Tisagenlecleucel

Identification

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Name
Tisagenlecleucel
Accession Number
DB13881
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Cell transplant therapies
Autologous cell transplant
Description

Tisagenlecleucel is a CD19-directed genetically modified autologous T cell immunotherapy, or a CAR-T cell therapy for B-cell acute lymphoblastic leukemia. It was granted approval by FDA in August 2017 under the market name Kymriah. Tisagenlecleucel is an immunocellular therapy that involves autologous T cells that are collected from each individual patient and genetically engineered to express a specific protein called a chimeric antigen receptor (CAR) that specifically target CD19 antigens. Modified T cells are infused back into the patient's body. These CD19-directed chimeric antigen receptors (CD19 CAR-T cells) direct the T cells to targt and kill leukiemia cells that express a specific antigen (CD19) on the cell surface.

In a multicenter clinical trial involving pediatric and young adult patients with relapsed or refractory B-cell precursor ALL, the overall remission rate within three months of treatment was 83 percent 4.

Synonyms
  • Adoptive immunotherapy agent CTL019
  • CAR.CD19-Redirected T cells
  • Tisagenlecleucel-T
External IDs
CART-19 / CART19 / CTL-019 / CTL019
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
KymriahInjection, suspension2000000 1/1IntravenousNovartis Pharmaceuticals Corporation2017-08-30Not applicableUs
KymriahSuspension600000000 cellsIntravenousNovartis2019-05-24Not applicableCanada
KymriahInjection, suspension60000000 1/1IntravenousNovartis Pharmaceuticals Corporation2018-05-01Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
Q6C9WHR03O
CAS number
1823078-37-0

Pharmacology

Indication

Indicated for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse Label.

Associated Conditions
Pharmacodynamics

Tisagenlecleucel demonstrates efficacy in re-inducing remission in patients with refractory B-cell precursor acute lymphoblastic leukemia. The sole purpose of the therapy is to eliminate CD19-expressing malignant and normal cells with specificity and increased chance of remission.

Mechanism of action

Tisagenlecleucel is a CD19-directed genetically modified autologous T cell immunotherapy that involves genetically modified autologous T cells isolated from each individual patient. The reprogramming of the patient's T cells uses a lentiviral vector to encode an anti-CD19 chimeric antigen receptor (CAR). The CAR is comprised of a murine single-chain antibody fragment (scFv) specific for CD19, followed by a CD8 hinge and transmembrane region that is fused to the intracellular signaling domains from 4-1BB (CD137) and CD3 zeta Label. These intracellular costimulatory signaling domains increase the expansion, longer-term persistence and potency of CAR T cells 1,3: the CD3 zeta component is critical for initiating T-cell activation and antitumor activity, while 4-1BB enhances the expansion and persistence of tisagenlecleucel {FDA Label, A20379]. Upon binding to CD19-expressing cells, the CAR transmits a signal to promote T-cell expansion, activation, target cell elimination, and persistence of the tisagenlecleucel cells Label.

TargetActionsOrganism
AB-lymphocyte antigen CD19
antibody
Humans
Additional Data Available
Adverse Effects

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available
Blackbox Warnings

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Absorption

In pediatric and young adult relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) patients receiving tisagenlecleucel infusion, the mean peak plasma concentration was approximately 34,700 copies/mcg with a median time of 9.91 days to reach this value (Tmax ) Label.

Volume of distribution

The drug is found to be distributed in the blood as well as the bone marrow. Blood to bone marrow partitioning suggested that tisagenlecleucel distribution in bone marrow was 44% of that present in blood at Day 28 while at Months 3 and 6 tisagenlecleucel distributed at 67% and 69%, respectively, indicating high distribution to bone marrow Label.

Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

The mean half life was 16.8 days in pediatric and young adult relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) patients Label.

Clearance
Not Available
Toxicity

Genotoxicity assay, carcinogenicitiy assay, and studies assesssing the effect of drug on fertility have not been conducted for tisagenlecleucel. According to in vitro T cell expansion studies involving transduced T cells from healthy donors and patients, there is no evidence of transformation and immortality Label.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
Not Available

References

General References
  1. Tasian SK, Gardner RA: CD19-redirected chimeric antigen receptor-modified T cells: a promising immunotherapy for children and adults with B-cell acute lymphoblastic leukemia (ALL). Ther Adv Hematol. 2015 Oct;6(5):228-41. doi: 10.1177/2040620715588916. [PubMed:26425336]
  2. Wei G, Ding L, Wang J, Hu Y, Huang H: Advances of CD19-directed chimeric antigen receptor-modified T cells in refractory/relapsed acute lymphoblastic leukemia. Exp Hematol Oncol. 2017 Apr 14;6:10. doi: 10.1186/s40164-017-0070-9. eCollection 2017. [PubMed:28413717]
  3. Davila ML, Brentjens RJ: CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia. Clin Adv Hematol Oncol. 2016 Oct;14(10):802-808. [PubMed:27930631]
  4. FDA Press Announcements: FDA approval brings first gene therapy to the United States [Link]
External Links
PubChem Substance
347911451
Wikipedia
Tisagenlecleucel
FDA label
Download (222 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0Active Not RecruitingTreatmentLymphoma, Hodgkins1
0Active Not RecruitingTreatmentMalignant Neoplasm of Pancreas1
0CompletedTreatmentMalignant Lymphomas1
1Active Not RecruitingTreatmentAcute Biphenotypic Leukemia (ABL) / Acute Lymphoblastic Leukaemias (ALL) / Blasts 5 Percent or More of Bone Marrow Nucleated Cells / CD19 Positive / Leukemias / Malignant Lymphomas / Minimal Residual Disease / Non-Hodgkin's Lymphoma (NHL) / Small Lymphocytic Lymphoma / Stage III Chronic Lymphocytic Leukemia / Stage IV Chronic Lymphocytic Leukemia1
1CompletedTreatmentAcute Lymphocytic Leukemia (ALL)1
1CompletedTreatmentAdult Acute Lymphoblastic Leukemia in Remission / B-cell Adult Acute Lymphoblastic Leukemia / B-Cell Chronic Lymphocytic Leukemia / Chronic Lymphocytic Leukemia (CLL) - Refractory / Hematopoietic/Lymphoid Cancer / Leukemia, Prolymphocytic / Recurrent Adult Diffuse Large Cell Lymphoma / Recurrent Grade 1 Follicular Lymphoma / Recurrent Grade 2 Follicular Lymphoma / Recurrent Grade 3 Follicular Lymphoma / Recurrent Mantle Cell Lymphoma / Stage III Adult Diffuse Large Cell Lymphoma / Stage III Chronic Lymphocytic Leukemia / Stage III Grade 1 Follicular Lymphoma / Stage III Grade 2 Follicular Lymphoma / Stage III Grade 3 Follicular Lymphoma / Stage III Mantle Cell Lymphoma / Stage IV Adult Diffuse Large Cell Lymphoma / Stage IV Chronic Lymphocytic Leukemia / Stage IV Grade 1 Follicular Lymphoma / Stage IV Grade 2 Follicular Lymphoma / Stage IV Grade 3 Follicular Lymphoma / Stage IV Mantle Cell Lymphoma1
1CompletedTreatmentB Cell Leukemias / Lymphoma, B Cell1
1CompletedTreatmentMultiple Myeloma (MM)1
1Not Yet RecruitingTreatmentPrimary Central Nervous System Lymphoma (PCNSL) / Refractory Primary CNS Lymphoma / Relapsed Primary CNS Lymphoma1
1RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL)1
1RecruitingTreatmentB-cell Acute Lymphoblastic Leukemia1
1RecruitingTreatmentLeukemia, Lymphocytic, Acute, B-Cell / Leukemia, Lymphocytic, Chronic, B-Cell / Lymphoma, B-Cell1
1RecruitingTreatmentLeukemias1
1RecruitingTreatmentLymphoma, B Cell1
1RecruitingTreatmentLymphoma, Large B-Cell, Diffuse (DLBCL)2
1, 2RecruitingTreatmentAcute Lymphoblastic Leukaemia Recurrent / Chronic Lymphocytic Leukemia (CLL) - Refractory / Chronic Lymphocytic Leukemia Recurrent / Recurrent B-Cell Lymphoma / Refractory Follicular Lymphoma1
1, 2RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML)1
1, 2RecruitingTreatmentLeukemia, B-Cell1
1, 2RecruitingTreatmentLeukemia, Lymphocytic, Acute1
2Active Not RecruitingTreatmentAcute / Childhood / High Risk / Leukaemia, Lymphoblastic / Lymphoblastic Leukemia, Acute, Childhood1
2Active Not RecruitingTreatmentCurative Treatment Options Who Have a Limited Prognosis With Currently Available Therapies / Non-Hodgkins Lymphoma (NHL) Patients, With CD19+B Cell Lymphomas / Non-Hodgkins Lymphoma (NHL) Patients, With CD19+B Cell Lymphomas With no Available Potentially1
2CompletedTreatmentAdult Patients Who Have Relapsed or Refractory CLL (3rd Line) or SLL1
2CompletedTreatmentB-cell Acute Lymphoblastic Leukemia / Refractory B-cell Acute Lymphoblastic Leukemia / Relapsed B-Cell Acute Lymphoblastic Leukemia1
2CompletedTreatmentCurative Treatment Options (Such as Autologous or Allogeneic Stem Cell / Patients With B Cell ALL, Relapsed or Refractory, With no Available / Patients With B Cell ALL, Relapsed or Refractory, With no Available Curative Treatment Options / Transplantation) Who Have Limited Prognosis (> 12 Weeks Survival Expectancy) / With Currently Available Therapies1
2Not Yet RecruitingTreatmentB-cell Acute Lymphoblastic Leukemia1
2Not Yet RecruitingTreatmentPrecursor B-Lymphoblastic Lymphoma/Leukaemia Refractory1
2RecruitingTreatmentB-cell Acute Lymphoblastic Leukemia1
2RecruitingTreatmentFollicular Lymphoma (FL)1
2RecruitingTreatmentLymphoma, Large B-Cell, Diffuse (DLBCL)1
2RecruitingTreatmentNon-Hodgkin's Lymphoma (NHL)1
2TerminatedTreatmentAcute Lymphoblastic Leukaemias (ALL)1
2TerminatedTreatmentMultiple Myeloma (MM)1
2WithdrawnTreatmentB-cell Acute Lymphoblastic Leukemia / Refractory B-cell Acute Lymphoblastic Leukemia / Relapsed B-Cell Acute Lymphoblastic Leukemia1
2, 3RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL)1
2, 3RecruitingTreatmentRelapsed/Refractory B-cell ALL1
3Not Yet RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL)1
3Not Yet RecruitingTreatmentB-cell Acute Lymphoblastic Leukemia / Lymphoma, Large B-Cell, Diffuse (DLBCL)1
3RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL)1
3RecruitingTreatmentNon-Hodgkin's Lymphoma (NHL)1
Not AvailableActive Not RecruitingTreatmentChronic Lymphocytic Leukemia or Small Lymphocytic Leukemia (CLL or SLL)1
Not AvailableActive Not RecruitingTreatmentLymphoblastic Leukemia, Acute, Childhood1
Not AvailableAvailableNot AvailableAcute Lymphoblastic Leukaemias (ALL) / Lymphoma, Large B-Cell, Diffuse (DLBCL)1
Not AvailableRecruitingNot AvailableAcute Lymphoblastic Leukaemias (ALL) / Large B-cell Lymphoma / Refractory CD19+ B-cell Pediatric ALL / Refractory Diffuse Large B Cell Lymphoma / Refractory Large B-cell Lymphoma / Relapsed CD19+ B-cell Pediatric ALL / Relapsed Large B-cell Lymphoma1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, suspensionIntravenous2000000 1/1
Injection, suspensionIntravenous60000000 1/1
SuspensionIntravenous600000000 cells
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antibody
General Function
Receptor signaling protein activity
Specific Function
Assembles with the antigen receptor of B-lymphocytes in order to decrease the threshold for antigen receptor-dependent stimulation.
Gene Name
CD19
Uniprot ID
P15391
Uniprot Name
B-lymphocyte antigen CD19
Molecular Weight
61127.985 Da

Drug created on September 01, 2017 12:43 / Updated on December 02, 2019 10:07