Cytokine Release Syndrome and Neurotoxicity: Ongoing Efforts to Enhance Safety. Sattva S. Neelapu, MD

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2 Cytokine Release Syndrome and Neurotoxicity: Ongoing Efforts to Enhance Safety Sattva S. Neelapu, MD

3 Disclosures Research support from Kite, Merck, BMS, Cellectis, Poseida, Karus, Acerta Advisory Board Member/Consultant for Kite, Merck, Celgene, Novartis, Unum Therapeutics, Pfizer I will discuss investigational use of anakinra and siltuximab in my presentation

4 Cytokine Release Syndrome (CRS) Systemic inflammatory response caused by cytokines released by CAR T cells and other immune cells and results in reversible organ dysfunction Brudno JN, Kochenderfer JN. Blood June 30;127(26):

5 Neurotoxicity Typically manifests as a toxic encephalopathy o Word-finding difficulty, confusion, disorientation, agitation, dysphasia, aphasia, somnolence, tremors, and impaired handwriting o In more severe cases, seizures, motor weakness, incontinence, increased intracranial pressure, papilledema, and cerebral edema may also occur Onset may be during CRS or after CRS symptoms have subsided May last few hours to several days Generally reversible with no permanent neurological deficits

6 CRS Deaths After CD19 CAR T-Cell Therapy CAR T-cell product Malignancy Day of death post- CAR T Cause of death Reference CD z B-ALL 5 CRS (+Influenza B) Frey NV, et al. Blood. 2014;124:2296. CD z B-ALL 15 CRS (+Pseudomonas sepsis, pneumonia) Frey NV, et al. Blood. 2014;124:2296. CD z B-ALL 15 CRS (+Steno-trophomonas sepsis, pneumonia) Frey NV, et al. Blood. 2014;124:2296. CD z B-ALL 3 CRS CD z NHL 30 CRS (+GI bleed) CD19-28-z CLL 2 CRS CD19-28-z PMBCL 16 CD19-28-z NHL N/A Cardiac arrest CD19-28-z DLBCL N/A HLH Unknown (possibly cardiac arrhythmia) Turtle CJ, et al. J Clin Invest June 1;126(6): Turtle CJ, et al. Sci Transl Med Sep 7;8(355):355ra116. Brentjens R, et al. Mol Ther Apr;18(4): Kochenderfer JN, et al. J Clin Oncol Feb 20;33(6): Neelapu SS, et al. N Engl J Med Dec 28;377(26): Neelapu SS, et al. N Engl J Med Dec 28;377(26):

7 Neurotoxicity Deaths After CD19 CAR T-Cell Therapy CAR T-cell product Malignancy Day of death post- CAR T Cause of death Reference CD z B-ALL 122 Neurotoxicity Turtle CJ, et al. J Clin Invest June 1;126(6): CD z NHL 13 Neurotoxicity (+CNS bleed) Turtle CJ, et al. Sci Transl Med Sep 7;8(355):355ra116. CD z FL N/A Encephalitis Schuster SJ, et al. N Engl J Med Dec 28;377(26): CD19-28-z ALL N/A CD19-28-z NHL N/A Cerebral edema (5 cases) Cerebral edema (1 case) Juno press release Kite press release

8 Safety in Multicenter CD19 CAR T Trials in Adult NHL Study/ Sponsor Product N CRS all grades CRS Grade 3 NT all grades NT Grade 3 Toci usage Steroid usage Reference ZUMA-1 Kite CD19/CD3z/ CD % 13% 65% 31% 45% 29% Neelapu SS, et al. N Engl J Med Dec 28;377(26): JULIET Novartis CD19/CD3z/ 4-1BB % 22% 21% 12% 15% 11% Borchmann P, et al. EHA Learning Center. June 16, 2018; TRANSCEND Juno CD19/CD3z/ 4-1BB % 1% 23% 13% 17% 21% Abramson JS, et al. J Clin Oncol May;36(15 suppl): Lee criteria used for CRS grading on ZUMA1 and TRANSCEND U Penn criteria used for CRS grading on JULIET All trials used CTCAE criteria for neurotoxicity (NT) grading 3 deaths on ZUMA1 due to AEs 1 cardiac arrest, 1 HLH, 1 pulmonary embolism

9 Factors Associated With Toxicity After CAR T Therapy Host/Tumor Factors Type of malignancy (ALL > DLBCL) Tumor burden Baseline inflammatory state Therapy-Related Factors Lymphodepleting therapy CAR T dose CAR T design (CD28 > 4-1BB) CAR T expansion Cytokine profile References Maude SL, et al. N Engl J Med Davila ML, et al. Sci Transl Med Lee DW, et al. Lancet Teachey DT, et al. Cancer Discov Turtle CJ, et al. J Clin Invest Turtle CJ, et al. Sci Transl Med Gust J, et al. Cancer Discov Hay KA, et al. Blood Neelapu SS, et al. N Engl J Med Maude SL, et al. N Eng J Med Park JH, et al. N Engl J Med Santomasso BD, et al. Cancer Discov. 2018

10 CAR T-Cell Response to Antigen CAR T cell Proliferate Make cytokines Kill the target cells

11 CAR T-Cell Expansion and Persistence After Axi-Cel Infusion Locke FL, et al. Mol Ther Jan 4;25(1): Peak expansion observed within 2 weeks CAR T cells detectable beyond 2 years after infusion Each infused CAR T cell can proliferate to > 10,000 cells in the body

12 ZUMA-1: CAR T-Cell Expansion Was Associated With ORR and Grade 3 NE, but not Grade 3 CRS ORR NE CRS Neelapu SS, et al. N Engl J Med Dec 28;377(26): Unique pharmacokinetics compared with traditional therapeutic agents Up to 4-log difference in peak levels and AUC across patients Need for tunable CARs!

13 Cytokine Pattern After Axi-cel CAR T Infusion IL-6 IL-8 IL-10 IL-2 IL-7 IL-15 IFNg TNFa Granzymes Perforin Perez A, et al. ASH Session 801. Poster I.

14 ZUMA-1: Distinct Biomarkers Peak Within 7 Days After Axi-cel Treatment Proliferative Inflammatory Immunemodulating Chemokine Effector IL-15 IL-2 IL-6 CRP SAA IL-5 Ferritin IL-1Ra IL-2Rα GM-CSF IFN-γ IL-10 IL-8 IP-10 MCP-1 Granzyme B Baseline Day 0 Day 1 Day 3 Day 5 Day 7 Day 14 Day Fold increase above baseline Analytes shown were elevated in 50% of patients with 2-fold induction above baseline out of a panel of 44 measured Locke FL, et al. AACR Abstract CT019.

15 IL-6 Levels Correlate With Severity of CRS Tocilizumab (anti-il-6r Ab) or siltuximab (anti-il-6 Ab) are used for management of severe CRS Tocilizumab was approved for management of CRS in the US and EU Maude SL, et al. N Engl J Med Oct 16;371(16):

16 ZUMA-1: Peak Levels of Biomarkers Associated With Grade 3 CRS and NE Locke FL, et al. AACR Abstract CT019. Function Homeostatic Inflammatory Immune-modulating Chemokine Effector Analyte IL-15 IL-6 IL-1Ra IL-2Rα IFN-γ IL-10 IL-8 MCP-1 Granzyme B CRS Grade 3 vs Grades 0-2 NE Grade 3 vs Grades 0-2 *Peak levels after axi-cel infusion were used in the comparison. P < < P <.10 Adjusted P values are calculated from Holm's procedure after multiple testing using the Wilcoxon rank sum test

17 Pathophysiology of CRS Maude SL. Blood Nov 23;130(21):

18 ZUMA-1: Tocilizumab/Steroid Use Did Not Impact Responses But Was Associated With Higher CAR T-Cell Levels Without n = 58 Tocilizumab With n = 43 P Value Without n = 74 Steroids With n = 27 ORR, n (%) 47 (81.0) 36 (83.7).8 62 (83.8) 21 (77.8).56 CR, n (%) 33 (56.9) 22 (51.2) (54.1) 15 (55.6) 1 Ongoing, n (%) 28 (48.3) 16 (37.2) (44.6) 11 (40.7).82 Median peak CAR, cells/μl (range) 27 (1-1226) 61 (1-1514) (1-1226) 50 (1-1514) P Value.0618 Median CAR AUC, cells/μl days (range) 290 ( ) 744 ( ) ( ) 725 ( ).0967 Neelapu SS, et al. Hematol Oncol June 07;35(suppl S2):28.

19 Prophylactic Tocilizumab After Axi-cel: Baseline Characteristics Prophylactic tocilizumab given on Day +2. Characteristic ZUMA-1 Primary Analysis 1 (N = 101) SMS Cohort 3 (N = 34) Median (range) age, y 58 (23 76) 51 (21 74) 65 y, n (%) 24 (24) 7 (21) Men, n (%) 68 (67) 19 (56) ECOG PS 1, n (%) 59 (58) 19 (56) Disease type, n (%) DLBCL PMBCL/TFL 77 (76) 24 (24) 21 (62) 13 (38) Disease stage III/IV, n (%) 86 (85) 20 (59) IPI score 3-4, n (%) 47 (47) 11 (32) 3 prior therapies, n (%) 70 (69) 25 (74) Refractory subgroup before enrollment Primary refractory 2 (2) 1 (3) Refractory to second- or later-line therapy, n (%) 78 (77) 25 (74) Relapse post-asct, n (%) 21 (21) 8 (24) Locke FL, et al. Blood. 2017;130(suppl 1). ASH abstract 1547.

20 Prophylactic Tocilizumab: Safety Event, n (%) ZUMA-1 Primary Analysis SMS Cohort 3 (N = 101) (N = 34) Any CRS 94 (93) 32 (94) Worst grade 1 37 (37) 12 (35) Worst grade 2 44 (44) 19 (56) Worst grade 3 9 (9) 0 Worst grade 4 3 (3) 1 (3) Worst grade 5 1 (1) 0 Worst grade 3 13 (13) 1 (3) Any NE 63 (62) 29 (85) Worst grade 1 21 (21) 9 (26) Worst grade 2 14 (14) 6 (18) Worst grade 3 26 (26) 12 (35) Worst grade 4 2 (2) 1 (3) Worst grade (3) Worst grade 3 28 (28) 14 (41) Locke FL, et al. Blood. 2017;130(suppl 1). ASH abstract 1547.

21 Grading and Management of CRS and neurotoxicity Overall goal is to maximize the benefit from the CAR T-cell therapy while minimizing the risk for life-threatening complications of toxicities Ideal grading system Objective Reproducible Easy to use Usable by all healthcare providers involved in patient care Allow rapid and dynamic assessment Practical tool for grade-based management of toxicities CARTOX Guidelines Nat Rev Clin Oncol, Jan 2018 ASBMT Workshop on Consensus Grading of CRS and Neurotoxicity June 20-21, 2018 Manuscript submitted

22 Determine the Grade of CRS (CARTOX Grading) CRS grade should be determined at least twice daily and any time there is a change in patient s status Category Symptom/Sign CRS Grade 1 a Adapted from Lee DW, et al. Blood Jul 10;12492): Neelapu SS, et al. Nat Rev Clin Oncol Jan;15(1): CRS Grade 2 b CRS Grade 3 b Vital signs Temp 38 0 C Yes Any Any Any SBP < 90 No Responds to IV fluids or low-dose vasopressor Needing oxygen for O 2 sat > 90% Needs high-dose or multiple vasopressors d CRS Grade 4 b Life- threatening No FiO2 <40% FiO2 40% Needing ventilator support Organ toxicity c See Step 1 Grade 1 Grade 2 Grade 3 or grade 4 transaminitis Grade 4 except grade 4 transaminitis a Grade 1 CRS may manifest as fever and/or Grade 1 organ toxicity. b For Grades 2, 3, or 4 CRS, any one of the criteria other than temperature is sufficient. c Use CTCAE, version 4 for grading of organ toxicity. d See Lee DW, et al. Blood Jul 10;124(2): for definition of high-dose vasopressors.

23 ASBMT Consensus Grading of CRS CRS Parameter* Grade 1 Grade 2 Grade 3 Grade 4 Fever # Temperature 38 C Temperature 38 C Temperature 38 C Temperature 38 C With either: Hypotension # None Not requiring vasopressors Requiring one vasopressor with or without vasopressin Hypoxia # None Requiring low-flow nasal cannula^ or blow-by And/ or Requiring high-flow nasal cannula^, facemask, nonrebreather mask, or Venturi mask Requiring multiple vasopressors (excluding vasopressin) Requiring positive pressure (eg: CPAP, BiPAP, intubation and mechanical ventilation) # Not attributable to any other cause In patients who have CRS then receive tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity CRS grade is determined by the more severe event ^Low-flow nasal cannula is 6 L/min and high-flow nasal cannula is > 6 L/min *Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS grading

24 Management of CRS (CARTOX Gudelines) * High risk for severe CRS: Bulky disease, comorbidities, early onset CRS (< 3 days) CRS Grade Symptom or Sign Management Grade 1 Fever or Grade 1 organ toxicity Acetaminophen and hypothermia blanket as needed for fever Ibuprofen may be used as second option for fever if not contraindicated Assess for infection with blood and urine cultures, and chest x-ray Empiric broad-spectrum antibiotics and filgrastim if neutropenic Maintenance IV fluids for hydration Symptomatic management of constitutional symptoms and organ toxicities Consider IL-6 antagonist for persistent (> 3 days) or refractory fever Grade 2 Hypotension IV fluid bolus of ml normal saline May give a second IV fluid bolus if SBP remains < 90 mm Hg Consider IL-6 antagonist for hypotension refractory to fluid bolus If hypotension persists after two fluid boluses and anti-il-6 therapy, start vasopressors, consider transfer to ICU, and obtain ECHO and initiate other methods of hemodynamic monitoring In patients at high-risk* or if hypotension persists after IL-6 antagonist, may use dexamethasone 10 mg IV q 6h Manage fever and constitutional symptoms as in grade 1 CRS Hypoxia Supplemental oxygen IL-6 antagonist +/- corticosteroids and supportive care as in hypotension Grade 2 organ toxicity Symptomatic management of organ toxicity as per standard guidelines Use IL-6 antagonist +/- corticosteroids and supportive care as in hypotension Neelapu SS, et al. Nat Rev Clin Oncol Jan;15(1): Maximum of one siltuximab dose per patient

25 Management of CRS (cont.) CRS Grade Symptom or Sign Management Grade 3 Hypotension IV fluid boluses as needed as in grade 2 IL-6 antagonist as in grade 2 if not administered previously Vasopressors as needed Transfer to ICU, ECHO and hemodynamic monitoring as in grade 2 Start dexamethasone 10 mg IV q 6h; increase to 20 mg IV every 6h if refractory Manage fever and constitutional symptoms as in grade 1 Hypoxia Supplemental oxygen including high flow oxygen delivery and non-invasive positive pressure ventilation IL-6 antagonist + corticosteroids and supportive care as above Grade 3 organ toxicity or grade 4 transaminitis Symptomatic management of organ toxicity as per standard guidelines IL-6 antagonist + corticosteroids and supportive care as above Grade 4 Hypotension IV fluids, IL-6 antagonist, vasopressors, and hemodynamic monitoring as in grade 3 High-dose corticosteroids (e.g. Methylprednisolone IV 1 g/day x 3 days followed by rapid taper at 250 mg q12 h x 2 days, 125 mg q12 h x 2 days, and 60 mg q12 h x 2 days); taper of corticosteroids may be individualized Manage fever and constitutional symptoms as in grade 1 Hypoxia Mechanical ventilation IL-6 antagonist + corticosteroids and supportive care as above Grade 4 organ toxicity excluding transaminitis Symptomatic management of organ toxicities as per standard guidelines IL-6 antagonist + corticosteroids and supportive care as above Neelapu SS, et al. Nat Rev Clin Oncol Jan;15(1):47-62.

26 Determine the Grade of Neurotoxicity (CARTOX Grading) Symptom/Sign Grade 1 Grade 2 Grade 3 Grade 4 Neurological assessment Mild (7-9) Moderate (3-6) Severe (0-2) Critical/obtunded score (see below) Raised intracranial pressure - - Stage 1 or 2 papilledema a with CSF opening pressure < 20 mmhg Stage 3, 4, or 5 papilledema a ; or CSF opening pressure 20 mmhg; or cerebral edema Seizures or motor weakness - - Partial seizure; non-convulsive seizures on EEG responding to benzodiazepine Generalized seizures; convulsive or non-convulsive status epilepticus; new motor weakness CARTOX 10-point neurological assessment (Assign one point for each task performed correctly; score of 10 = normal) Orientation to year, month, city, hospital, president: 5 points Name three objects (point to clock, pen, button): 3 points Ability to write a standard sentence (e.g. Our national bird is the bald eagle): 1 point Count backwards from 100 by 10: 1 point a Papilledema grading is performed according to Modified Frisén scale (Appendix 3). Neelapu SS, et al. Nat Rev Clin Oncol Jan;15(1):47-62.

27 ASBMT Consensus Encephalopathy Assessment Tool CARTOX Tool Orientation: Orientation to year, month, city, hospital, President: 5 points Naming: Name 3 objects (e.g., point to clock, pen, button): 3 points Writing: Ability to write a standard sentence (e.g., Our national bird is the bald eagle): 1 point Attention: Count backwards from 100 by ten: 1 point Neelapu SS, et al. Nat Rev Clin Oncol Jan;15(1): Immune-Effector Cell-Associated Encephalopathy (ICE) Tool Orientation: Orientation to year, month, city, hospital: 4 points Naming: Name 3 objects (e.g., point to clock, pen, button): 3 points Following commands: (e.g., Show me 2 fingers or Close your eyes and stick out your tongue): 1 point Writing: Ability to write a standard sentence (e.g., Our national bird is the bald eagle): 1 point Attention: Count backwards from 100 by ten: 1 point Manuscript Submitted

28 ASBMT Consensus Grading of ICANS (IEC-Associated Neurotoxicity Syndrome) Neurotoxicity Domain Grade 1 Grade 2 Grade 3 Grade 4 ICE Score (patient is unarousable and unable to perform ICE) Depressed level of consciousness Awakens spontaneously Awakens to voice Awakens only to tactile stimulus Seizure N/A N/A Any clinical seizure focal or generalized that resolves rapidly ; or Nonconvulsive seizures on EEG that resolve with intervention Patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse or stupor or coma Life-threatening prolonged seizure (>5 min); or Repetitive clinical or electrical seizures without return to baseline in between Motor findings N/A N/A N/A Deep focal motor weakness such as hemiparesis or paraparesis Raised intracranial pressure / Cerebral edema N/A N/A Focal/local edema on neuroimaging Diffuse cerebral edema on neuroimaging; Decerebrate or decorticate posturing; or Cranial nerve VI palsy; or Papilledema; or Cushing's triad ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, raised ICP/cerebral edema) not attributable to any other cause.

29 Management of Neurotoxicity (CARTOX Guidelines) Grade Management Grade 1 Vigilant supportive care; aspiration precautions; IV hydration Withhold oral intake of food, medicines, and fluids and assess swallowing Convert all oral medications and/or nutrition to IV if swallowing is impaired Avoid medications that cause central nervous system depression Low doses of lorazepam ( mg IV every 8h) or haloperidol (0.5 mg IV every 6h) may be used for agitated patients with careful monitoring Neurology consultation Fundoscopic exam to assess for papilledema MRI brain with and without contrast; diagnostic lumbar puncture with opening pressure; MRI spine if focal peripheral neurological deficits; CT scan of brain may be performed if MRI brain is not feasible Daily 30-min EEG until toxicity symptoms resolve; if no seizures on EEG, continue levetiracetam 750 mg every 12h If EEG shows non-convulsive status epilepticus, treat as per algorithm in Appendix 4 Consider IL-6 antagonist if associated with concurrent CRS Grade 2 Supportive care and neurological work-up as per grade 1 If associated with concurrent CRS symptoms, IL-6 antagonist If NOT associated with CRS, dexamethasone 10mg IV every 6h or methylprednisolone 1 mg/kg IV every 12h or if refractory to IL-6 antagonist Consider ICU transfer if associated with Grade 2 or greater CRS Neelapu SS, et al. Nat Rev Clin Oncol Jan;15(1): Maximum of one siltuximab dose per patient

30 Management of Neurotoxicity (cont.) Grade Management Grade 3 Supportive care and neurological work-up as per Grade 1 ICU transfer is recommended IL-6 antagonist if associated with concurrent CRS as per Grade 2 and if not administered previously If NOT associated with CRS, corticosteroids as above or for worsening symptoms despite anti-il-6 therapy; Continue corticosteroids until improvement to grade 1 and then taper Stage 1 or 2 papilledema with CSF op < 20 mm Hg, treat as per algorithm in Appendix 6 Consider repeat neuro-imaging (CT or MRI) q 2-3 days if persistent neurotoxicity Grade 3 CRES Grade 4 Supportive care and neurological work-up as per grade 1 ICU monitoring; Consider mechanical ventilation for airway protection IL-6 antagonist and repeat neuro-imaging as per Grade 3 High-dose corticosteroids (e.g. methylprednisolone IV 1 g/day x 3 days followed by rapid taper at 250 mg q12 h x 2 days, 125 mg q12 h x 2 days, and 60 mg q12 h x 2 days); Continue corticosteroids until improvement to Grade 1 and then taper For convulsive status epilepticus, treat as per algorithm in Appendix 5 Stage 3, 4, or 5 papilledema, CSF op 20 mm Hg, or cerebral edema, treat as per algorithm in Appendix 6 Neelapu SS, et al. Nat Rev Clin Oncol Jan;15(1):47-62.

31 Endothelial Activation and BBB Disruption Drive Neurotoxicity Gust J, et al. Cancer Discov Dec; 7(12):

32 Role of IL-1 in CRS and/or Neurotoxicity June 2018 June 2018 Rooney C, Sauer T. Nat Med Jun;24(6):

33 Summary and Future Directions CAR T-cell expansion and inflammatory cytokines are associated with CRS and/or neurotoxicity Use of tocilizumab and steroids for management of toxicities did not appear to impact efficacy after axi-cel therapy Prophylactic tocilizumab decreased severe CRS but did not impact neurotoxicity Training of all healthcare providers involved in the management of patients is necessary for safe administration of CAR T-cell therapy Agents to target myeloid cells, IL-1 blockade, and/or to stabilize endothelial cells may further improve safety in the future ASBMT Consensus Grading System for CRS and neurotoxicity has been proposed

34 ASH 2018: Abstracts of Interest on CAR-T Toxicity Abstract # Brief title Authors Presentation time 91 Real world experience with Axi-cel Nastoupil LJ, et al. Saturday, 9:30 am 96 Safety of axi-cel in elderly DLBCL patients Sano D, et al. Saturday, 10:45 am 223 Late effects of CD19 CAR T-cell therapy Cordeiro A, et al Saturday, 4:00 pm 2967 Safety and efficacy at 2 years on ZUMA-1 Neelapu S, et al Sunday, 6:00 pm Elevated expansion of axi-cel by immunotyping and association with toxicity Hu19-CD828Z CAR T-cells and low levels of neurologic toxicity Updated efficacy and safety analysis of tisagenlecleucel Spiegel JY, et al. Kochenderfer JN, et al. Grupp SA, et al. Monday, 8:15 am Monday, 10:30 am Monday, 4:30 pm 961 Anti-GM-CSF reduces CRS and neurotoxicity Sterner RM, et al Monday, 4:30 pm 4190 Consensus grading of CRS in JULIET Schuster SJ, et al Monday, 6:00 pm 4183 Grading of neurotoxicity in JULIET Maziarz RT, et al Monday, 6:00 pm