Engineering an Immunity to Cancer: A New Era of Adoptive ... Oct 17 Final.pdfA New Era of Adoptive Cellular Therapy with Tisagenlecleucel (Kymriah) in Pediatric ALL Diana Schreier,

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Engineering an Immunity to Cancer: A New Era of Adoptive Cellular Therapy with Tisagenlecleucel (Kymriah) in Pediatric ALLDiana Schreier, Pharm.D., M.B.A.Pharmacy Grand RoundsOctober 17, 2017


Objectives• Define Chimeric Antigen Receptor (CAR) T-Cell

Therapy and its role in the treatment of pediatric ALL

• Describe the process of engineering, administering and monitoring tisagenlecleuceltreatment

• Review complications and management strategies for treatment-related adverse effects


Patient case• JM is a 6 year old male brought in by his

mother. She is very concerned that JM has been looking very pale recently and is covered in bruises.

• Upon further evaluation, JM’s workup shows the following: lymphadenopathy, Hgb 7.4, leukocytes 6.3, plt 87, > 20% lymphoblasts on bone marrow biopsy


Question• JM was diagnosed with ALL. What is the first

line therapy for treating JM’s leukemia?

1. Tisagenlecleucel (Kymriah)2. Intensive chemotherapy followed by HSCT3. HSCT without chemotherapy4. Clinical trial


Phases of Pediatric ALL Treatment• Remission induction:

• Achieve remission• Consolidation/intensification:

• Eradicate remaining cancerous cells • Extracompartment therapy:

• CNS-directed• Maintenance:

• Suppress re-emergence

Cooper et al. Pediatr Clin North Am. 2015; 62(1): 61-73.National Comprehensive Cancer Network. Acute Lymphoblastic Leukemia (Version 4.2017). https://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed October 6, 2017.


Relapsed Pediatric ALL Treatment• Relapses occur most frequently within 2 years of

treatment completion• Oftentimes patients undergo re-induction and

consolidation to achieve 2nd complete response• Followed by allogeneic hematopoietic stem cell

transplant (HSCT)• Cure rate of 30%-50% after chemotherapy and

allogeneic HSCT

Cooper et al. Pediatr Clin North Am. 2015; 62(1): 61-73.Inaba et al. Lancet. 2013;381(9881): 1943-55.Locatelli et al. Blood. 2012; 12(14): 2807-16.


Immuno-oncology• Hallmark of cancer:

• Ability to avoid immune destruction

• Immunosurveillance• Host recognizes and eliminates immunogenic

tumors

• Novel therapies in immuno-oncology• Check point antibodies (PDL-1, CTLA-4 inhibitors)• Cytokine therapy (interleukins, interferons)• Chimeric Antigen Receptor (CAR) T-cells

Hanahan et al. Cell. 2011;100:57-70.Finn et al. Ann Oncol. 2012;23(8): vii6-vii9.


Immuno-oncology

• Unregulated tumor growth occurs when tumor subverts immune response

1. Loss of immunogenicity2. Microenvironment with immunosuppressive cells

Cancer cell

Cancer cell

1 2

Cancer cell


Immunosurveillance mechanismExpansion and differentiation

T cell

Cancer cell

Cytokine signaling

Cytotoxicity

Kymriah® [package insert]. Novartis Pharmaceuticals Corporation. New Hanover, NJ; 2017.


Tisagenlecleucel mechanism• Chimeric Antigen Receptor (CAR) T cells

• Autologous T-cells that have been genetically altered to express a disease-associated antigen

Eshhar, Z et al. Proc Natl Acad Sci USA. 1993; 90(2):720-724.

Tisagenlecleucel

ALL B cell


Dahan R, Reiter Y. Expert Rev Mol Med. 2012; 14: e6.Kochenderfer JN et al. J Immunother. 2009; 32(7): 689-702.

Structure of tisagenlecleucel CAR

scFv

Anti-CD19Transmembrane domain

Costimulationsignaling domain 41BB (CD137)

CD3ʓ signaling domain


Treatment process

Leukapheresis Administration

Transport to manufacturer

Transduction

Final product

Lymphodepleting chemotherapy


Tisagenlecleucel preparation• Preparation and transduction with lentiviral vector

• The vector is self-inactivating• Has not demonstrated signs of genotoxicity

Lentiviral transduction with anti-CD19 CAR

transgene

Li et al. Transl Med. 2010;8:104.Tisagenlecleucel (CTL019). FDA Advisory Committee Briefing Document. 2017

Cavazzana et al. Hum Gene Ther. 2016;27: 108-116.Hacein-Bey-Abina et al. JAMA. 2015; 313: 1550-1563.Heinrich et al. Mol Ther. 2013;21:1160-1168.


Cellular Expansion• Utility of lymphodepletion

• Inhibits endogenous T cells that secrete regulatory cytokines

• Facilitates the expansion of transferred cells

Tisagenlecleucel

Porter D, et al. Sci Transl Med. 2015; 7(303):303ra139.Ramos et al. Cancer J. 2012;20(2): 112-118.


Lymphodepleting chemotherapy• Infuse tisagenlecleucel 2 to 14 days after

completion of lymphodepleting therapy

• Fludarabine 30 mg/m2 IV daily for 4 days; AND• Cyclophosphamide 500 mg/m2 IV daily for 2 days

starting with the first dose of fludarabine

Porter D, et al. Sci Transl Med. 2015; 7(303):303ra139.Ramos et al. Cancer J. 2012;20(2): 112-118.


Patient case• After JM’s first course of treatment he achieved

complete remission. It was determined that JM’s ALL had cytogenetic abnormalities that increased his risk of relapse, so after achieving remission he also underwent an allogeneic HSCT.

• After 12 months in remission JM returns to his 1 year follow-up appointment. Unfortunately it is determined that JM’s ALL has relapsed and he needs additional treatment.


Patient case• JM is started on tisagenlecleucel. After his

infusion he develops a high fever, difficulty breathing, chills, severe nausea and hypotension. Which of the following is the most likely cause of this reaction?

1. Neurological toxicity2. Febrile neutropenia3. Cytokine release syndrome4. Hypofibrinoginemia


CAR-T Toxicities

Challice L Bonifant, published online. 20 April 2016. doi:10.1038/mto.2016.11


Tisagenlecleucel REMS• Enroll in the Risk Evaluation and Mitigation

Strategy (REMS) program• Created to mitigate the risk of cytokine release

syndrome (CRS) and neurotoxicity• Ensures that facilities and prescribers have

appropriate training and access to management medications

Risk Evaluation and Mitigation Strategy (REMS): Cytokine release syndrome and neurological toxicities. Novartis Pharmaceuticals Corporation. 2017.


Treatment of CRS

CRS severity ManagementProdromal syndrome:

low-grade fever, fatigue, anorexia

Observe, exclude infection, administer antibiotics if neutropenic

Overt CRS (> 1 of the following)

- High fever- Hypoxia- Mild hypotension

Administer antipyretics, oxygen, IV fluids and/or vasopressors as needed



Treatment of CRSCRS severity ManagementSevere or Life-Threatening CRS (> 1 of the following):

- Refractory hemodynamic instability

- Worsening respiratory distress

- Rapid clinical deterioration

Administer vasopressors, oxygen, mechanical ventilation

Administer tocilizumab

Resistant CRS

No clinical improvement in 12 to 18 hours, or worsening despite management

Administer methylprednisolone

Repeat tocilizumab



Management of CRS in B2202

CRSmanagement

Total n = 53; [n(%)]

Systemic Anticytokine given 26 (49)

Tocilizumab• 1 dose• 2 doses• 3 doses

26 (49)16 (30)7 (13)

Siltuximab 5 (9)Corticosteroids 14 (26)Other 2 (4)

FDA Briefing Document Oncologic Drugs Advisory Committee Meeting. BLA 125646: 2017.Lee et al. Blood. 2014; 124(2): 188-195.Sebba et al. Am J Health Syst Pharm. 2008; 65(15):1413-8.


Cytokine release syndrome in the B2202 Trial• CRS occurred in 79% of patients

• Grade 3 or 4 CRS occurred in 49% (33/68) of patients

• Median time to onset was 3 days• Range 1 to 22 days

• Time to grade 3 or 4 onset• Within 6 days

• Median time to resolution was 8 days• Range 1 to 36 days

FDA Briefing Document Oncologic Drugs Advisory Committee Meeting. BLA 125646: 2017.


Cytokine release syndrome in the B2202 Trial (n=68)• No correlation between tisagenlecleucel dose and CRS


Morbidity ConsequenceFever 49 (72%) of subjects had fevers lasting for a mean of 8 days

with a range of 1 to 36 daysRenalimpairment

Seven subjects (10%) required dialysis for a mean of 11 days

Respiratory 10 subjects (15%) required ventilatory support for a mean of 8.5 days (range 4 to 19 days)

ICU admission 31 subjects (46%) were admitted to an ICU with a mean LOS of 11 days (range 1 to 34 days)

Coagulopathy Hypofibrinoginemia grade 3: 14 subjects; grade 4: 18 subjects.One death due to intracranial hemorrhage

Tumor burden Trend toward a correlation between higher tumor burden and CRS


B2202 CRS-Related Adverse Events

0%

10%

20%

30%

40%

50%

60%

70%

80%

Fever Renalimpairment

ICU admission Coagulopathy

Adverse Event Frequency


72%

10%

46% 47%


Neurotoxicity in the B2202 trial• Reported in 44% (n=30) subjects

• Neurotoxicity was generally related to CRS development• In 6 patients neurotoxicity occurred after CRS

resolution

• Supportive treatment• Maintain airway• Seizure prophylaxis• Corticosteroids

• Study had 1 death due to respiratory failure



Prolonged Cytopenias• Cytopenias can occur for several weeks following

lymphodepleting chemotherapy and tisagenlecleucelinfusion

• Myeloid growth factors are not recommended

• Prolonged cytopenias are associated with infection

• Grade 3 and 4 cytopenias:

Cytopenia (n=52) Day 28 Day 56Neutropenia 40% 17%

Thrombocytopenia 27% 12%



Serious Infections• Infection prophylaxis prior to tisagenlecleucel

administration should follow local guidelines

• Types of infections in B2202• Unknown source: 41%• Viral: 26%• Bacterial: 19%• Fungal: 13%

Infection Incidence (n=68)All grades 40 (59%)

Grade 3 or 4 24 (35%)Fatal 2 (3%)



Post-Infusion Deaths in B2202 trial• ALL: 7

• Infections: 2• Respiratory tract infection• Systemic mycosis• Encephalitis CSF positive for HHV6B

• Cerebral hemorrhage: 1



Tisagenlecleucel Efficacy

Results N=63CR/CRi N=52, (83%)

95% confidence interval (71% to 91%)P < 0.0001

CR N=40 (63%)CRi N=12 (19%)CR or CRi with MRD-negative bone marrow

52 (83%)95% confidence interval (71% to 91%)P < 0.0001

Duration of remission N=52 (not reached)


CR: Complete responseCRi: Complete response with incomplete blood count recovery


Balancing Risk and Benefit

Tisagenlecleucel benefit

Adverse effects


Summary• Tisagenlecleucel is a novel CAR-T therapy that

uses a patient’s own T cells to treat ALL• The process of engineering, administering and

monitoring tisagenlecleucel is complex and requires a well-coordinated team

• Despite clinical efficacy, tisagenlecleucelexhibits multiple serious and life-threatening toxicities


Questions & Discussion

Documents

Engineering an Immunity to Cancer: A New Era of Adoptive ... Oct 17 Final.pdfA New Era of Adoptive Cellular Therapy with Tisagenlecleucel (Kymriah) in Pediatric ALL Diana Schreier,