Axicabtagene ciloleucel

Identification

Name
Axicabtagene ciloleucel
Accession Number
DB13915
Description

Axicabtagene ciloleucel is a chimeric antigen receptor (CAR) T cell therapy for the treatment of Diffuse large B-cell lymphoma (DLBCL), which is a type of a non-Hodgkin lymphoma (NHL). It is the second cell-based gene therapy that is FDA-approved but the first in the treatment of large B-cell lymphoma in adult patients. Uniquely, axicabtagene ciloleucel utilizes each patient’s own immune system where each dose of the drug consists of the patient's genetically modified T-cells that were previously collected. The modified version of the T-cell expresses a new gene that targets and kills the lymphoma cells and is infused back into the patient.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL in adults that mostly originates from the lymph nodes but can initiate outside of the lymphatic system. Lymphoma cells appear to be much larger in size than normal lymphocytes. In a multicenter clinical trial, the patients who were treated with axicabtagene ciloleucel achieved the complete remission rate of 51%.

Developed by Kite Pharma, Inc., it was approved on October 18th, 2017 by the FDA as an intravenously infused anticancer therapy and is marketed under the brand name Yescarta.

Type
Biotech
Groups
Approved
Biologic Classification
Cell transplant therapies
Autologous cell transplant
Synonyms
  • Autologous T cells transduced with retroviral vector encoding an anti-CD-19 CD28/CD3-zeta chimeric antigen receptor
External IDs
  • KTE-C19

Pharmacology

Indication

Indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

The levels of cytokines, chemokines and other blood molecules were measured over a 4-week interval after the drug infusion. There were transient elevations of chemokines such as IL-6, IL-8, IL-10, IL-15, TNF-α, IFN-γ, and sIL2Rα where the peak elevation was reached within the first 14 days after infusion, and the levels gradually returned to baseline within 28 days Label. It is likely that axicabtagene ciloleucel may lead to B cell aplasia, or low numbers of B cells or absent B cells, as expected by other chimeric anntigen receptor T-cell therapies.

Mechanism of action

The CD 19 antigen is a 95 kDa integral membrane glycoprotein expressed on lymphocytes of the B-cell lineage but noton pluripotent stem cell. While this antigen is ubiquitously expressed on B lymphocyte lineage, the expression of this Ig protein is downregulated during terminal differentiation of premature and mature B cells into plasma cells 1. In blood disorders, however, the expression CD19 is maintained in in B-lineage cells that has undergone neoplastic transformation 1. Thus CD19 plays a critical role in clinical oncolgy as it aids in the diagnosis of blood cancers such as leukemias and lymphomas and serves as a therapeutic target for immunotherapies.

Axicabtagene ciloleucel is a CD19-directed genetically modified autologous T cell immunotherapy that binds to CD19-expressing cancer cells and normal B cells. First, the patient's own peripheral blood mononuclear cells are obtained. The T cells are then harvested and genetically modified ex vivo by retroviral transduction to express a chimeric antigen receptor (CAR) comprising a murine anti-CD19 single chain variable fragment (scFv) linked to CD28 and CD3-zeta co-stimulatory domains Label. These anti-CD19 CAR T cells are expanded and infused back into the patient.

Once the modified CAR T cells recognize the CD19-expressing target cells, the CD28 and CD3-zeta co-stimulatory domains activate downstream signaling cascades that lead to T-cell activation, proliferation, acquisition of effector functions and secretion of inflammatory cytokines and chemokines Label. These events lead to elimination of the target cells.

TargetActionsOrganism
AB-lymphocyte antigen CD19
antibody
Humans
Absorption

Following infusion of YESCARTA, anti-CD19 CAR T cells exhibited an initial rapid expansion followed by a decline to near baseline levels by 3 months. Peak levels of anti-CD19 CAR T cells occurred within the first 7-14 days after YESCARTA infusion Label. The mean AUC in Day 0-28 in responding patient was 557.1 days x cells/μL Label.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half-life
Not Available
Clearance
Not Available
Adverse Effects
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Toxicity

Axicabatagene ciloleucel is reported to induce cytokine release syndrome (CRS) and neurotoxicity. No carcinogenicity or genotoxicity studies as well as reproductive toxicity studies have not been conducted with axicabatagene ciloleucel.

Affected organisms
  • Humans and other mammals
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

Products

Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
YescartaSuspension200000000 cellsIntravenousGilead Sciences2019-11-27Not applicableCanada flag
YescartaSuspension2000000 1/68mLIntravenousKite Pharma, Inc.2017-10-18Not applicableUS flag
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

Drug Categories
Classification
Not classified

Chemical Identifiers

UNII
U2I8T43Y7R
CAS number
Not Available

References

General References
  1. Scheuermann RH, Racila E: CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy. Leuk Lymphoma. 1995 Aug;18(5-6):385-97. [PubMed:8528044]
PubChem Substance
347911476
RxNav
1987398
Wikipedia
Axicabtagene_ciloleucel
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
FDA label
Download (210 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentRelapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)1
2Active Not RecruitingTreatmentRelapsed/Refractory Mantle Cell Lymphoma1
2Not Yet RecruitingPreventionB-Cell Non-Hodgkin Lymphomas(NHL)1
2Not Yet RecruitingTreatmentRecurrent B-Cell Lymphoma / Refractory Follicular Lymphoma1
2RecruitingPreventionDiffuse Large B-Cell Lymphoma, Not Otherwise Specified / High Grade B-cell Lymphoma / High-grade B-cell Lymphoma / Progressive Disease / Recurrent Diffuse Large B-Cell Lymphoma / Recurrent High Grade B-Cell Lymphoma / Recurrent Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma / Recurrent Transformed Follicular Lymphoma to Diffuse Large B-Cell Lymphoma / Refractory Diffuse Large B Cell Lymphoma / Refractory High Grade B-Cell Lymphoma / Refractory Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma / Refractory Transformed Follicular Lymphoma to Diffuse Large B-Cell Lymphoma1
2RecruitingTreatmentCytokine Release Syndrome / Neurologic toxicity / Neurotoxicity Syndromes / Non-Hodgkin's Lymphoma (NHL) / Refractory Non-Hodgkin's lymphoma / Relapsed Non Hodgkin Lymphoma1
2RecruitingTreatmentFollicular Lymphoma (FL) / Indolent Non-Hodgkin's Lymphomas / Marginal Zone Lymphoma (MZL)1
2RecruitingTreatmentLymphoma, B-Cell1
2RecruitingTreatmentRefractory Large B-cell Lymphoma1
1, 2Active Not RecruitingTreatmentHigh Grade B-cell Lymphoma (HGBCL) / Primary Mediastinal B-cell Lymphoma (PMBCL) / Refractory Diffuse Large B Cell Lymphoma (DLBCL) / Relapsed, Diffuse Large B-cell Lymphoma / Transformed Follicular Lymphoma (TFL)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
SuspensionIntravenous2000000 1/68mL
SuspensionIntravenous200000000 cells
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

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 October 19, 2017 09:01 / Updated on October 25, 2020 09:16

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