FDA批准上市CAR-T产品药理毒理研究汇总
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2024-09-13 21:47 作者:   积风
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根据FDA官网公布的药理毒理审评报告，进行简单梳理汇总。具体细节见审评报告全文

　 PHARMACOLOGY STUDIES SAFETY PHARMACOLOGY STUDIES PHARMACOKINETIC STUDIES(Biodistribution) TOXICOLOGY STUDIES
KYMRIAH In Vitro Studies
  1. CD19 mRNA and protein expression in normal human and cynomolgus macaque brain sections by ICH/ISH/RT-PCR [ Study #1, #2]
  2. Human membrane protein off-target binding of CD19 scFv [#3]
  3. Transduction efficiency and expansion potential in vitro(Lymphocytes from a HD/patient) [#4 #5 #6 #7]

In Vivo Studies
  1. Efficacy of four CART-19 receptor constructs: αCD19-ζ, αCD19-BB-ζ, αCD19-28-ζ, and αCD19-28-BB-ζ in tumor-bearing XX mouse model [#8 #9] 		 None 1. Evaluation  Biodistribution in Human Immune-reconstituted XX Mice [#11 #12]
*conjunction with the toxicology study		 • Toxicology Studies:
  Evaluation of CART-19 Biotoxicity  in Human Immune-reconstituted XX Mice [#11 #12]
• Developmental and Reproductive Toxicology Studie: None
• Genotoxicity Studies: Lentivirus integration site analysis (ISA)
• Carcinogenicity/Tumorigenicity Studies: None
• Other Safety/Toxicology Studies: None
YESCARTA In Vitro Studies
  1. Characterization of Patient-Derived Anti-CD19 CAR T cells [#3]
  2. CD19 Expression on Normal and Malignant B-lineage Cells [#1]
  3. Development of a γ-Retroviral Vector Encoding an Anti-CD19 CAR [#2]

In Vivo Studies  [#4 Publication]
  1. Anti-Murine CD19 CAR T-Cell Activity in a Syngeneic Mouse Lymphoma Model，including：
  • Characterization of T Cells with Different CAR Constructs
  • Effects on Mice with 38c13 Murine Lymphoma Cells/ Subcutaneous Lymphoma Masses
  • Effect of Radiation-Induced Lymphodepletion and Supplemental IL-2
  • On-target, Off-tumor Effect 		 None No biodistribution studies with KTE-C19 were conducted.
Publication  (Study #4)
examined the persistence of anti-murine CD19 CAR T cells following administration into immune competent tumor-bearing mice.
* detection of CD8+ and CD4+ anti-murine CD19 CAR T cells in the spleen at 8 days after T cell infusion.		 • Toxicology Studies: No toxicology studies with KTE-C19 were conducted. However, Publication (Study #4), evaluated overall safety following administration of the anti-murine CD19 CAR T cells into immune competent tumor-bearing mice. Some mice were followed out to Day 209. No overt toxicity, but normal B cells were decreased which is consistent with the clinical trial data for KTE-C19
• Developmental and Reproductive Toxicology Studie: None
• Genotoxicity Studies: None
• Carcinogenicity/Tumorigenicity Studies: Publications
  1. non clinical：Assessment of potential oncogenicity of KTE-C19 due to transformation and clonal expansion was based on published in vivo studies in mice
  2. clinical: Carcinogenicity/Tumorigenicity outcomes in subjects administered γ-retroviral vector transduced HSC/T cells
• Other Safety/Toxicology Studies: None
TECARTUS In Vitro Studies
  1. Characterization of the Activation, Transduction, and Expansion and Functional Characterization of Anti-CD19 CAR T-cell Products [#1 #2]
  2. Development of a γ-retroviral Vector Encoding an Anti-CD19 CAR [#3]
  3. Undisclosed [#4 #5]

In Vivo Studies
  Same with YESCARTA		 None.  Same with YESCARTA • Toxicology Studies:
  Same with YESCARTA
• Developmental and Reproductive Toxicology Studie: None
• Genotoxicity Studies: Integration Site Analysis
• Carcinogenicity/Tumorigenicity Studies:
  review of the literature regarding the potential for oncogenicity due to transformation and clonal expansion.
• Other Safety/Toxicology Studies: None
BREYANZI In Vitro Studies
  1. Activity/ Cytolytic Activity/ Growth and Viability of JCAR017 [#1 #2 #3 #4 #5]
  2. CAR of JCAR017 Intracellular Domain Mechanism of Action [#6]
  3. Binder Characterization/Epitope Analysis/ Binding Profile of FMC63(a murine CD19-specific mAb)  [#7 #14]
  4. CD19-Specific Cytolytic Activity/ Cell Surface Phenotype and Cytokine Production Analysis (GMP) [#8 #9 #10]
  5. JCAR017 CD19 Species Cross-Reactivity/CD19 Expression in various species/human tissues [#11 #12 #13 #15]
  6. Combination with XX(immunomodulating agents) or Lenalidomide/Epacadostat/ Anti-PD-L1 Antibody (Durvalumab)/ Ibrutinib or Acalabrutinib(BTKi)/ Cetuximab(anti-EGFR antibody) [#16 #17 #18 #19 #20]
  7. EGFR expression/ Cetuximab(anti-EGFR antibody) in Mouse Serum/ JCAR017 Cells in Mouse Whole Blood Specimens with Cetuximab [#20 #21 #22]

In Vivo Studies
  1. Efficacy of JCAR017  in XX Mice Engrafted with Raji [#23]
  2. Characterization of CD19-Specific CAR T Cell(Tumor Growth and Survival) [#24]
  3. Efficacy Evaluation of JCAR017 in Combination with Ibrutinib or Acalabrutinib(BTKi) /Cetuximab [#25 #26 #27]
  4. PK of Erbitux [#28]		 None None • Toxicology Studies: None
• Developmental and Reproductive Toxicology Studie:
  An unbiased, genome-wide, assay assessed viral integration events across 54 CAR T cell products derived from 34 patients
• Genotoxicity Studies:
  Genomic Mapping of Lentiviral Integration Sites in JCAR017 Cryopreserved Drug Product [#29]
• Carcinogenicity/Tumorigenicity Studies: None
• Other Safety/Toxicology Studies:
  1. 60-Day In Vitro CAR T Cell Proliferation Study [#30]
  2. A Tissue Cross-Reactivity Study of XX in Normal Human Tissues [#31]
ABECMA In Vitro Studies
  1. Pharmacologic Activity of bb2121 [#1]
  2. BCMA Expression on various tumor cells [#2]
  3. Binding profile/Cross-reactivity Study of Anti-BCMA Antibodies [#3 #4]

In Vivo Studies
  1. Pharmacologic Activity/ Pharmacologic Dose Response of bb2121 in Tumor-bearing Mice [#5 #6 #7 #8 #9]		 None 1. Pharmacologic Activity, Pharmacokinetics, Pharmacodynamics, Biodistribution and General Safety of bb2121 in Mice with and Without BCMA+ Human Multiple Myeloma Subcutaneous Xenografts [#10] • Toxicology Studies: None
• Developmental and Reproductive Toxicology Studie: None
• Genotoxicity Studies:
Vector Insertion Site Analysis of 20 Clinical bb2121 [#11]
• Carcinogenicity/Tumorigenicity Studies:
 IL-2 Independent Growth as a Gain of Function Assessment in Clinical and Normal HD bb2121 [#12]
• Other Safety/Toxicology Studies: None
CARVYKTI In Vitro Studies
  1. Pharmacologic Activity (Characterization/ Cytotoxicity Assay/Cytokine Release) of LCAR-B38M CAR-T [#4 #8 #16]
  2. possible off-target evaluation( Cytotoxicity,  Binding Profiling) [#7 #10 #13]
  3. Binding study of BCMA to LCARB38M CAR [#9]
  4. Undisclosed [#1 #2 #3 #5 #6 #11 #14 #17 #18]

In Vivo Studies
  1. Dose escalating study/ Efficacy Study of LCAR-B38M on XX Engrafted Immune Deficient Mouse [#19 #20] 		 None None • Toxicology Studies:
 Pilot Tolerability of LCAR-B38M in Monkeys [#21]
• Developmental and Reproductive Toxicology Studie: None
• Genotoxicity Studies: Lentivirus Vector ISA Testing
• Carcinogenicity/Tumorigenicity Studies: None
• Other Safety/Toxicology Studies: Characterization of Cytokine Independent Growth