CAR T Cell Therapy: What, When, How. Elizabeth Budde, MD, PhD Dept. of Hematology & HCT Beckman research Institute

Transcription

1 CAR T Cell Therapy: What, When, How Elizabeth Budde, MD, PhD Dept. of Hematology & HCT Beckman research Institute March 23, 2019

2 DISCLOSURES Advisory board: Promab Biotechnologies; Gilead, Roche Consultancy/Speaker Bureau: AstraZeneca, Gilead Research support: Leukemia and Lymphoma Society, Mustang Therapeutic, Merck, Amgen Inc, and Private donations

3 Presentation Objectives Introduction of tumor immunology Overview of CAR T mechanism of action Current status of relevant CAR T trials CAR T Toxicity CAR T Program at COH

4 CAR T Therapy: an Evolution of Cancer Therapy 1940s 1st Chemotherapy approved st targeted antibody approved Checkpoint inhibitors CD19 CAR T approved therapy Approved Indiscriminate Kills both healthy & cancer cells Target receptor/ molecular Oncogenic drivers Immuno-oncology modulators Cell based engineered T cell immunotherapy

5 T cells are Central Players of Adaptive Immunity Innate Immunity Adaptive Immunity T cells enable a highly specific response against a particular target. - eliminate infections - eliminate tumor cells Michaela Sharpe, and Natalie Mount Dis. Model. Mech. 2015;8:

6 Immunoediting and Tumor Development

7 What Is CAR T Cell Therapy It is a combination of cellular, immune, and gene therapies. Harness the power of immune system to recognize and eliminate cancer cells.

8 The Goal of CAR T Cell Therapy Genetically modification of T cells to redirect them to transform to robust tumor specific T cells. T

9 constructs constructs (FIG. (FIG. 2) has 2) been has been demonstrated to enhance to enhance reactivity reactivity with with similar similar parts parts of other of other molecules molecules that are that are cytokine cytokine secretion secretion and and tumour tumour growth growth inhibition inhibition in expressed expressed on normal on normal cells 52 cells. 52. mice mice Interestingly, under under some some circumstances, In addition In addition to the to the antigen-binding region region of CARs, of CARs, enhanced enhanced T cell T cell function function can can also also be achieved be achieved by by there there are several are several other other domains domains that are that crucial are crucial for mediatinating T cell T responses cell responses against against cancer cancer cells. cells. These These domains domains for medi- the the transgene-mediated expression of the of ligands the ligands for co-stimulat for co-stimulat ory molecules ory molecules directly directly in T in cells T cells so that so that include include a molecular a molecular hinge hinge region region that that is positioned is positioned constitutive co-stimulation is provided is provided by the by T the cells T cells between between the scfv the scfv and the and cell the membrane, cell membrane, which which both both lifts lifts themselves 47. The 47. The development of new of new combinations the the antigen-binding domain domain away away from from the membrane the membrane of signalling of signalling moieties moieties continues continues with TCRs with a view a view to enhancing T ing cell T function cell function 48. However, 48. However, the benefits the benefits of includ- of includessaressary to bind to bind antigen. antigen. Members Members of the of the immunoglobulin to enhanc- v.s. and provides and CARs provides flexibility flexibility for the for CAR the CAR to reorientate to reorientate if nec- if necing multiple ing multiple co-stimulatory domains domains into into CARs CARs are are superfamily excel excel in terms in terms of flexibility, of flexibility, and hinge and hinge regions regions not always not always clear clear and and other other factors factors such such as the as target the target from from superfamily members members such such as CD8, as CD8, CD28 CD28 and IgG and IgG antigen, antigen, the method the method of T of cell T cell production and and the the are often are often used. used. Assessments of the of relative the relative capacity capacity for the for the TCR-mediated IR CAR-mediated IR a a b Tumour Tumour cell cell b Tumour Tumour cell cell T cellt cell T cell T either cell either naturally naturally occurring occurring or or from from a transgenic a transgenic mouse mouse β2 β2 TCR TCR α βα MHCI MHCI Tumour Tumour peptide peptide β γ ε γ ε ε δ ζε δ ζ CD3 complex CD3 complex Extra and intracellular antigens Peptide α- α-β processing β required Restricted by patient s HLA Peptide:MHC Kd =10-6 to 10-4 M No ligand on HLA-negative tumor Non-immunogenic b b T cellt cell B cellb cell antibody antibody from from B cells B cells CD8 CD8 CD3ζ CD3ζ or FcεRIγ or FcεRIγ Tumour Tumour antigen antigen V H V L scfv scfv T cellt cell Direct recognition a a of extracellular Nature Reviews Cancer tumor-associated antigens Peptide processing not required HLA-independent, Kd = 10-9 to 10-6 M Immunogenicity might be a problem α- α-β β γ- δ-γ- ε-δ- ε-ζ ζ V H V L ζ ζ 8 Adapted 528 AUGUST AUGUST from 2013 Kershaw 2013 VOLUM et VOLUM al, E Nature 13 E Reviews 13 Cancer reviews/ reviews/ cancer cancer

10 CAR Design Signal 1 ζ ζ Costim signal 2 Costim signal 2 ζ Costim signal 2 ζ 1 st generation CAR 2 nd generation CAR 3 rd generation CAR

11 The Development of CAR T Based Adoptive Cellular Therapy Ab structure -AlloHCT -identification of T & B cells Discovery of TCR Discovery of IL-2 T cell activation DLI RV transduction Chimeric TcR (1987, 1989) Addition of costim domain for CAR T 1 st clinical trials CD20CAR CD19CAR Adoptive cell transfer for tumor immunity -Discovery of HLA -discovery of IFN T cell restriction to MHC -generation of mcab 1990 LAK VST TIL 1 st gen CAR T (1993) CAR concept Generation and optimization of CARs 11

12 The Development of CAR T Based Adoptive Cellular Therapy Ab structure -AlloHCT -identification of T & B cells Discovery of TCR Discovery of IL-2 T cell activation DLI RV transduction Chimeric TcR (1987, 1989) Addition of costim domain for CAR T 1 st clinical trials CD20CAR CD19CAR Adoptive cell transfer for tumor immunity -Discovery of HLA -discovery of IFN T cell restriction to MHC -generation of mcab 1990 LAK VST TIL 1 st gen CAR T (1993) 2017 FDA approval Kymriah ( ) Yescarta ( ) CAR concept Generation and optimization of CARs 12

13 Clinicaltrials.gov assessed o8/17/2018 EMBO Molecular Medicine Volume 9, Issue 9, pages , 1 AUG 2017 Clinical Development of CAR T Cell Trials (n=770) US: 318 China: 252 Europe: 117

14 Adoptive Therapy Using CAR T Cells 3. CAR delivery 4. Ex vivo cell engineering and processing 6. T cell infusion 2. T cell activation 1. PBMC collection 5. Lymphodepletion Variables: - the starting population: VST, subset enrichment/depletion, - manufacturing process activation method, cytokines, expansion time, - infused products: bulk or defined population,

15 Presentation Objectives Introduction of tumor immunology Overview of CAR T mechanism of action Current status of relevant CAR T trials CAR T Toxicity CAR T Program at COH

16 CD19CAR: The first CAR with demonstrated clinical benefits Blanc et al. Clin Cancer Res :6448 CD19 Limited normal tissue expression restricted to B cells CD19 expresses on almost all B cell malignancies.

17 CD19CAR T Induced High CR Rates in B-ALL Trials Study N (txd) Age HSCT T cell Dose Lympho depletion CR% MRD-% Survival FHCRC (20-73) 37% M/kg Cy, Flu/Cy, Cy/E 93 -Flu/Cy group superior 86 SCH 45 (45) 12 (1-27) 62% M/kg Cy/Flu NA EFS 51% at 12 mo 89 CHOP (1.7-24) 66% 1M- 20M/kg Any RFS 55% at 12 mo OS 79% NCIped 55 (52) MSKCC 83 (53) 13 (4-30) 19% 40 (22-74) 35% N: number at enrollment; Txd: treated with CAR T 1-3M/kg Cy, Cy/Flu 62 LFS 56% for MRD-CR 55 median f/u -2.2 yrs 1-3M/kg Cy, Cy/Flu 82 DFS 27% MRD-CR mo

18 CD19CAR T Cell Pharmaceutical Trials in B-ALL Novartis ELIANA Pediatric/young adult B-ALL CTL019 (co-stimulatory domain 41BB) Juno - ROCKET Adult B-ALL JCAR015 (co-stimulatory domain CD28) Discontinued due to 5 patient death with cerebral edema

19 ELIANA: Study Design International, multicenter, open-label, single-arm phase 2 study Pts aged 3-21 yrs 5% BM lymphoblasts; no isolated extramedullary disease, no prior CD19-directed therapy, no prior gene therapy Fludarabine 30 mg/m²/d IV QD x 4 Cyclophosphamide 500 mg/m²/d IV x 2 CTL x 10 6 /kg IV 50 kg x 10 8 IV if > 50 kg (n = 92 ) 17 pts discontinued before infusion: deaths (n = 7), manufacturing failures (n = 7), AEs (n = 3). Primary endpoint: ORR (CR + CRi) within 3 mos; 4-wk maintenance of remission required. Null hypothesis: ORR higher than 20%. Secondary endpoints MRD status, DoR, OS, cellular kinetics, safety SL Maude et al. N Engl J Med 2018;378:

20 ELIANA: Safety ICU admission 47% (35 of 75) with median stay of 7 days (range, 1-34) 10% mechanical ventilation 25% high dose vasopressors SL Maude et al. N Engl J Med 2018;378:

21 ELIANA: DOR, OS and EFS Duration of Remission, Event-free Survival, and Overall Survival. DOR Median follow-up: 13.1 months DOR: not reached (n = 75) 8 CR patients: allohct - 2 w/mrd+ - 2 w/ B cell recovery w/i 6 mos OS 76% EFS: 50% Relapse CD19 expression + 1 pt - 15 pts unknown 4 pts SL Maude et al. N Engl J Med 2018;378:

22 Acute Lymphoblastic Leukemia FDA approval 8/30/2017 Indication patients up to 25 years of age with ALL that is refractory or in second or later relapse. $475,000 per product

23 B-NHL ZUMA-1 (NCT ): Multicenter Phase II Trial of KTE19 (Axi-cel) Done JULIET (NCT ): Multicenter Phase II trial of CTL019 (Tisagenlecleucel) Done TRANSCEND NHL 001 (NCT ): Multicenter Phase I/II trial of JCAR017 (Liso-cel) Done, final report is in preparation

24 CD19CARs for Aggressive B Cell Lymphoma ZUMA-1 N = 111 JULIET N = 147 TRANSCEND N = 140 total 73 in the core group Costim domain CD28 4-1BB 4-1BB T cell type PBMC PBMC CD4: CD8 (1:1) 11 non-conforming ALC 100 /ul 300 /ul No requirement Cell dose 1-2M/kg M 100M (DL2S) Product success 99% 94% 99% Product not given 10 (9%) 43 (29%) 20 (14%) Patients Ref DLBCL, tfl, PMBCL R/R DLBCL tfl R/R DLBCL NOS tfl, FLgr3b (core group) CNS no no 2 nd CNS, allowed ECOG PS ASH 2017, 2018

25 Probability of Relapse Free (%) % Survival Duration of Response & AEs KITE: ZUMA-1 Novartis: JULIET JUNO: TRANSCEND (CORE) Median DoR: NR Pts at Mos From Onset of Response Risk, n CORE CR: NR (5.0, NR) All: 9.2 mos (3.7, NR) PR: 2.1 mos (1.0, 5.0) Time from first response (months) 15 Median follow-up 15.4m ORR 82% CR 54% Ongoing CR 42% CRS grade 3: 12% NT grade 3: 31% Median follow-up 6 mo ORR 53% CR 40% Ongoing CR 37% 74% RFS CRS grade 3: 23% NT grade 3: 12% Median follow-up 6 mo ORR 78% CR 54% Ongoing CR 44% CRS grade 3: 1% Full cohort NT grade 3: 13% ASH 2017; ASCO 2018

26 Approved on 10/18/2017 Approved on 5/1/2018 Indication Adult pts with rel/ref BCL after 2 lines, tfl, High grade B cell lymphoma primary mediastinal B cell lymphoma Indication Adult pts with rel/ref LBCL after 2 lines, tfl, High grade B cell lymphoma Price $373,000 per product Price $373,000 per product

27 A DLBCL patient on ZUMA-1 Pre CAR T treatment Feb 11, 2016 Post CAR T treatment Mar 31, 2016

28 CAR T in MM Targets: BCMA, CD19, SLAMF7 (CS1), NKG2D, CD56, CD70, CD38, CD138, CD44v6, IgKLC

29 TABLE 1. Selected CAR T-Cell Targets and Trials for Myeloma* COH: CS-1 CAR T trial just opened 3/2019. Published in: Adam D. Cohen; American Society of Clinical Oncology Educational Book 38e6-e15. Copyright 2018 American Society of Clinical Oncology

30 CAR T for Acute Myeloid Leukemia High risk for on-target, off leukemic effects CD123AR T Trials for R/R AML costim Gene delivery T cell source dose Status NCT COH CD28 lentivirus allo or auto M active NCT Penn 4-1BB mrna electroporation auto 4M/kg x 4 4M/kg x 6 Terminated NCT Cellectis 4-1BB lentivirus universal donor (UCART) 6.25x 10 4 /kg to 6.25 x10 6 /kg Opened On Hold Reopened Several trials opened in China

31 A Phase 1 First-in-Human Clinical Trial Using CD123 CAR T for Patients with Rel/Ref AML and BPDCN (PI: Budde, COH) Manufacturi ng of Cell product ~ 2 weeks Manufacturing time: 13 to 16 day process Turnaround time ~ 21 days Success rate: 93% (13/14 products) AML cohort: 6 patients treated BPDCN cohort: 1 patient treated Budde et al. ASH 2017

32 UPN 167: Recovery of Hematopoiesis ANC >500 on d 22 Bone marrow examination last RBC transfusion on d17 last PLT transfusion on d10

33 Approaches to Improve CAR T-cell Therapy More potent gene editing combination Dual/bispecific More regulated conditional switch Shorter delivery time Production time off the shelf (ipsc, NK-CAR, UCAR) Jackson, H. J. et al. (2016) Driving CAR T-cells forward Nat. Rev. Clin. Oncol. doi: /nrclinonc

34 Presentation Objectives Introduction of tumor immunology Overview of CAR T mechanism of action Current status of relevant CAR T trials CAR T Toxicity CAR T Program at COH

35 CAR T cell therapy: toxicity overview Target specific toxicities Lymphodepletion chemo related events CAR T cell related/emergent events Short term & long term

36 CAR T cell therapy: toxicity overview Target specific toxicities: on target off tumor effect The immune-mediated recognition of TAAs in normal tissues Target tumor off tumor concerns outcome CD19 B cell malignancies Normal B cells B cell aplasia CD33 AML Normal HSC Myeloablation Her2 (4D5) Colon Cancer lung epithelium Serious Death reported CEA Colorectal Cancer Colonic epithelium carboxyanhydras e-ix Renal cell carcinoma bile duct epithelium Severe Colitis cholestasis Morgan et al, Mol Ther, 18 (2010; Parkhurst et al. Mol. Therapy 2011; Lamers et al. Mol Ther, 21 (2013)

37 CAR T cell therapy: toxicity overview Target specific toxicities On target off tumor event Lymphodepletion chemo related events Myelosuppression nausea/vomiting Fever (fludarabine) Hemorrhagic cystitis (cyclophspohamide) tumor lysis syndrome organ dysfunction (i.e. cardiac, liver, renal, pulmonary) Immunosuppression Neurotoxicity (fludarabine, cyclophosphamide) Hypersensitivities CAR T cell related/emergent events

38 CAR T Cell Therapy: toxicity overview Target specific toxicities Lymphodepletion chemo related events CAR T cell related/emergent events Short term ( within 8 weeks) Cytokine release syndrome Neurotoxicity Macrophage activation syndrome (HLH/MAS) Infection Coagulopathy Cardiac toxicity Long term (>8 weeks) prolonged cytopenia Infection Secondary malignancy due to insertional mutagenesis Deconditioning

39 Cytokine Release Syndrome A common toxicity to CAR T cell therapy Not restricted to a particular antigen constellation of inflammatory symptoms from cytokine elevations. Association with T cell activation and proliferation Association with clinical benefit and toxicity in some CAR T product treatment. Temp: fever Cytokine level: IFN-γ, IL-6 Tumor burden CAR T expansion Jennifer N. Brudno, and James N. Kochenderfer Blood 2016;127:

40 CRS Management Goal: reduce serious CRS symptoms and signs, and prevent life-threatening complications Tocilizumab is the first choice for CRS mitigation humanized IgG1 anti-hil-6r mab, FDA approved in 8/ mg/kg iv over 1 hour x1, can repeat in 24 to 48 hours Would prophylactic tocilizumab increase safety without compromising efficacy? (likely not) What to do in tocilizumab refractory cases (no improvement after 2 doses of Tocilizumab)? - Steroids, Methylpred 2mg/kg/d or Dex 0.5mg/kg max 10mg/dose, quick taper. - Siltuximab, Etenercept, Roxilitinib, ibrutinib

41 Case: 47 yo F with AML, 4 prior lines of treatment and prior MRD AlloSCT (sister), Tocilizumab: D5, D6, D7; Dex:D6, D8 200M CAR T cell infusion D0 D5 D6 hypoxia, intubation, BAL-> adenovirus D1 D8 D10 extubation Ferritin (ng/ml)

42 Neurologic Toxicity Presentation: headaches, encephalopathy, delirium, aphasia, ataxia, confusion, hallucinations, headaches, tremor, seizure, obtundation. Last days to months Can occur independently from CRS or presence of CAR T cells in CSF. No correlation with CNS disease Can result in patient death ROCKET trial: 5 cerebral edema FHCRC: 1 irreversible neurotoxicity (d10 to d122) MSKCC: 1 seizure ZUMA-1: 1 cerebral edema

43 Neurologic Toxicity D0 D3 D6 D14 D21 D28

44 Neurologic Toxicity Management Prophylaxis is common but efficacy is unknown Workup generally includes neurology consult, blood and cerebrospinal fluid analyses, neuro-imaging, and electroencephalography Gold standard of treatment is steroids Cytokine blockade can be given but its unknown if these are effective or detrimental (be cautious) Intervention is based on neurologic toxicity severity

45 CRS and Neurotoxicity Grading Pre-existing CRS grading systems CTCAE 4.03; MSKCC criteria; Penn criteria; Lee criteria; CARTOX criteria; CTCAE 5.0 Pre-existing neurotoxicity grading systems CTCAE 4.03; CARTOX; CTCAE 5.0 New CRS & Neurotoxicity grading system

46 ASBMT CRS Consensus Grading

47 ICANS Grading ICANS: Immune effector Cell Associated Neurotoxicity Syndrome Immune Effector Cell- Associated Encephalopathy(ICE) score

48 Presentation Objectives Overview of CAR T cell toxicities Management of CAR T cell related toxicities Safety data from relevant clinical trials Clinical considerations

49 Adverse ELIANA Events (Tisagenlecleucel of Special Interest in within ALL): 8 Weeks Safety after Infusion, Regardless of Relationship to ICU admission 47% (35 of 75) with median stay of 7 days (range, 1-34) 10% mechanical ventilation 25% high dose vasopressors SL Maude et al. N Engl J Med 2018;378:

50 CAR T cell therapy is not benign ZUMA-1 KTE-019 JULIET CTL-019 TRANSCEND JCAR17 core group CRS grade 3 12% 23% 0% (n=29) Grading Median TTO Lee s 2d (1-12) Penn scale 3d (1-9) NT grade 3 31% 12% 7% Grading Median TTO CTCAE4.03 5d (1-17) CTCAE4.03 n/a Lee s 5d (1-14) CTCAE d (3-23) Outpatient 0% 26% 20% (4/20) ASH 2017

51 Infection : Dancing with the Devil Study N ZUMA JULIET & ELIANA 174 FHCRC 133 Dx Incidence MTTO Bacterial viral Fungal Severe infection B-NHL 38% 6 days 9% 4% NA 23% ( grade 3) B-NHL ALL NHL & ALL 55% n/a n/a n/a n/a 33% ( grade 3) 3% fatal (2 ALL, 1 DLBCL) 23% 6 days 17% 11% 5% 4% fatal Don t assume fever is due to CRS Could be bacterial, viral, or fungal infection Could be fatal ID prophylaxis is recommended - lack of standard approach - autohct guideline - anti-fungal prophylaxis in pts with prior HCT Hill et al.blood 2017 Budde and Zaia. Blood

52 Prolonged Cytopenia Incidence: grade 3 & above TRIALS Neutropenia ( grade 3) Thrombocytopenia (( grade 3) ELIANA 40% (>= 4 weeks) 17% (>= 8 weeks) 27% (>= 4 weeks) 12% (>= 8 weeks) JULIET 25% (>= 4 weeks) 40% (>= 4 weeks) ZUMA-1 15% (beyond day 30) 18% (beyond day 30) Fried et al. BBMT 2019

53 Patient Eligibility Considerations H/o AI, CVA, seizure Performance status Organ function Might at increased risks for toxicity Excluded in trials ECOG 0-1 physically able to deal with CAR T toxicities Prior Allogeneic HCT? No impact on efficacy Might increase infection risk (esp. aspergillus and viral infection)

54 Presentation Objectives Introduction of tumor immunology Overview of CAR T mechanism of action Current status of relevant CAR T trials CAR T Toxicity CAR T Program at COH

55 COH CAR T Program COH Clinical Trial COH Manufactured Product COH Clinical Trial Partner Manufactured Product COH Clinical Care with FDA Approved Product Total CAR T patients treated from 1999 to ~ 20 CAR T clinical trials (Lymphoma, MM, AML, ALL, CLL, GBM, prostate ca, breast cancer with brain mets) More to come 55

56 Clinical Cellular Immunotherapy Committee (CCIC) Patient /MD Referral NPS CT.GOV CRC MD/MD CIM PRS Intake MD Triage MD/Appt CCIC FDA Approved Treatment Clinical Trial 56

57 Conclusion 57

58 Questions??????? Elizabeth Budde, MD, PhD Tel: