Chimeric Antigen Receptor Engineered T-Cell Therapy Presenters: Overview and Clinical Management Date:
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1 Title: Chimeric Antigen Receptor Engineered T-Cell Therapy Presenters: Overview and Clinical Management Date: L. Elizabeth Budde, MD, PhD Department of Hematology & HCT T cell Therapeutics Research Laboratory City of Hope National Medical Center/Beckman Research Institute
2 DISCLOSURES Conflict of Interest: none. Discussion of off-label drug use: Tocilizumab.
3 Chimeric Antigen Receptor (CAR) Ab TCR complex Eshhar, 1993 First Generation TCR CD3z signaling Signal 1 Second/Third Generation Costimulatory signaling CD28, 41BB, OX40 Signal 2 Chekmasova & Brentjens; Discovery Today; 2010
4 Advantages of CARs TCR tumor CAR highly specific: targets could be TAA, ligand, etc HLA-independent target recognition Living drug: in vivo expansion and multiple rounds of killing Travel to places that antibodies can t Endogenous The potential to generate long-term antitumor immunity Minimal risks of GVHD
5 CAR T Cell Therapy lymphodepletion
6 CD19CAR The first CAR with demonstrated clinical benefit Over Blanc et al. Clin Cancer Res :6448
7 Not all CD19CARs Are Created Equal CD19-28 CAR (MSKCC) CD19-28 CAR (NCI) CD19-28 CAR (COH) CD19-BB CAR (UPENN) CD19-BB CAR (FHCRC/SCH) CD28 CD28 CD28 4-1BB 4-1BB ζ ζ ζ ζ ζ ζ ζ ζ ζ ζ
8 CAR T Cell Therapy: Efficacy
9 COH Case Presentation CS: 37 yo F with refractory Ph+ ALL Initial Dx July 2008: Mutiple lines of treatments: hypercvad+ Gleevec Dasatinib Double cord blood transplant (TBI+Cy) in 1/2009 Campath and clofarabine + clofarabine Double cord blood transplant (Flu/Mel) in 7/2010 Ponatinib in 5/2013 Blinatumomab x 2 11/2014 to 2/2015 -> no response
10 COH Case Presentation 2/2015,Leukopharesis on CD19CAR T protocol # /16/3015: BM -70% blasts with + BCR-ABL transcripts CD34
11 D-3 & -4, Cy 1.5mg/m 2 x 2 D0: CAR T infusion 200M Tcm MRD ve CR!
12 COH Case Presentation D14 marrow: (-) blasts D28 marrow: (-) abn blasts; (-) BCR-ABL transcript 100% donor contribution Pre-treatment Post-treatment Response to CD19 CAR treatment MRD ve CR!
13 CD19CAR T : ALL Trials Study N CR CR (MRD -) Relapse OS Months 1 FHCRC 21-91% - - 2,*U Penn ped 59 93% 82% 34% at 6 mo 45% at 12 mo 79% at 12 mo 3 NCI-ped 45 60% 51% 39% 40% at 14.5 mo 4,* MSKCC 45 82% 67% 49% (18/37) Median: 9 mo 1. Turtle C et al. ASH Grupp S et al.ash Lee D et al. ASH Park J et al. ASH 2015 *Breakthrough therapy designation in 2014
14 Probability of Event-free and Overall Survival at 6 Months. CD19-BB CAR (UPENN) EFS 67% N = 30 at 1 month, -27 (90%) CR 22 MRD - ve 3 MRD +ve 2 N/A 4-1BB ζ ζ OS 78% at median f/u 7 months -19 (63%) remains in CR 15 no further Tx ASH 2015 update: No relapse post 1year Maude SL et al. N Engl J Med 2014;371:
15 CD19CAR T Cell NHL Trials Study N ORR N, % CR Lymphodepletion Patient Population UPenn % 40% any DLBCL UPenn % n/a any FL FHCRC % 8% Non-Cy/Flu NHL FHCRC % 50% Cy/Flu NHL NCI % 52% Flu/Cy (300mg/kg x 3) DLBCL, FL NCI % 23% Flu/Cy (60-120mg/kg x1) DLBCL, FL ZUMA % 51% Flu/Cy DLBCL 1. Schuster et al. ASH 2015; 2. Turtle, C et al. ASH 2015; 3. Kochendefer J, et al.nci immutherapy meeting 2014; ASCO Locke F et al. ASH 2015
16 CD19CAR T Cell: CLL Trials Study N ORR N, % CR N, % CR Durability UPenn , 42% 9, 21% All CR are MRD-ve & durable FHCRC 2 9 8, 89% 4, 44% All CR are durable ( 2-14 months) MSKCC 3 7 3, 43% 1, 14% - Cy Lymphpdeple tion any Cy, Cy/Flu, Flu 1. Porter et al. ASCO 2015; Sci Trans Med Turtle, C et al. ASH 2015; 3. Park, J et al. ASCO 2014
17 CD19CAR T: Impact on CNS Disease CTL019 (UPENN): (Rheingold et al. ASH 2015) Patient population and design: 53 pediatric ALL patients, 12 with CNS3 relapse CNS1 or CNS 2 disease at the time of T cell infusion LP at day 28, 3, 6, 9, & 12 months. Results: - d-1, 4 pts with CNS 2 - D28, all 4 became CNS1; no pt with CNS relapse CSF from 46/47 (98%) treated patients had detectable CAR by PCR - 12 months, 9/9 patients in CR at 1 year have CTL019 in CSF - no CNS relapse in all 53 patients regardless of prior CNS history, - Neurologic oxicity: Encephalopathy: not increased, 25% in the 12 pts vs 29% (12/41) pt with no prior CNS dz. Seizure: grade 2 to 4 in 4 pts; only one with prior CNS disease and a h/o seizure A cohort of patients with CNS3 disease at the time of infusion is enrolling.
18 Resistance to CD19CAR T Treatment No response no T cell proliferation ( T cell intrinsic mechanism) CD19+ relapse: 1/3 to 80% of recurrence CD19- relapse: 20 to 67% of recurrence Grupp, ASH 2015 Turtle, ASH 2015
19 CD19 CAR T Multicenter Clinical Trials ALL 1. ZUMA-3 adult ALL (KTEC19, Kite Pharma, Phase 1/2) 2. ZUMA-4 ped ALL (KTEC19, Kite Pharma, phase 1/2) 3. ELIANA ped ALL (Novatis, Phase2) 4. ROCKET adult ALL (Juno Therapeutics, phase 2) NHL 1. ZUMA-1: refractory DLBCL (KTEC19, phase 1/2) 2. ZUMA-2: refractory MCL (KTEC19, phase 1/2) 3. JCAR017: r/r NHL (JCAR017, phase 1) 4. JULIET: recurrent DLBCL (CTL0109, phase 2)
20 CD19CAR Trial for aggressive B-NHL in asct setting COH:CD19-28 CAR NHL3 PI: Leslie Popplewell, MD Pts: transplant eligible CAR T: Tcm or Tcm+Tn given on day 2 dose escalation: 50M, 200M, 600M MSKCC:JCAR 015 PI: Craig Saulter, MD Pts: detectable disease prior to asct CAR T: pbmc-derived given on day 2 and day 3 Dose escalation: 5M/kg, 10M/kg, 20M/kg Results Formal analysis not performed yet No death CRS and neurotoxicity observed Results Interim results presented at ASCO /11 grade 3 &4 CRS (MS changes) 1 pt died from infection
21 Efficacy Summary CD19CAR T cell mediates potent anti-tumor effect Response does not correlate with CD19 expression density, disease risk factors, or disease burden. High CNS penetration Post treatment relapse are linked to early loss of CAR T cells generation of CD19- variants.
22 CAR T Cell Therapy: Complications Commonly reported important adverse events On target off tumor effects, i.e. B cell aplasia Lymphodepletion chemo related toxicity Tumor lysis syndrome Macrophage activation syndrome (HLH/MAS) Cytokine release syndrome Neurotoxicity
23 B Cell Aplasia On target, off tumor effect CD19 expresses throughout normal B cell development Clinical outcome -indicator for CD19CAR T cell persistence and response -hypogammaglobulinemia (serum IgG < 400 or 500 mg/dl) -No significant increase of severe infection Management -ivig replacement if IgG less than 400 mg/dl
24 B-cell depletion and rapid recovery in peripheral blood in responding patients (n=14). CD19-28 CAR (NCI) CD28 ζ ζ Lee DW et al. Lancet 2014, Oct 10 (NCI: Crystal Mackall group)
25 Cytokine Release Syndrome A constellation of inflammatory symptoms from cytokine elevations. Association with T cell activation and proliferation in T cell-engaging therapies. Association with clinical benefit. CRS-related death reported after Blinatumomab and CAR T treatment.
26 Clinical Signs and Symptoms Associated with CRS Organ system Constitutional Skin Gastrointestinal Respiratory Cardiovascular Coagulation Symptoms Fever ± rigors, malaise, fatigue, anorexia, myalgias, arthalgias, nausea, vomiting, headache Rash Nausea, vomiting, diarrhea Tachypnea, hypoxemia Tachycardia, widened pulse pressure, hypotension, increased cardiac output (early), potentially diminished cardiac output (late) Elevated D-dimer, hypofibrinogenemia ± bleeding Renal Hepatic Neurologic Lee DW et al. Blood 2014 Azotemia Transaminitis, hyperbilirubinemia Headache, mental status changes, confusion, delirium, word finding difficulty or frank aphasia, hallucinations, tremor, dymetria, altered gait, seizures
27 IFNg (pg/ml) pg/ml IL-6 (pg/ml) pg/ml Correlates of severe cytokine release syndrome (CRS) IL 6 Temperature IL-6 p<0.001 No IFNg Severe CRS yes IFN-γ Temp IFN-γ IL-6 p<0.001 CR o NR M. L. Davila et al., Sci Transl Med 2014;6:224ra25 Maude SL et al. N Engl J Med 2014;371: No Severe CRS Yes
28 Bone Marrow Blasts, % Correlates with Severe CRS: Disease Burden Highly Predictive 100 Baseline Disease Burden P < No Severe CRS Yes Maude et al. NEJM 2014
29 CRP is a Good Biomarker for CRS Fig. 4. CRP levels in patients infused with 19-28z CAR T cells. Published by AAAS M. L. Davila et al., Sci Transl Med 2014;6:224ra25
30 CD19CAR for NHL CRS Toxicities Study CRS scrs Penn adult-nhl Most grade 2; 4/32 Penn ped 88% 3 NIH ped n/a 14.6% grade 4 MSK (Park) 44% in 5% blasts 0% in MRD 2 (1 arrhythmia; 1 seizure) FHCRC 63% 13% (7% (n=3) died) CRS correlates with disease burden and response
31 CRS Grading Grade 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
32 CRS Management Goal: not to extinguish all evidence of CRS but to prevent life-threatening toxicity while maximizing the potential for antitumor effects. Tocilizumab is the first choice for severe CRS (selective grade 2, all grade 3 and 4 cases). humanized IgG1 anti-hil-6r mab 4 8 mg/kg iv over 1 hour x1, can repeat in 24 to 48 hours AE: <1% grade 3 AST/ALT elevation; <1% grade 3 cytopenia Steroids is the second choice First choice if there is concurrent neurotoxicity Consider steroids if no improvement after 2 doses of Tocilizumab Methylpred 2mg/kg/d or Dex 0.5mg/kg max 10mg/dose Quick wean over several days
33 The Effect of Steroids and/or Tocilizumab on the Expansion of CAR T cells in Patients with Severe CRS. steroids tocilizumab CAR T Tmax M. L. Davila et al., Sci Transl Med 2014;6:224ra25 Published by AAAS
34 COH CRS treatment algorithm Grade 1 CRS Grade 2 CRS Grade 3 CRS Monitor for CRS symptoms including vital signs & neurologic changes at least q 8 hours Follow serum CRP, CMP, UA, LDH, PT/INR/PTT Conduct infectious disease work-up Empiric antibiotics coverage as appropriate Medical supportive measures as appropriate Monitor for CRS symptoms including vital signs & neurologic changes at least q 4 hours Follow serum CRP, CMP, UA, LDH, Ferritin, PT/INR/PTT Conduct infectious disease work-up Medical supportive measures as appropriate Tocilizumab 4-8mg/kg IV indicated in patients with persistent fever, grade 2 neurotoxicity, or hypotension greater than 7 days or patients older than 60. ICU monitor Follow serum CRP, CMP, UA, LDH, Ferritin, PT/INR/PTT Vigilant medical supportive measures Tocilizumab 4-8 mg /kg IV If no improvement within 12 hours, start dexamethasone 10mg IV Q 12 hours until improvement If predominant neurotoxicity, start dexamethasone instead of tocilizumab Grade 4 CRS ICU monitor Vigilant medical supportive measures Follow serum CRP, CMP, UA, LDH, Ferritin, INR/PTT Tocilizumab 4-8 mg /kg IV. May repeat in 12 to 24 hours AND Dexamethasone 10mg IV Q 12 hours or methylprednisolone 1mg/kg Q12 hours until improvement
35 Neurologic Toxicity incidenc e MSKCC NCI-ALL UPENN NHL FHCRC-NHL 34% Gr3 G4: 5/47 (11%) Neurotoxicity gr3: 3/32 (9%) 8/32 (25%) Gr3 Grade 5 8% (n=3) 0 1 encephalitis 1 (pontine bleeding) AEs: encephalopathy, delirium, aphasia, ataxia, confusion, hallucinations, headaches, tremor, seizure, obtundation 3 pts in MSKCC trials required intubation for airway protection Can occur independently from CRS or presence of CAR T cells in CSF Management: CSF, CT or MRI study. Supportive care (fluid, electrolytes, avoid drugs with CNS toxicity). Dex is preferred over Tocilizumab in severe cases.
36 CAR T Clinical trials in Hematologic Malignancies CAR Number of Trials Patient Population CD19 > 30 NHL, ALL, CLL, MM CD22 2 ALL CD20 1 NHL CD30 6 CD30+ lymphomas Kappa LC 1 NHL, CLL, MM NKG2D Ligands 1 AML/MDS, MM BCMA 1 MM CD123 2 AML CD33 1 AML
37 COH CAR T Cell Clinical Trials Active trials CD19CAR IRB# 13277: NHL post autologous SCT (PI: Popplewell) IRB# 13447; ALL (PI: Khaled) IRB# 13551: NHL and CLL (PI: Siddiqi) CD123CAR IRB#13272; AML (PI: Budde) IL-3Rα2 CAR IRB#13384: malignant GBM(PI Badie)
38 COH CAR T Cell Trials Protocol development CD123 CAR for BPDCN (2016) Bi-specific CMV/CD19CAR for CD19+ tumors (2017) CSI CARs for multiple myeloma/amyloidosis (2017) More to come in the near future
39 COH CAR T Cell Therapy Clinical Team Stephen Forman, M.D. Elizabeth Budde, M.D., Ph.D. Leslie Popplewell, M.D. Samer Khaled, M.D. Tanya Siddiqi, M.D. Ryotaro Nakamura, M.D. Ibraham Aldoss, M.D. Myo Htut, M.D. Michael Rosenzweig, M.D. Behnam Badi, M.D. Mihaela Cristea, M.D. Michelle Mott, R.N. Neena Kennedy, RN
40 Questions??????? Elizabeth Budde, MD, PhD Tel:
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