Title: Chimeric Antigen Receptor T-Cell Therapy: Presenters: Promises and Challenges Date: Elizabeth Budde, MD, PhD Department of Hematology & HCT T Cell Therapeutics Research Laboratory Beckman Research Institute City of Hope National Medical Center Duarte, CA
DISCLOSURES Advisory board for Precision Biosciences, Promab Biotechnologies Research supports from Mustang Therapeutics, Amgen Inc, Merck & Co. Speaker Bureau for Kite Pharma, AstraZeneca, Gilead Inc.
Presentation Objectives Overview of CAR T mechanism of action Current status of relevant CAR T trials Toxicity management Patient screening and consultation CAR T therapy optimization
2017 A Year of CAR T Cell Breakthroughs FDA Approval for CD19-CAR T Therapy KYMRIAH August 30, 2017 Novartis Receives Approval For Acute Lymphoblastic Leukemia $475,000/cell product YESCARTA October 18, 2017 Kite/Gilead Receives Approval For Diffuse Large B Cell Lymphoma $373,000/cell product
Clinicaltrials.gov assessed on 3/15/2018 EMBO Molecular Medicine Volume 9, Issue 9, pages 1183-1197, 1 AUG 2017 Clinical Development of CAR T Cell Trials In 2018 (n=501) US: 194 China: 177 Europe: 82
Chapter 1: The Tool CART-Cell Therapy: Mechanism of Action
constitutive constitutive co-stimulation co-stimulation is provided is by provided the T cells by the between T cells the between scfv and the scfv cell and membrane, the cell membrane, which both which lifts both lifts themselves themselves 47. The development 47. The development of new combinations of new combinations the antigen-binding the antigen-binding domain away domain from away the membrane from the membrane of signalling of moieties signalling continues moieties with continues a view with to enhancing T cell function ing T cell 48. function However, 48. the However, benefits TCRs the of benefits includ-v.s. of essary to CARs bind essary antigen. to bind Members antigen. of Members the immunoglobulin of the immunoglobulin a view to enhanc- and provides and flexibility provides for flexibility the CAR for to the reorientate CAR to reorientate if nec- if necing multiple ing co-stimulatory multiple co-stimulatory domains into domains CARs into are CARs superfamily are superfamily excel in terms excel of flexibility, in terms of and flexibility, hinge regions and hinge regions not always not clear always and other clear factors and other such factors as the such target as the from target superfamily from superfamily members such members as CD8, such CD28 as CD8, and IgG CD28 and IgG antigen, the antigen, method the of method T cell production of T cell production and the and are often the used. are Assessments often used. Assessments of the relative of capacity the relative for capacity the for the TCR-mediated IR CAR-mediated IR a a Tumour cell b Tumour cell b Tumour cell Tumour cell T cell T cell T cell either T cell either naturally naturally occurring or occurring or from a transgenic from a transgenic mouse mouse TCR β2 MHCI Tumour peptide β TCR α β T cell γ ε ε δ γζ ε ε δ ζ CD3 complex CD3 complex Adapted from Kershaw et al, Nature Reviews Cancer 2013 β2 Extra and intracellular antigens α- β α- β Peptide processing required Restricted by patient s HLA Kd =10-6 to 10-4 M No ligand on HLA-negative tumor Non-immunogenic α b b MHCI Tumour peptide B cell antibody fromantibody from B cells B cells T cell B cell CD8 CD3ζ or FcεRIγ Tumour antigen Tumour antigen V H V L CD8 CD3ζ or FcεRIγ scfv T cell Direct arecognition a of extracellular Nature Reviews Cancer α- β α- β γ- δ- ε- γ- ζ δ- ε- ζ ζ V H V L ζ scfv T cell tumor-associated antigens Peptide processing not required HLA-independent, Kd = 10-9 to 10-6 M Immunogenicity might be a problem
Design & Engineering of CARs Costim 1 Costim 1 Signal 2 Signal 2 Signal 1 Costim 2 Eshhar 1993 Signal 1 Signal 1 Amelia E Firor; Alexander Jares; Yupo Ma; Exp Biol Med (Maywood) 240, 1087-1098. with Modification
Not All CD19CARs Are Created Equal MSKCC JCAR-015 NCI KTE19 COH UPENN CTL-019 FHCRC/SCH JCAR017 CD28 CD28 CD28 4-1BB 4-1BB ζ ζ ζ ζ ζ ζ ζ ζ ζ ζ
The Common Process of CAR T Therapy cell engineering expansion and processing T cell activation CAR delivery PBMC collection lymphodepletion Variables: - the starting population: VST, subset enrichment/depletion, - manufacturing process activation method, cytokines, expansion time, - infused products: bulk or defined population,
Chapter 2: The Speed and Accidents Efficacy and Safety of Current Relevant CAR T-Cell Therapies
NHL ZUMA-1 (NCT02348216): Multicenter Phase II Trial of Axi-cel (sponsor: KITE Pharma/Gilead) JULIET (NCT02445248): Multicenter Phase II trial of Tisagenlecleucel (sponsor: Novartis) TRANSCEND NHL 001 (NCT02631044): Multicenter Phase I/II trial of Liso-cel (Sponsor: Juno Therapeutics/Celgene)
ZUMA-1 N = 111 NHL:CD19CARs JULIET N = 149 Costim domain CD28 4-1BB 4-1BB TRANSCEND N = 140 T cell type PBMC PBMC CD4: CD8 (1:1) 11 non-comforming ALC 100 /ul 300 /ul No requirement Cell dose 1-2M/kg 100-500M 100M (DL2S) Product success 99% 94% 98% (126/128) Product not given 10 43 20 Patients Ref DLBCL, tfl, PMBCL R/R DLBCL tfl R/R DLBCL NOS tfl, FLgr3b high grade BCL Prior auto allowed allowed allowed CNS no no 2 nd CNS, allowed ECOG PS 0-1 0-1 0-1
NHL: Potential Best in Profile CR + durability+ Safety ZUMA-1 KTE-019 JULIET CTL-019 Lymphodepletion Flu/Cy Flu/Cy, Benda Flu/Cy TRANSCEND JCAR17 core group Best CR 54% (n=101) 40% (n = 81) 63% (n = 27) CR at 3 mos months 52% 32% 68% CR at 6 mos 36% 30% 50% Transplant 2 -> allohct 0% responders n/a 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) CTCAE4.03 10d (3-23) Outpatient 0% 26% 20% (4/20) ASH 2017
Probability of Relapse Free (%) % Survival ZUMA-1 Duration of Response JULIET TRANSCEND (CORE) 100 80 60 40 20 Median DoR: NR 0 0 1 2 3 6 9 12 Pts at Mos From Onset of Response Risk, n 43 18 9 2 0 100 80 60 4 0 20 0 At Risk CR: NR (5.0, NR) All: 9.2 mos (3.7, NR) PR: 2.1 mos (1.0, 5.0) 0 3 6 9 12 15 Time from first response (months) CR 36 22 12 7 1 1 PR 16 2 0 All 52 24 12 7 1 1 -Median PFS 5.9 Mo -most pts with CR at Mo 6 remained in CR - 74% RFS at Mo 6 -No responders moved to HCT - Most pts achieving CR at Mo 3 remained in CR 80% CR at Mo 3 remain in CR at Mo 6 92% CR at Mo 6 remains in CR at a longer term ASH 2017
Other CAR T for NHL CAR No. of Sites Malignancy CD22 CAR at least 10 sites B-NHL, ALL CD30 CAR at least 7 sites HL, ALCL IgK CAR 1 (Baylor) B-NHL CD20 CAR at least 10 sites B-NHL CD7 CAR 1 TCL and T-ALL CD5 CAR 1 (Baylor) TCL CD4 CAR Being planned TCL CCR4 CAR Being planned TCL
CAR T Therapy for Lymphoma at COH Therapies in the following diseases DLBCL, tfl, PMBCL (3 sponsored trials, 1 COH trial, Yescarta) MCL (1 active sponsored trial, 1 COH trial being planned) CLL (1 active sponsored trial) CAR T Physician Team Stephen Forman Elizabeth Budde Alex Herrera Leslie Popplewell Tanya Siddiqi Jasmine Zain And others
Acute Lymphoblastic Leukemia Indication patients up to 25 years of age with ALL that is refractory or in second or later relapse.
Primary endpoint: ELIANA: Study Design International, multicenter, open-label, single-arm phase 2 study Pts (N =107) aged 3-21 yrs 5% BM lymphoblasts; no isolated extramedullary disease, no prior CD19-directed therapy, no prior gene therapy ORR (CR + CRi) within 3 mos; 4-wk maintenance of remission required (the null hypothesis, ORR 20%) Secondary endpoints MRD status, DoR, OS, cellular kinetics, safety Maude, et al. NEJM. 2018;378: 439-48. Fludarabine 30 mg/m²/d IV QD x 4 Cyclophosphamide 500 mg/m²/d IV x 2 CTL019 2.0-5.0 x 10 6 /kg IV 50 kg 1.0-2.5 x 10 8 IV if > 50 kg (n = 62 ) 17 pts discontinued before infusion: deaths (n = 7), manufacturing failures (n = 7), AEs (n = 3).
ELIANA: Baseline Characteristics at Enrollment Characteristic CTL019 (N = 107) Median age, yrs (range) 11 (3-23) Male, % 55 Prior allohct, n (%) 46 (61%) Median previous lines of therapy, n (range) 3 (1-8) Median marrow blast, % 74% (5% to 99%) Current disease status, % Primary refractory Chemotherapy refractory Relapsed 10 11 79 Maude, et al. NEJM. 2018;378: 439-48.
Adverse Events of Special Interest within 8 Weeks after Infusion, Regardless of Relationship to Tisagenlecleucel.* 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;378:439-448.
CD19CAR T Induced High CR Rates in B-ALL Trials Study N (txd) Age,yrs HSCT T cell Dose Lympho depletion CR% MRD-% Survival FHCRC 30 40 (20-73) 37% 0.2-20M/kg Cy, Flu/Cy, Cy/E 93(F) -Flu/Cy group superior 86 SCH 45 (45) 12 (1-27) 62% 0.5-10M/kg Cy/Flu NA EFS 51% at 12 mos 89 CHOP 59 12 (1.7-24) 66% 1M- 20M/kg Any 93 88(F) RFS 55% at 12 mos OS 79% NCIped 55 (52) 13 (4-30) 19% 1-3M/kg Cy, Cy/Flu 62 LFS 56% for MRD-CR* 55 median f/u -2.2 yrs MSKCC 51(50) ELIANA 107(75) 40 (22-74) 35% 11 (3-23) 56% 1-3M/kg Cy, Cy/Flu 82 DFS 27% MRD-CR # 61 12 mos 2-5M/kg or 100-250M if >50kg Cy/Flu 81 77 N: number at enrollment; Txd: treated with CAR T; F: flow cytometry RFS 59% at 12 mos OS 76% at 12 mos
Duration of Remission, Event-free Survival, and Overall Survival. ELIANA: DOR, OS and EFS Median follow-up: 13.1 months DOR: not reached (n = 61) 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;378:439-448.
A Phase 1 Trial of CD22CAR T Cells for Pediatric and Young Adults with Rel/Ref CD22+ B Cell Malignancies (NCT02315612) Inclusion/Exclusion Criteria Pts aged 1-30 yrs 2 lines of prior therapies 100 days if prior allohct 30 days from prior CD19CAR with < 5% CAR T by flow CNS3 not allowed Fludarabine 25 mg/m²/d IV QD x 3 Cyclophosphamide 900 mg/m²/d IV x 1 N = 21 DL1: 3 x 10 5 /kg DL2: 1 x 10 6 /kg DL3: 3 x 10 6 /kg 23 patients enrolled 1 manufacturing failure 1 DLBCL Patient Characteristics median age 19 (7-30) All had at least one allohct; 17 had prior CD19 directed therapy; 15 CD19CAR T 10 CD19dim or CD19neg blasts Median marrow blast%: 70.5% No active CNS involvement Maude, et al. NEJM. 2018;378: 439-48.
NCI-Ped CD22CAR Trial (NCT02315612) Toxicity - most common AE is CRS in 16 pts, 9 grade 1 and 7 grade 2. - Neurotoxicity: transient and reversible. No seizure - 1 grade 5 death due to gram negative sepsis - B cell aplasia in all CR patients Response - CR rate 73% in DL2 + DL3 (11/15 patients) - Most are MRD-ve (9/12) - Regardless prior CD19 CAR treatment - Correlates with CAR T expansion & B cell aplasia - DOR is 6 months Nature Medicine volume 24, pages 20 28 (2018)
NCI-ped CD22CAR trial (NCT02315612) Relapse - 8/12 relapsed at 1.5-12 months - diminished CD22 Ag density in 7 of 8 relapses no mutation identified Nature Medicine volume 24, pages 20 28 (2018)
Trials using CAR T Cells targeting both CD19 & CD22 Duotargeting approach T cells transduced with CD19CAR and CD22CAR at Seattle Children s (PLAT-05 trial) Sequential approach CD22CAR T (day 1)+ CD19CAR T (day 14/15) at Tongji Hospital, China Bivalent approach CD19/CD22 CAR T at Stanford and NCI
CAR T for Acute Myeloid Leukemia Targets: CD123, CD33, NKG2D - Ideal target: only on leukemic stem cells No targets with a profile as favorable as CD19 or BCMA - Clonal heterogeneicity of LSCs. - Similarity of LSC with normal stem cells. - Lack of antigens with lineage specific expression - High risk for on-target, off tumor effects
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
UPN 167: ref AML, 47 F, 4 prior lines of treatment and prior MRD AlloSCT (sister), 200M Donor-CAR T cell infusion D0 D1 D5 D8 Tocilizumab: D5, D6, D7 Dex:D6, D8 IVIG: D7 D6 hypoxia, intubation, BAL-> adenovirus D10 extubation Ferritin (ng/ml) 7000 6000 5000 4000 3000 2000 1000 0-10 0 10 20 30
UPN 167: Recovery of Hematopoiesis ANC >500 on d 22 Bone marrow examination last RBC transfusion on d17 last PLT transfusion on d10
BPDCN Cohort: UPN 203 Pretreatment 72 y.o. man with BPDCN with disease progression after 5 cycles of SL-401 - Lymphodepletion D -5 to -3 Flu 25mg/m2/d Cy 300 mg/m2/d Pre D14 H&E CD123 CD4 CD56 CD3 Day 6 - Autologous CD123 CAR T D0, 100 x 10 6 D28 D14: skin biopsy -> NED D28: skin biopsy -> NED D28: bone marrow biopsy-> NED Budde et al. ASH 2017
CAR T Therapy for Acute Leukemia at COH Active Therapies for the following diseases ALL AML BPDCN CAR T Physician Team Stephen Forman Elizabeth Budde Samer Khaled Anthony Stein Guido Marcucci Joseph Rosenthal (ped) Weili Sun (ped) Ana Pawlowsky (ped) And others
CAR T in MM Targets: BCMA, CD19, SLAMF7 (CS1), NKG2D, CD56, CD70, CD38, CD138, CD44v6, IgKLC Study CAR/c ostim Dose + lymphodepletion Response AEs UPENN N=24 BCMA 4-1BB C1:100-500M C2:10-50M+Cy C3: 100-500M+Cy ORR: 46% ORR in 100M: 53% gr3 CRS: 33% gr3 NT: 13% 2 DLT: gr 4 PRES 1 Gr4 hemorrhage and gr3 Cardiomyopathy CRB-401 N=21 BCMA 4-BB 50M 150M 450M 800M Flu/Cy ORR: 94% CR: 56% No DLT gr3 CRS: 10% NT: 0% Cohen AD, et al. ASH 2017. Abstract 505; Berdeja JG et al. ASH 2017. Abstract 740.
phase I trial of bb2121 anti-bcma CAR T- cell therapy in patients with R/R MM bb2121: 2nd-Generation Autologous T-cells transduced with lentiviral vector Anti-BCMA scfv VH α VL VL α VH R/R MM 3 prior lines of therapy or double-refractory MM >50% BCMA+ in dose escalation cohort Lymphodepletion: fludarabine 30 mg/m 2 /d x 3 cyclophosphamide 300 mg/m 2 /d x 3 Co-stim domain: 4-1BB T cell activation domain: CD3ζ 50, 150, 450, or 800 x 10 6 bb2121 CAR T-cells Berdeja JG, et al. ASH 2017. Abstract 740.
Pts (%) CRB-401: Depth of Response to bb2121 Over Time Responses continued to deepen in pts receiving 150-800 x 10 6 CAR T-cells over median follow-up of 40 wks Outcome in Cohort 150 10 6 CAR+ T-Cells Median time to first response, mos (range) Median time to best response, mos (range) Median time to CR, mos (range) Median duration of response, mos (range) Median PFS, mos (range) Pts (N = 18) 1.02 (0.5-3.0) 3.74 (0.5-13.7) 3.84 (0.5-13.7) NR NR PFS at 6 mos, % 81 PFS at 9 mos, % 71 ORR in Cohorts 150 10 6 CAR+ T-Cells ORR: 100% ORR: 94% 100 80 60 40 20 0 27 47 27 04 MAY 2017 (N=15) 56 33 6 02 OCT 2017 (N=18) Progression independent of tumor burden, bb2121 dose, CRS, bb2121 persistence (N = 4) CR 27% CR 56% VGPR 74% Berdeja JG et al. ASH 2017. Abstract 740. CR/sC R VGPR PR VGPR 89%
CRB-401: Conclusions Investigators conclude that bb2121 confers deep, durable responses at active doses (150-800 x 10 6 CAR T cells) in heavily pretreated pts with R/R MM ORR: 94%, VGPR: 89%, CR: 56% 90% of evaluable pts MRD negative at 40 wks of follow-up PD in 4 pts; 3 of 3 evaluable patients remain BCMA positive at progression Safety profile of bb2121 manageable up to 800 x 10 6 CAR T-cell dose 2 cases of grade 3 CRS during dose escalation; resolved within 24 hours 1 case of delayed, reversible grade 4 neurotoxicity during dose expansion associated with TLS and CRS in patient with highest tumor burden Global pivotal phase II KarMMa trial evaluating bb2121 at doses of 150-300 x 10 6 CAR T-cells open for enrollment (NCT03361748) Berdeja JG et al. ASH 2017. Abstract 740.
CAR T Therapy for MM at COH Targets: BCMA, CS-1 (coming) CAR T Physician Team Myo Htut Michael Rosenzweig And others
Chapter 3. CAR Repair Toxicity Management
CAR T Cell Therapy: Complications Commonly reported important adverse events On target off tumor effects, i.e. B cell aplasia (CD19CAR) Lymphodepletion chemo-related toxicity Tumor lysis syndrome Macrophage activation syndrome (HLH/MAS) Coagulopathy Cytokine release syndrome Neurotoxicity Infection
Cytokine Release Syndrome A constellation of inflammatory symptoms from cytokine elevations. Association with T cell activation and proliferation Association with clinical benefit and toxicity Jennifer N. Brudno, and James N. Kochenderfer Blood 2016;127:3321-3330
Bone Marrow Blasts, % IL-6 (pg/ml) pg/ml 1 100 10000 IFNg (pg/ml) pg/ml 5 50 500 5000 Correlates of severe cytokine release syndrome (CRS) Temperature IL-6 IL 6 p<0.001 IFN-γ IFNg CR o NR p<0.001 No Severe CRS yes No Severe CRS Yes Temp Cytokine level: IFN-γ, IL-6 Tumor burden CAR T expansion M. L. Davila et al., Sci Transl Med 2014;6:224ra25 Maude SL et al. N Engl J Med 2014;371:1507-1517 1 0 80 0 6 0 4 0 2 0 0 N o Severe CRS P <.002 Ye s
CRS Grading Grade 1 2 3 4 Clinical Signs and Symptoms Fever ± symptoms such as rigors, malaise, fatigue, anorexia, myalgias, arthalgias, nausea, vomiting, headache Hypotension responding to fluid resuscitation or one low dose pressor, or Hypoxia responding to 40% FiO2, or Grade 3 transaminitis, other grade 2 organ toxicity according to CTCAE v4.03 Hypotension requiring >3 hours of two pressors, or one pressor at high dose, or Hypoxia requiring >40% FiO2, or Grade 4 transaminitis, other grade 3 organ toxicity according to CTCAE v4.03 Requirement of mechanical ventilator support, or Grade 4 organ toxicity excluding grade 4 transaminitis 5 Death Lee DW et al. Blood 2014
CRS Management Goal: reduce serious CRS symptoms and signs, and prevent lifethreatening complications Tocilizumab is the first choice for CRS mitigation (selective grade 2, all grade 3 and 4 cases). humanized IgG1 anti-hil-6r mab, FDA approved in 8/2017 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
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 Neurologic Toxicity Presentation: headache, 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
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
Infection: Dancing with the devil Incidence: 23% FHCRC trials; 27% JULIET trial; 38% ZUMA-1; 41% ELIANA Pretreatment factors - impaired immune function - tissue damage from prior chemoregimens Treatment factors - cytopenia from lypmphodepletion, - immunosuppressive drugs such as toci/dex - ICU stay - hypogammaglobulinemia Other risk factors - ALL patients - >= 4 lines of prior therapies - Higher CAR dose - Severe CRS Hill et al.blood 2017
Infection: Dancing with the devil FHCRC cohort, N=133 Incidence: 23% Median Time to onset: 6 Bacterial 17% (N =22) Viral 11% (N = 11) Fungal 5% (N = 6) Fatal infection 4% ( n=5) ZUMA-1 cohort, N=108 Incidence: 38% Median Time to onset: 6 Bacterial 9% Viral 4% Unspecified 16% Severe infection 23% ID prophylaxis is recommended - lack of standard approach - autohct guideline - anti-fungal prophylaxis in pts with prior HCT Hill et al.blood 2017; Yescarta.com Budde and Zaia, Blood 2017
Chapter 4. CAR Service Patient Consultation
Patient Eligibility Considerations Timing of referral H/o AI, CVA, seizure Performance status Organ function Early referral is strongly encouraged - Product ready time 2-4 weeks unless off the shelf - Discussion of treatment strategies Might at increased risks for toxicity Excluded in trials ECOG 0-1 physically able to deal with CAR T toxicities
Patient Eligibility Considerations Requirement of ALC Prior CD19 treatment Prior Allogeneic HCT? Prior CAR T cut off of 100 ALC/ul in ZUMA-1 300 ALC/ul in JULIET trial No impact on CD19CAR activity as long as tumor cells remain CD19+ No impact on efficacy Might increase infection risk (esp. aspergillus and viral infection) Might still respond to a different CAR T treatment CD19CAR -> CD22CAR or CTL119
What Is the Role of AlloHSCT if CR after CAR T Cell Therapy? - HSCT consolidation after CAR correlates with decreased relapsed rate in some studies but not others. NCI-ped B-ALL CD19CAR study Post CAR Allo Yes, N =21 Relapse (N, %) Transplant related Mortality Median LFS 2, 9% 5 (24%) Not reached 65% at 18 mos No, N=7 6, 86% N/A 4.9 months 14% at 9.8 mos OS MSKCC ALL trial, subsequent allohct did not improve OS (p = 0.8). Park et al. JCO 2017)
Chapter 5. CAR Improvement
Approaches to Improve CAR T-cell Therapy More potent gene editing combination More regulated conditional switch Shorter delivery time Production time off the shelf (ips, NK- CAR, UCAR) Jackson, H. J. et al. (2016) Driving CAR T-cells forward Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2016.36
Off-The-Shelf UCART Cost: $4000 to 6000/treatment
UCART Clinical Trials Study CAR/c ostim Dose lymphodepletion Response AEs PALL N=5 CD19 4-1BB 20x10 6 or 1.1-2.2x10 6 /kg FC or FCA CRi: 100% CRS: 1gr1, 3gr2, 1gr3 GVH: 2gr1-skin NT: 0 3 died (2 PD, 1 HCT complication) CALM N=6 CD19 4-BB 6x10 6 FC or FCA CRi: 4/6 PD:1 CRS: 1 gr1, 4 gr2, 1 gr4 NT:1 gr1; GVHD: 1 gr1-skin 1 died on d15 due to gr4crs and sepsis AML N=1 CD123 4-1BB 6.25x10 5 /kg FC n/a gr3 CRS, gr4cls BPDCN N=1 CD123 4-1BB 6.25x10 5 /kg FC Not evaluable gr5 CRS, gr4cls gr3 lung infection Benjamin et al ASH 2017 Benjamin ASH 2017; Qasim ASH 2017; cellectis.com
Future Directions Bring CAR T therapy earlier in the disease treatment course - First salvage - Upfront? Can CAR T replace autologous transplant? ZUMA-7: phase 3 randomized trial, chemo-based vs CD19CAR Roles of CAR T as Maintenance - High risk patients DH-DLBCL in CR1 high risk ALL in CR1 with no donor Other indications - Follicular lymphoma, MCL, etc.
Conclusions Major advances have been made in the CAR T therapy. Understanding the biology and resistance mechanism is important for the design of the future versions of CARs. More non-cd19 targets are emergent. There is urgent need to design more potent, and safer CARs for patients. CAR T therapy should be given only in FACT accredited transplant centers for the time being.
Questions??????? Elizabeth Budde, MD, PhD Tel: 626-218-0612 Email: ebudde@coh.org
Quiz 1. Which of the following B-ALL patients is the best candidate to receive CD19CAR T therapy? A. 70 yo man with newly diagnosed CD19+ B-ALL, and COPD on 2L O2 at baseline, ECOG 3 B. 40 yo woman with refractory B-ALL, with CD19-ve disease after blinatumumab, ECOG 0, no comorbidities C. 30 yo man with newly diagnosed B-ALL, ECOG 0, no comorbidities D. 35 yo woman with refractory CD19+ B-ALL following a prior allohct, ECOG 1, no cormorbidities Answer: D
Quiz 2. Which of the following intervention is appropriate during CD19 CAR T therapy? A. Daily dexamethasone up to 4 mg per day B. Steroids should only be used in a patient with grade 4 encephalopathy if tocilizumab does not work. C. Patients can be followed on a weekly basis once they receive CAR T infusion. D. Tocilizumab is indicated if a patient develops persistent hypotension refractory to iv fluid. Answer: D