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Chimeric Antigen Receptor (CAR) T Cell Therapy ToxicityLori Muffly MD MSStanford University
Conflict of Interest DisclosureLori Muffly MD MS• Consulting Fees: Pfizer, KITE• Contracted Research: Baxalta, Adaptive, Astellas• Ownership Interest: Corvus (stock)
Objectives• Overview of CAR T Cell Therapy
• Common CAR T Cell Toxicities:– Cytokine Release Syndrome (CRS)– Neurological Toxicity (Neurotox)– On target, off tumor side effects– Cytopenias and infections
• The Patient Experience
Case Presentation: Mr. W. • 58 year old rancher diagnosed with B-cell acute lymphoblastic
leukemia (ALL) in May, 2018
• Initial remission with chemotherapy quickly followed by relapse in the marrow and skin
• No response to salvage blinatumomab or inotuzumab
• March, 2019: Skin involvement throughout trunk, face, neck; circulating blasts; declining KPS
• Enrolled onto CCT5001: Phase 1 Dose Escalation Study of CART 19-22 in Adults with Relapsed or Refractory Diffuse Large B-cell Lymphoma or Acute Lymphoblastic Leukemia (NCT 03233854)
Refractory Blood Cancers Continue to Have Very Poor Outcomes
Crump M, et al. Blood. 2017
Success with Targeting Tumor Antigens in Blood Cancers
Structure of CARs and T Cell Receptors
June C NEJM 2018
T cell
Viral DNAInsertion
Tumor cell
Expressionof CAR
CAR T cellsmultiply and release cytokines
Tumor cell apoptosis
CAR enables T cell to recognize tumor cell antigen
Antigen
CAR T Cells A re a Living Therapy!
How CAR T Cells Work
9
CAR T Cell Therapy Delivery
Patient Evaluation & Consent
2-6 weeksBridging therapy often
necessary
Lymphodepletion Chemotherapy
HospitalizationToxicities
Relocation
Pivotal Multicenter Trials in ALL & DLBCL
n engl j med 378;5 nejm.org February 1, 2018 443
Tisagenlecleucel in B-Cell Lymphoblastic Leukemia
B-Cell AplasiaAll patients with a response to treatment had B-cell aplasia, and most patients in the study received immunoglobulin replacement in accor-dance with local practice. The median time to B-cell recovery was not reached (Fig. S4 in the Supplementary Appendix). The probability of maintenance of B-cell aplasia at 6 months after infusion was 83% (95% CI, 69 to 91).
Cytokine ResponseAmong the 75 patients who received tisagenlec-leucel, transient increases in serum interleu-kin-6, interferon gamma, and ferritin levels oc-curred during the cytokine release syndrome after infusion; these increases tended to be more pronounced in patients with grade 4 cytokine release syndrome than in patients with lower grades (Fig. S5 in the Supplementary Appendix). Similar trends were observed in the levels of other cytokines, including interleukin-10, inter-leukin-12p70, interleukin-1β, interleukin-2, inter-leukin-4, interleukin-8, and tumor necrosis fac-tor α. A transient increase in the C-reactive
protein level was observed in most patients, but with large variability.
SafetyThe safety analysis set included all 75 patients who received an infusion of tisagenlecleucel; the median time from infusion to data cutoff was 13.1 months (range, 2.1 to 23.5). Eighteen pa-tients (24%) received their infusions in an outpa-tient setting. All patients had at least one adverse event during the study; 71 of 75 patients (95%)
Prob
abili
ty o
f Con
tinue
d Re
mis
sion
1.0
0.8
0.9
0.7
0.6
0.4
0.3
0.1
0.5
0.2
0.00 4 8 12 14 16 2220
Months since Onset of Remission
B Event-free and Overall Survival
A Duration of Remission
No. of patients, 61No. of events, 17Median duration of remission, not reached
No. at Risk 61 43
2
54 23
6
33 8
10
18 7 3 0
18
1
Prob
abili
ty
1.0
0.8
0.9
0.7
0.6
0.4
0.3
0.1
0.5
0.2
0.00 4 8 12 14 16 2220
Months since Tisagenlecleucel Infusion
Overall SurvivalEvent-free
Survival
7575
1927
19.1not
reached
90 (81– 95)73 (60– 82)
No. ofPatients
No. ofEvents
MedianSurvival Rate at 6 Mo
mo % (95% CI)
No. at RiskOverall survivalEvent-free survival
7575
6451
2
7264
5533
6
5837
3013
10
4019
208
123
00
18
83
21
Overall survival
Event-free survival
Figure 2. Duration of Remission, Event-free Survival, and Overall Survival.
Panel A shows the duration of remission, defined as the time to relapse after the onset of remission, in the 61 patients who had a best overall response of either complete remission or complete remission with incom-plete hematologic recovery. Panel B shows event-free survival among the 75 patients who received an infusion, defined as the time from tisagenlecleucel infusion to the earliest of the following events: no response (8 pa-tients), relapse before response was maintained for at least 28 days (2), or relapse after having complete re-mission or complete remission with incomplete hema-tologic recovery (17). A total of 32 patients had still not had an event at the time of data cutoff. Data for 16 more patients were censored for event-free survival — 8 pa-tients for allogeneic stem-cell transplantation during remission, 7 patients for new cancer therapy other than stem-cell transplantation during remission (4 received humanized anti-CD19 CAR T cells, 1 received ponatinib, 1 received vincristine sulfate and blinatumomab, and 1 received antithymocyte globulin), and 1 patient for lack of adequate assessment. Ten patients were followed for relapse after new therapy, 4 of whom had a relapse or died. Panel B also shows overall survival among the 75 patients who received an infusion from the date of tisagenlecleucel infusion to the date of death from any cause. Nineteen patients died after tisagenlecleucel in-fusion, and 56 patients had their data censored at the time of the last follow-up. Tick marks indicate the time of censoring.
T h e n e w e ngl a nd j o u r na l o f m e dic i n e
n engl j med 378;5 nejm.org February 1, 2018 439
The authors’ full names, academic de-grees, and affiliations are listed in the Appendix. Address reprint requests to Dr. Maude at 3012 Colket Translational Research Bldg., 3501 Civic Center Blvd., Philadelphia, PA 19104, or at maude@ email . chop . edu.
Drs. Pulsipher and Grupp contributed equally to this article.
N Engl J Med 2018;378:439-48.DOI: 10.1056/NEJMoa1709866Copyright © 2018 Massachusetts Medical Society.
BACKGROUNDIn a single-center phase 1–2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).
METHODSWe conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months.
RESULTSFor this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remis-sion was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported.
CONCLUSIONSIn this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849.)
A BS TR AC T
Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia
S.L. Maude, T.W. Laetsch, J. Buechner, S. Rives, M. Boyer, H. Bittencourt, P. Bader, M.R. Verneris, H.E. Stefanski, G.D. Myers, M. Qayed, B. De Moerloose,
H. Hiramatsu, K. Schlis, K.L. Davis, P.L. Martin, E.R. Nemecek, G.A. Yanik, C. Peters, A. Baruchel, N. Boissel, F. Mechinaud, A. Balduzzi, J. Krueger,
C.H. June, B.L. Levine, P. Wood, T. Taran, M. Leung, K.T. Mueller, Y. Zhang, K. Sen, D. Lebwohl, M.A. Pulsipher, and S.A. Grupp
Original Article
The New England Journal of Medicine Downloaded from nejm.org at Lane Medical Library, Stanford University Med Center on March 12, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.
Maude et al. NEJM 2018; Neelapu SS et al. NEJM 2017
CAR Therapy: Past, Present, Future
Development of Chimeric T-cell receptor expressing CTL with antibody specificity1
1. Gross G et al; Transplant Proc. 1989 Feb;21(1.1):127-302. Esshar Z et al; Proc Natl Acad Sci U S A. 1993 Jan
15;90(2):720-43. Hwu P et al; Cancer Res. 1995 Aug 1;55(15):3369-734. Gross G et al; Biochem Soc Trans. 1995 Nov;23(4):1079-825. 5. Maus MV et al; Nat Biotechnol. 2002 Feb;20(2):143-8
Development and demonstration of in-vivo activity for scFvCAR2,3
Development of scFv CAR against a B-cell lymphoma idiotype4
6. Kershaw MH et al; Clin Cancer Res. 2006 Oct 15;12(20.1):6106-157. Milone MC et al; Mol Ther. 2009 Aug;17(8):1453-648. Kochendorfer JN et al; J Immunother. 2009 Sep;32(7):689-7029. Konchendorfer JN et al; Blood. 2010 Nov 18;116(20):4099-102
Use of ligands to CD28 & 4-1bb to enhance CTL expansion5
First in-human data for the use of scFv CAR against Ovarian Cancer6
Development of CAR directed against CD197,8
First in-human data for the use of CAR against CD19 expressing NHL9
Clinical Evaluation and Approval of Anti-CD19 CAR-T therapy in B-cell malignancies
1989 2019
>300 CAR T CellClinical Trials
Across CancerTypes
Case Presentation: Mr. W, cont.• 58 year old man with relapsed B-ALL, enrolled on clinical trial of CART 19-22
• Lymphodepletion followed by infusion of CART 3x106/kg April 10, 2019 (Day 0)
• Day +4: febrile with hypoxemia requiring high flow oxygenation consistent with Grade 3 CRS
• Received tocilizumab 8mg/kg IV x 1 and dexamethasone 10mg IV x 1
13
Cytokine Release Syndrome (CRS)
CAR T expansion by RTPCR ZUMA-1 Trial
• CRS: Supraphysiologic response following immunotherapy- clinically presents asfever, hypotension, capillary leak
Hay K et al Blood 2017
Associated with rise in IFN-, IL-6, IL-10, IL-2, others
CRS Grading Scale
Lee D et al BBMT 2019
Day 8 CAR T expansion by FACS in Our Patient
American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading System
• CRS is common after CAR T cell therapy (50-95% incidence)
• Grade 3-4 CRS occurs in 5-30%
CRS Management
Supportive Care Tocilizumab+/- Steroids
Tocilizumab+ Steroids (Dex q6)
Solumedrol 1 gm x 3
Alert ICUICU Care
Tocilizumab: IL6 receptor antagonist, FDA approved for the treatment of CAR T associated CRS in Aug, 2017
Additional agents under investigation for CRS:• Anakinra: IL1 receptor antagonist (FDA Indication: Rheumatoid arthritis)• Siltuxumab: IL6 antibody (FDA Indication: Castleman’s disease)
Case Presentation: Mr. W, cont.• 58 year old man with relapsed B-ALL, enrolled on clinical trial of CART 19-22
• Lymphodepletion followed by infusion of CART 3x106/kg April 10, 2019 (Day 0)
• Day +4: developed Grade 3 CRS. Received Tocilizumab + dexamethasone
• Day +6: declining neurological status, ICE score 1/10 consistent with Grade 3 Neurotox.
• Started on dexamethasone 10mg q6, increased Keppra to 1000mg BID, continuous EEG
• Day +7: somnolent, ICE score 0/10, Transferred to ICU and intubated for airway protection. Now consistent with Grade 4 Neurotox.
• Solumedrol 1 gram x 3 days ordered. No seizure activity noted.
17
Immune Effector-Cell Associated Neurotoxicity (ICANS)
18Lee D et al BBMT 2019
Immune Effector Cell-Associated Encephalopathy Score (ICE)
19Neelapu SS Nat Rev Clin Oncol 2018; Lee D et al BBMT 2019
ICANS Consensus Grading
20Lee D et al BBMT 2019
21Lee D et al BBMT 2019
Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)
Grade 1 Grade 2 Grade 3 Grade 4Some or all of the following: Some or all of the following: Some or all of the following: Some or all of the following:
Spontaneous awakening Awakening to voice Awakening to tactile stimulus Coma/posturingMild Confusion Moderate Confusion Global aphasia Focal weakness
Word-finding difficulty Expressive aphasia Myoclonus Status epilepticusTremor Perseveration Clinical seizure Pupillary/CN abnormalities
No clinical seizures No clinical seizures Brief electrographic seizures Diffuse cerebral edemaICE 7-9 ICE 3-6 ICE 0-2 ICE 0
BMT P
hysicia
n • Monitor for progression • Consult Neurology • Notify Neurology consultant • ABC's; stabilize patient• Evaluate/treat other causes of encephalopathy
• Consider neuro checks q2h • Discuss imaging with neurology • Page MICU and give handoff to MICU team• Order neuro checks q2h
• Document neurologic exam • Discuss with MICU • Emergent CT head when stable to travel• Consult psycho-oncology• Order neuro checks qhour pending ICU transfer
BMT N
urse
• Neuro checks q4h • Neuro checks q4h to q2h • Neuro checks q2h • Neuro checks qhour while awaiting ICU transfer• Monitor for progression • ICE score with neuro checks • ICE score with neuro checks
• Notify Crisis RN • Notify Crisis RN • ICE score with neuro checks• Telemetry and continuous O2 • Pupillometry with neuro checks
if indicated• Notify Crisis RN• Pupillometry with neuro checks
• Telemetry and continuous O2 • Telemetry and continuous O2• Give handoff to E2 RN
Neurolo
gy Con
sult
• Consider CT head if focal symptoms
• Consider urgent imaging • Emergent CT head when stable to travel• Consider EEG
• Consider EEG • Follow up EEG read in 1h if ordered
• Continuous EEG after imaging• Follow up EEG read in 1h • Discuss steroids/AED regimen with
BMT• Consider empiric increase in AED regimen
• Consider empiric increase in AED regimen • Page Neurocritical Care and give
neuro-specific handoff• Consider possibility of diffuse cerebral edema• Discuss with Neurocritical Care
Interv
ention
s
• Continue Keppra 500 mg BID prophylactically
• Consider increasing Keppra to 1000 mg BID empirically
• Continue Keppra 1000 mg BID; may add Vimpat 100 mg BID
• Adjust antiepileptic drugs based on EEG and discussion with NCC
• Reconcile medications to identifyother potential contributors
• Dexamethasone 10mg IV q6-12h depending on CAR-T product
• Dexamethasone 10mg IV q6h; reassess daily
• Methylprednisolone 1g IV daily; reassess daily, taper when able
• Delirium precautions • Tocilizumab 8mg/kg if concurrent CRS
• Tocilizumab 8mg/kg if CRS, not to exceed 3 doses in 24 hours
• Tocilizumab 8mg/kg if CRS, not to exceed 3 doses in 24 hours
• Consider melatonin at bedtime • Consider atypical antipsychotic if hyperactive Consult psycho-oncology for delirium management when indicated
• Consider Anikinra
STEROIDS
CAR T Neurotoxicity: CRS, Cytokines, and Vascular Endothelial Activation
22Gust J Cancer Discovery 2019
Why Did Mr. W Develop Grade 3-4 CRS/Neurotoxicity?
23
Case Presentation: Mr. W, cont.• 58 year old man with relapsed B-ALL, enrolled on clinical trial of CART 19-22
• Lymphodepletion followed by infusion of CART 3x106/kg April 10, 2019 (Day 0)
• Day +4: Grade 3 CRS
• Day +7 to D+10: Intubated in ICU with Grade 4 Neurotoxicity
• Day +11: neuro status improving, extubated transferred to floor
• Day +12 to D+25: Remained inpatient on BMT/CART floor. Steroids tapered. Very debilitated-working with PT daily. Neurological status improved but with intermittent delirium.
• Day +26: Discharged to local housing with ongoing transfusion needs due to prolonged severe pancytopenia.
24
Other CAR T Related Side Effects• Pancytopenia- often prolonged
• On target/off tumor effects– Example: hypogammaglobulinemia following CD19 CART
• Infections
• Delirium, cognitive decline, debilitation
25
CAR T Cell Therapy: The Patient Experience??
26BBMT 2019
CAR T Cell Therapy: Patient and Societal Financial Toxicity?
27Lin J et al JCO 2019
Patient costs:• Travel, co-pays• Local housing (often extended)• Mandatory caregiver• Numerous follow-ups• Outpatient Physical Therapy• Skilled Nursing Facility
The Reason to Continue On…• 58 yo with refractory B-ALL, enrolled on clinical trial of CART 19-22
• No other treatment options at the time
• Received CAR T cells on April 10, 2019
• Day 28 evaluation showed a complete remission, MRD-negative
• Month 2 evaluation:
• Mr. W. is now at home with his family, mostly independent
28
CAR T Cell Therapy Toxicity: Summary• CAR T Cell therapy represents an exciting “living” cancer
immunotherapy now available to patients commercially and through clinical trials
• CRS and neurological toxicity are common and can be severe; grading and management require multidisciplinary expertise
• Mainstay of therapy is currently tocilizumab (CRS) and steroids (CRS, neurotoxicity)
• Additional work is required to understand the impact of CAR T on patient-reported symptoms and functioning over time
29
Stanford CAR T Team
Crystal Mackall – Director
David Miklos - Clinical OpsLori Muffly, Kara Davis, Liora SchultzJay Spiegel, Matt Frank, Nash HossainJanet McDowell, Juliana Craig, Jenny Yoon, Sharan Craig
Steve Feldman – ManufacturingMatt Abramian, Shabnum Patel
Sharon Mavroukakis – RegulatoryEmily Egeler
Bita Sahaf - Correlative ScienceSean Bendall
Pathology: Jean OaksEric Yang, Michael OzawaKatie Kong
30