Updates in Immuno- Oncology: Focus on CAR-T Cell Therapy
Mary Nauffal, PharmD, MS Hematology/ Oncology Clinical Pharmacist Brigham and Women’s Hospital MSHP Annual Meeting 2019 May 15, 2019 Objectives
• Review the role of immunology and rationale for CAR-T cell therapy
• Present the evidence supporting CAR-T cell therapy
• Discuss the complications and management options for CAR-T cell therapy Objectives
• Review the role of immunology and rationale for CAR-T cell therapy
• Present the evidence supporting CAR-T cell therapy
• Discuss the complications and management options for CAR-T cell therapy History of Immunotherapy William B. Coley, MD injected live and inactivated Streptococcus pyogenes into patients’ tumors in 1891 to harness the immune system to treat the cancer
Decker W.K. et al. Front. Immunol. 2017 8:829;1-13 Immunotherapy Milestones
Voena C. et. al. Discovery Medicine 2016 114:125-133 Immunotherapy
• Cancer immunotherapy harnesses the power of the immune system to eradicate malignant tissue • Graft-versus-leukemia • Monoclonal antibodies • Therapeutic cancer vaccines • Checkpoint inhibitors • Bi-specific monoclonal antibodies (BiTE) • Chimeric Antigen Receptor (CAR) T cells What are CAR-T Cells? • Genetically modified autologous T-cells that express tumor specific antigens • Fusion proteins that incorporate • Tumor antigen recognition domains • Anti-CD 19 • Anti-BMCA • T-cell activation/signaling domains • CD 3 complex
June C.H. et al. N Engl J Med. 2018; 379:64-73 Road Blocks for Successful CAR-T Therapy
• Expansion in the host • Young T-cells
• T-cell persistence • Memory T-cells • Early loss of T-cells correlated to risk of relapse
• Antigen specific to tumor cells • Risks vs. benefits • Recognize only cell surface antigens
• Initial lymphocyte count and optimal CAR-T dose
June C.H. et al. Science 2018; 359:1361-1365 Principles of CAR Design
Gill S. et al. Immunological Reviews 2015;263:68-89. Evolution of CARs
June C.H. et al. Science 2018; 359:1361-1365 CAR “Manufacturing and Delivery”
Gill S. et al. Immunological Reviews 2015;263:68-89. CAR “Manufacturing and Delivery”
Kochenderfer J.N. et al. Nat Rev Clin Oncol. 2013;10:267-76. Mechanism of Action
1 2
5 3 4
June C.H. et al. N Engl J Med. 2018; 379:64-73 Timeline Phases of CAR Therapy
Kevin A. H. et al. Drugs 2017; 77 (3):237-245 FDA Approved Indications
• Tisagenlecleucel - Kymriah® • Relapsed/ refractory large B-cell lymphoma after ≥ 2 lines of therapy • B-cell acute lymphoblastic leukemia up to 25 years of age
• Axicabtageneciloleucel - Yescarta® • Relapsed/ refractory large B-cell lymphoma after ≥ 2 lines of therapy Assessment Question #1
A CAR construct contains an antibody-derived scFv extracellular domain, a hinge, a transmembrane domain, and a CD3ζ intracellular signaling domain, but no costimulatory domains. What type of CAR is this?
A. Smart CAR B. 1st Generation CAR C. 2nd Generation CAR D. 3rd Generation CAR
Maus MV, et al. Blood 2014;123(17):2625-35. Objectives
• Review the role of immunology and rationale for CAR-T cell therapy
• Present the evidence supporting CAR-T cell therapy
• Discuss the complications and management options for CAR-T cell therapy Phase I/IIA Early Trials for Kymriah® in Children and Young Adults with ALL
Maude S.L. et al.
Product Tisagenlecleucel - Kymriah®
Method Phase I/IIA
Objective Evaluate efficacy and safety up to 2 years in CD19+ R/R ALL 0.76×106 to 20.6×106 CAR-T cells/kg Intervention n=25 (pt age 5-22 yrs) n=5 (pt age 26-60)
CR: n=27 (90%); OS: 78% Efficacy 6-mo EFS: 67% 6-mo persistence of CTL019: 68% and B-cell aplasia: 73%
Maude S.L. et al. N Engl J Med 2014; 371:1507-1517 Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia Overall Survival B-cell Aplasia
Maude S.L. et al. N Engl J Med 2014; 371:1507-1517 ELIANA: Kymriah® in Children and Young Adults with B-cell ALL • Multicenter-single cohort • n=75 • At 12 months • OS: 76% (95% CI, 63-86) • EFS: 50% (95% CI, 35-64) • Duration of remission not reached • Persistence of CAR T cells was as long as 20 months
Maude S.L. et al. N Engl J Med 2018; 378:439-448 JULIET: Kymriah® in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma Overall Survival Duration of Response
International, phase 2, pivotal trial (n=93) ORR 52% CR 40% Schuster S.J. et al. N Engl J Med 2019; 380:45-56 ZUMA-1: Yescarta® Therapy in Refractory Large B-Cell Lymphoma Overall Survival Duration of Response
Multicenter, phase 2 trial (n=101) – patients with R/R LBCL CR at 15.4 months: 40% OS at 18 months: 52% Neelapu S.S. et al. N Engl J Med 2017; 377:2531-2544 ZUMA-1: Yescarta® Therapy in Refractory Large B-Cell Lymphoma
Neelapu S.S. et al. N Engl J Med 2017; 377:2531-2544 Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single- arm, multicentre, phase 1-2 trial.
Locke F.L. et al. ZUMA-1 Product Axicabtagene ciloleucel (axi-cel) - Yescarta® Method Multicenter, phase 1-2 trial - (n=111) – patients with R/R LBCL Evaluate long term efficacy and safety of axi-cel in patients refractory to conventional Objective therapy Intervention 2×106 anti-CD19 CAR T cells/ kg post conditioning therapy n=101 assessable as of Aug. 2018 (median 27.1 months) CR: n=59 (58%) Efficacy Median OS: not reached (12.8 – not estimable) Median duration of response: 11.1 months (4.2 – not estimable)
Locke F.L. et al. Lancet Oncol 2019; 20:31-42 Overall Survival Duration of Response
Locke F.L. et al. Lancet Oncol 2019; 20:31-42 Assessment Question #2
Based on the long-term data from the ZUMA-1 trial, patients treated with axi-cel who had a partial or complete response at 3 months, were cured from their large B-cell lymphoma.
A. True
B. False Objectives
• Review the role of immunology and rationale for CAR-T cell therapy
• Present the evidence supporting CAR-T cell therapy
• Discuss the complications and management options for CAR-T cell therapy Toxicities Associated with CAR-T Infusion
• Cytokine release syndrome (CRS)
• Neurotoxicity
• Cytopenias and B-cell aplasia Cytokine Release Syndrome What is CRS?
• “A supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effectors” • Progressive symptoms • Fever at onset • Hypotension • Capillary leak • End-organ dysfunction • Median time to onset: 2-3 days
Lee W. D. et al. Biol Blood Marrow Transplant 2019;25:625-638 Mechanism of CAR T Toxicity
Leukemia cell
June C.H. et al. Sceince 2018; 359:1361-1365 Incidence of CRS in Clinical Trials
ELIANA ZUMA-1 JULIET
Product Kymriah® Yescarta® Kymriah®
Patients treated (n) 30 101 111
CRS (%) 73 93 58
Grade 3+ CRS (%) 27 13 22
Maude S.L. et al. N Engl J Med 2014; 371:1507-1517 Neelapu S.S. et al. N Engl J Med 2017; 377:2531-2544 Schuster S.J. et al. N Engl J Med 2017; 377:2545-2554 Factors Associated with Severe CRS
Maude S.L. et al. N Engl J Med 2014; 371:1507-1517 Factors Associated with Severe CRS
Maude S.L. et al. N Engl J Med Supplementary Appendix 2014; 371:1507-1517 CRS Grading
Grade Toxicity Grade 1 • Fever (T≥ 38ᵒC) • Constitutional symptoms (nausea, fatigue, myalgias)
Grade 2 • Hypotension responding to fluids and/or low dose pressor
• Hypoxia requiring FiO2< 40% Grade 3 • Hypotension requiring high-dose or multiple vasopressors
• Hypoxia requiring FiO2 ≥ 40%
Grade 4 • Life-threatening requiring ventilator support or vasopressor-refractory shock • Grade 4 organ toxicity Grade 5 Death due to CRS
Lee W. D. et al. Biol Blood Marrow Transplant 2019;25:625-638 Management of CRS Agents Used to Manage CRS
• Antipyretics • IV fluids • Pressors • Oxygen • Anti-cytokine therapies • Tocilizumab • Siltuximab • Corticosteroids Cytokine Levels After Infusion
Grupp S.A. et al. N Engl J Med 2013; 368:1509-1518 Tocilizumab • Humanized IgG1 휅 IL-6 receptor blocking monoclonal antibody
• Concern for increase in IL-6 levels post administration that may contribute to neurotoxicity
• Dose: 8 mg/kg (max 800 mg) Q8 h up to 4 doses
• Administered within 2-hours of CRS onset
• No known impact on decreased efficacy
• Patients need to enroll in REMS program
Lee W. D. et al. Biol Blood Marrow Transplant 2019;25:625-638 Tocilizumab
Le R.Q. et al. The Oncologist 2018; 23:943-947 Corticosteroids
• Indicated • High risk patients • Hypotension persists after 1-2 doses of tocilizumab
• Dexamethasone 10 mg IV Q6 hours
Dholaria B.R. et al. BioDrugs 2019; 33:45-60 Siltuximab
• Human-murine chimeric monoclonal antibody that binds to IL-6 directly
• Off label use for tocilizumab-refractory cases
• No published reports on efficacy and safety of siltuximab caution warranted with use
Mahmoujafari Z. et al. Biol Blood Marrow Transplant 2019;25:26-33 Grading Supportive definition Care
NCCN. Version 2.2019 – April 8, 2019 Neurotoxicity What is Neurotoxicity? • “A disorder characterized by a pathological process involving the central nervous system following any immune therapy that results in the activation or engagement of endogenous or infused T-cells and/or other immune effector cells” • Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS) • Progressive symptoms • Aphasia • Altered level of consciousness • Impaired cognitive skills • Motor weakness • Seizure • Cerebral edema
Lee W. D. et al. Biol Blood Marrow Transplant 2019;25:625-638 Neurotoxicity
• Pathophysiology • Cytokine-mediated endothelial activation and disruption of blood brain barrier • Increased CAR-T cells, pro-inflammatory cytokines and IL-6 levels in the CSF • Risk factors • Disease burden • Dose of CAR-T cells infused • Intensive chemotherapy bridging • High intensity lymphodepleting chemotherapy • Pre-existing neurologic co-morbidities
Lee W. D. et al. Biol Blood Marrow Transplant 2019;25:625-638 Neurotoxicity
• Can occur • Concurrently with CRS • Delayed post CRS • In absence of CRS
• Median time to onset: 4 days
Lee W. D. et al. Biol Blood Marrow Transplant 2019;25:625-638 Incidence of Neurotoxicity in Clinical Trials
ELIANA ZUMA-1 JULIET
Product Kymriah® Yescarta® Kymriah®
Patients treated (n) 30 101 111
Neurotoxicity (%) 43 64 21
Grade 3+ 15 28 12 neurotoxicity (%)
Maude S.L. et al. N Engl J Med 2014; 371:1507-1517 Neelapu S.S. et al. N Engl J Med 2017; 377:2531-2544 Schuster S.J. et al. N Engl J Med 2017; 377:2545-2554 Management of Neurotoxicity Agents Used to Manage Neurotoxicity
• Corticosteroids • Dexamethasone 10 mg IV Q6 hours • Methylprednisolone 1 mg/kg IV Q12 hours • Refractory cases: methylprednisolone 1 g IV Q24 hours
• Median time to resolution 4 days (range 1-64 days)
• Role for Tocilizumab? • Tocilizumab does not cross the blood brain barrier
Acharya U.H. et al. Exp Rev Hematol 2019; 12(3):195-205 Encephalopathy Assessment
Criteria ICE Criteria Assigned points
Orientation to year, month, city, Orientation 4 hospital
Naming Ability to name 3 objects 3
Following commands Ability to follow simple commands 1
Writing Ability to write a standard sentence 1
Ability to count backwards from 100 Attention 1 by 10
Lee W. D. et al. Biol Blood Marrow Transplant 2019;25:625-638 ICANS Grading Criteria
Neurotoxicity Grade 1 Grade 2 Grade 3 Grade 4 Domain ICE score 7-9 3-6 0-2 0 (unarousable) Depressed level Awakens Awakens to Awakens only to tactile Unarousable, stupor, coma of consciousness spontaneously voice stimulus Seizure Any clinical seizure focal Life-threatening prolonged seizure (>5 or generalized that min); or Repetitive clinical or electrical N/A resolves rapidly or seizures without return to baseline in N/A nonconvulsive seizures on between EEG that resolve with intervention Motor findings N/A N/A N/A Deep focal motor weakness such as hemiparesis or paraparesis Elevated ICP/ Focal/local edema on Diffuse cerebral edema on neuroimaging; cerebral edema N/A N/A neuroimaging decerebrate or decorticate posturing; or cranial nerve VI palsy; or papilledema; or Cushing's triad
Lee W. D. et al. Biol Blood Marrow Transplant 2019;25:625-638 NCCN. Version 2.2019 – April 8, 2019 Alternative Therapies? • Anti-GM-CSF antibodies
• Anakinra • Small peptide that can cross BBB
• Defibrotide • Endothelial stabilizing agent?
• Supportive care • Seizure prophylaxis
Acharya U.H. et al. Exp Rev Hematol 2019; 12(3):195-205 Cytopenias and Infection Cytopenias and Infection • Risk factors • Relapsed/ refractory hematologic malignancies • Lymphodepletion chemotherapy • Treatment of CRS and neurotoxicity with tocilizumab and steroids • B-cell aplasia and hypogammaglobinemia • Infection prophylaxis • Antibacterial • Antiviral • Antifungal • Anti- pneumocystis • Repletion and administration of IVIG
Mahmoujafari Z. et al. Biol Blood Marrow Transplant 2019;25:26-33 Assessment Question #3 MR is a 58 year-old-male with relapsed DLBCL that was treated with tisagenlecleucel. Two-days post CAR-T cell infusion, MR was febrile to 39.5 ᵒC, tachycardic, hypotensive to 82/58 and his ANC was 200. He was started on 2L IVF and broad-spectrum anti-biotics. His blood pressure improves with IV fluids. What grade CRS did MR encounter?
A. Grade 1 B. Grade 2 C. Grade 3 D. Grade 4 Assessment Question #4
MR, 4-hours later, again develops hypotension to 78/55. He receives 1L IVF but his BP does not bump. His oxygen saturation drops requiring 4L O2 via nasal canula. How should we manage MR’s grade 2 CRS?
A. Administer corticosteroids B. Administer corticosteroids and tocilizumab C. Administer vasopressin D. Administer vasopressin and tocilizumab Vizient Analysis: Costs with CAR-T Cell Therapy • Cost of CAR-T cell agents • Kymriah®: $475,000 • Yescarta®: $373,000
• Vizient Clinical Data Base is an administrative database of more than 400 hospitals that identified 1186 patients from May 2017-Dec 2018 who received CAR-T cell therapy • Median cost in adults • Pharmacy services: $23,150 • Accommodation: $21,561 • Adverse events: were not covered in analysis • Median hospital stay 15 days • Rate of 30-day re-admission: 17.1%
• Centers for Medicare & Medicaid (CMS) has assigned 2 ICD-10 procedure codes for CAR- T immunotherapy
Nelson R. Medscape.com. Accessed by May 2019. “‘Real World’ Data on Costs with CAR-T Cell Therapy.” Conclusions
• Efficacy is dictated by the length of persistence of CAR T-cells within patients • Long enough to eradicate malignant cells • Short enough to prevent off-target effects • Goal to attain durable response after complete remission • Management of CRS includes proactive assessment • Administer immunosuppression early for patients at highest risk • Avoid unnecessary immunosuppression to avoid risk of diminishing anti- tumor efficacy • Patients need to enroll in REMS program Future Directions
• Better understand CRS pathophysiology
• Delineate aspects of immune activation for anti-tumor effects
• Validate optimal treatment strategies
• Expanding CAR-T cells for indications
References
• Locke, Frederick L., et al. "Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial." The lancet oncology 20.1 (2019): 31-42. • Neelapu, Sattva S., et al. "Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma." New England Journal of Medicine 377.26 (2017): 2531-2544. • Grupp, Stephan A., et al. "Chimeric antigen receptor–modified T cells for acute lymphoid leukemia." New England Journal of Medicine 368.16 (2013): 1509-1518. • Maude, Shannon L., et al. "Chimeric antigen receptor T cells for sustained remissions in leukemia." New England Journal of Medicine 371.16 (2014): 1507-1517. • Schuster, Stephen J., et al. "Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma." New England Journal of Medicine 380.1 (2019): 45-56. • Lee, Daniel W., et al. "ASBMT consensus grading for cytokine release syndrome and neurological toxicity associated with immune effector cells." Biology of Blood and Marrow Transplantation (2018). • Mahmoudjafari, Zahra, et al. "American Society for Blood and Marrow Transplantation Pharmacy Special Interest Group survey on chimeric antigen receptor T cell therapy administrative, logistic, and toxicity management practices in the United States." Biology of Blood and Marrow Transplantation 25.1 (2019): 26-33. • Maus, Marcela V., et al. "Antibody-modified T cells: CARs take the front seat for hematologic malignancies." Blood 123.17 (2014): 2625-2635. References • Maude, Shannon L., et al. "Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia." New England Journal of Medicine 378.5 (2018): 439-448. • Acharya, Utkarsh H., et al. "Management of cytokine release syndrome and neurotoxicity in chimeric antigen receptor (CAR) T cell therapy." Expert review of hematology 12.3 (2019): 195-205. • Dholaria, Bhagirathbhai R., Christina A. Bachmeier, and Frederick Locke. "Mechanisms and Management of Chimeric Antigen Receptor T-Cell Therapy-Related Toxicities." BioDrugs 33.1 (2019): 45-60. • Le, Robert Q., et al. "FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell‐induced severe or life‐threatening cytokine release syndrome." The oncologist 23.8 (2018): 943-947. • June, Carl H., et al. "CAR T cell immunotherapy for human cancer." Science 359.6382 (2018): 1361-1365. • Hay, Kevin A., and Cameron J. Turtle. "Chimeric antigen receptor (CAR) T cells: lessons learned from targeting of CD19 in B-cell malignancies." Drugs 77.3 (2017): 237-245. • Kochenderfer, James N., and Steven A. Rosenberg. "Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors." Nature reviews Clinical oncology 10.5 (2013): 267. • June, Carl H., and Michel Sadelain. "Chimeric antigen receptor therapy." New England Journal of Medicine 379.1 (2018): 64-73. • Gill, Saar, and Carl H. June. "Going viral: chimeric antigen receptor T‐cell therapy for hematological malignancies." Immunological reviews 263.1 (2015): 68-89.