. 12, (2017); 31

32 BCMA CAR-T cells Phase 1 study of BB2121 with a 4-1BB CD3ζ lentiviral construct Dose Escalation Phase: Inclusion 3 lines of treatment failure, double-refractory, and had 50% BCMA expression on plasma cells Dose Expansion Phase: Failed Daratumumab and refractory to last line of therapy with no BCMA requirement. Prior to cell infusion patients received fludarabine 30 mg/m2 and Cytoxan 300 mg/m2 63% of patients had CRS, mostly Grade 1-2 and 33% experienced neurotoxicity 2 patients had Grade 3 CRS 9 patients required tocilizumab and 4 required corticosteroids. Raje et al. ASCO

33 Outcomes Median PFS in Dose-Escalation Phase was 11.8 months 16 patients were MRD negative a one more timepoint and PFS for this group was 17.7 months. Median Response Duration in patients who received 150 x 10^6 cells/kg has not been reached 33

34 BCMA CAR-T Phase 1 Study from China with BCMA CAR-T 19 patients relapsed/refractory MM 100% overall response rate 18/18 patients reached CR or near CR 14 patients mild CRS Early Data, only 7 patients followed >6 months, but very exciting Fan F, Zhao W, Liu J, et al: Durable remissions with BCMA-specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma ASCO Annual Meeting. Abstract LBA3001. Presented June 5,

35 Is the future of blood cancer therapy a series of CARs? 35

36 Limitations of CAR-T technologies 1) Effectiveness q q q q q q Questions remain on is this curative therapy or a bridge to an allogeneic transplant Limitations to finding suitable targets On target, off tumor toxicity Not all patients respond, even those that do respond, can progress Progression can occur via escape variants and selective pressure in a heterogenous disease (development of a CD19 negative clone). Among patients who relapse 14%-33% had CD19 negative relapses 36

37 Limitations of CAR-T technologies 2) Production/Costs q q q CAR-T production is limited to sites with expensive, GMP compliant closed system cell processing Lamborghini facilities to those Aventador participating in industry sponsored trials $500,000 Not financially sustainable for health care system Costs described include price of production alone (not costs to hospital to treat patients and manage complications) NY Times 37

38 Limitations: Current Production Model & Logistical Challenges 38

39 Limitations of CAR-T Technologies 3) Real World Application q Current outcomes represent a heavily biased population that are relapsed, refractory yet stable enough to travel to other centers and are healthy enough to await production time with likely few comorbid conditions given inclusion criteria q Juliet Trial (large, multicenter Phase II study in NHL) q q ~30% patients enrolled DID NOT receive CAR-T cells due to patient related reasons While ORR was high among treated patients, using an intention to treat analysis this number would be significantly lower. q The real world application and toxicity/efficacy of this remain unknown. 39

40 Advancing CAR-T cells at the Medical College of Wisconsin 40

41 Dealing with Limitations: Relapse Despite effectiveness, not all patients respond and even those that do respond, can relapse. Relapse is felt to be related to tumor heterogeneity and selection of a resistant clone via downregulation of the targeted receptor. Dual targeting of more than one B-cell receptor may mitigate tumor antigen escape. Ideal to target cell surface antigens that are widely expressed to allow for generalizability of CAR-T cell 41

42 MCW Phase 1 Clinical Trial - First-in-human dual targeted CAR-T cell against two B-cell antigens CD19 and CD20 using a lentiviral CD3z and 4-1BB construct - Dual targeting can decrease risk of antigen down-regulation and escape variants - Dual targetingà? Increased CRS Trial is open at MCW/FH, Phase 1 study, enrolling patients with non-hodgkin Lymphoma 42

43 Dealing with Limitations: Local CAR-T Production q At MCW we are using the CliniMACS Prodigy Device to produce CAR-T cells in a closed system that is GMP compliant for point-of-care CAR-T production. q 14 days to produce CAR-T cells q Fits on a standard laboratory table 43

44 Phase 1, Clinical Trial Design - Phase 1, Dose Escalation Study, 3+3 design - 3 escalation dose levels x 10 5 cells/kg x 10 5 cells/kg x 10 6 cells/kg - Inclusion: Relapsed, refractory B-cell NHL including DLBCL, Follicular Lymphoma, Mantle Cell, and Chronic Lymphocytic Leukemia - Either CD19 or CD20 positive disease 44

45 - 7 patients enrolled Clinical Laboratory Data - All produced in excess of targeted cell dose of transduced CD20_CD19 CAR-T cells via Prodigy. - ~14 days production - Day 8 in process testing suggests CAR-T levels may be adequate sooner than 14 days - Hope to share clinical outcomes in near future 45

46 The Future: A Decentralized Model of CAR-T production? CD20 Local Production at Treating Center CD19 BCMA CD22 ~14 days production CD38 46

47 Future Directions: CAR-NK cells NK cells are effector cells that can be modified for tumor specific targeting Several advantages of CAR-T cells Allogeneic NK cells can be used as they do not cause GVHD or require HLA-matching (can be acquired from cord blood, peripheral blood, etc) NK cells may lead to less CRS and limited off-target toxicity due to limited persistence and expression of different cytokines during activation (limited persistence may allow relapse) Ongoing third party CAR-NK cell anti-cd19 trials: 47

48 Future Directions: Allogeneic CAR-T cells UCART19 trial in B-cell ALL Genetically modified T-cell produced manufactured from healthy donor cells Anti-CD19 CAR (41BB- CD3ζ) with an RQR8 safety switch that is intended to allow targeted elimination by rituximab 4/6 patients MRD negative CR, 1 refractory, 1 treatment related death Toxicity: CRS in all patients 1 patient with skin GVHD G1 All MRD negative patients went to allo-hct, only 2 remain in CR 48

49 Armored CAR-T cells Armored CAR-T cells are modified second generation CAR-T cells that are optimized to secrete active cytokines or express ligands that improve efficacy and persistence. Different approaches under investigation IL12: CAR-T cells that can secrete IL-12 which enhances CD8+ T-cell activity and can improve cytotoxic function CD40 ligand: Expression of CD40L on CAR-T cells allows binding to CD40 on dendritic cells which leads to T-cell proliferation and CD8+ T-cell activity 41BB ligand: Expression of 41BB ligand on cell surface allows binding to 41BB receptor on monocytes, dendritic cells, NK cells. Can allow central memory T- cell maintenance and CD8+ expansion 49

50 Future Targets Anti-CD30 CAR-T cell Trial (NCI) - Combination CD19/CD22 CAR-T cell for ALL - CD33 CAR-T cells in AML

51 Ongoing CAR-T Clinical Trials 51

52 Conclusions 1) CAR-T cells are now approved for pediatric B-cell ALL and adult NHL and have changed the landscape of relapsed, refractory B-cell malignancies 2) Future approvals: Adult ALL, BCMA CAR-T, additional products for B-cell NHL 3) It is likely the CAR-T cells approved today may be obsolete in the next 5-10 years with armored CARs, dual-targeting CARs, CRISPR CAR-T, etc. 52

53 Acknowledgements MCW/FH Dr. Parameswaran Hari Dr. Carolyn Taylor Dr. Fenlu Zhu Dr. Bryon Johnson Dr. Tim Fenske Dr. Mehdi Hamadani Katie Worzalla Sharon Yim Marilyn Linde Debra Pastorek Lance Zimmerman Areyl Goff Clinical Trials Office Hem/Onc Division Froedtert Foundation MACC Fund-Peds/BMT group Industrial Partners Dr. Rimas Orentas Dr. Boro Dropulic Dr. Dina Schneider Lentigen/Miltenyi Our Courageous Patients 53