Updates in Immuno-Oncology:

Focus on CAR-T Cell Therapy

Mary Nauffal, PharmD, MSHematology/ Oncology Clinical Pharmacist

Brigham and Women’s HospitalMSHP 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

June C.H. et al. N Engl J Med. 2018; 379:64-73

1 2

3

4

5

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

Intervention

0.76×106 to 20.6×106 CAR-T cells/kgn=25 (pt age 5-22 yrs)n=5 (pt age 26-60)

Efficacy

CR: n=27 (90%); OS: 78% 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

Schuster S.J. et al. N Engl J Med 2019; 380:45-56

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%

Overall Survival Duration of Response

Neelapu S.S. et al. N Engl J Med 2017; 377:2531-2544

ZUMA-1: Yescarta® Therapy in Refractory Large B-Cell Lymphoma

Multicenter, phase 2 trial (n=101) – patients with R/R LBCLCR at 15.4 months: 40%OS at 18 months: 52%

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 ciloleucelin 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

Objective Evaluate long term efficacy and safety of axi-cel in patients refractory to conventional therapy

Intervention 2×106 anti-CD19 CAR T cells/ kg post conditioning therapy

Efficacy

n=101 assessable as of Aug. 2018 (median 27.1 months) CR: n=59 (58%)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

June C.H. et al. Sceince 2018; 359:1361-1365

Leukemia cell

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; 371:1507-1517Neelapu S.S. et al. N Engl J Med 2017; 377:2531-2544Schuster 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 𝜅 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

NCCN. Version 2.2019 – April 8, 2019

Gradingdefinition

Supportive Care

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+ neurotoxicity (%)

15 28 12

Maude S.L. et al. N Engl J Med 2014; 371:1507-1517Neelapu S.S. et al. N Engl J Med 2017; 377:2531-2544Schuster 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

OrientationOrientation to year, month, city, hospital

4

Naming Ability to name 3 objects 3

Following commands Ability to follow simple commands 1

Writing Ability to write a standard sentence 1

Attention Ability to count backwards from 100 by 10

1

Lee W. D. et al. Biol Blood Marrow Transplant 2019;25:625-638

ICANS Grading CriteriaNeurotoxicity Domain

Grade 1 Grade 2 Grade 3 Grade 4

ICE score 7-9 3-6 0-2 0 (unarousable)

Depressed level of consciousness

Awakens spontaneously

Awakens to voice

Awakens only to tactile stimulus

Unarousable, stupor, coma

Seizure

N/AN/A

Any clinical seizure focal or generalized that resolves rapidly or nonconvulsive seizures on EEG that resolve with intervention

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

Elevated ICP/ 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

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.