What are the current approved indications for Chimeric Antigen Receptor (CAR)-T cell therapies, including Tisagenlecleucel (tisagenlecleucel), Axicabtagene ciloleucel (axicabtagene ciloleucel), Idecabtagene vicleucel (idecabtagene vicleucel), and Lisocabtagene maraleucel (lisocabtagene maraleucel)?

Current Approved CAR-T Cell Therapies and Their Indications

The FDA has approved six CAR-T cell therapies for specific hematologic malignancies, each with distinct indications targeting either CD19 or BCMA antigens on cancer cells. 1

CD19-Directed CAR-T Cell Therapies

Tisagenlecleucel (Kymriah)

• Indications:
  • B-cell acute lymphoblastic leukemia (B-ALL): Patients up to 25 years with refractory disease or in second or later relapse
  • Diffuse large B-cell lymphoma (DLBCL): Adults with relapsed or refractory disease after two or more lines of systemic therapy
  • Follicular lymphoma: Adults with relapsed or refractory disease after two or more lines of systemic therapy

Axicabtagene Ciloleucel (Yescarta)

• Indications:
  • Large B-cell lymphoma (LBCL): Adults with refractory disease or relapse within 12 months of first-line chemoimmunotherapy
  • LBCL: Adults with relapsed or refractory disease after two or more lines of systemic therapy
  • Follicular lymphoma: Adults with relapsed or refractory disease after two or more lines of systemic therapy

Brexucabtagene Autoleucel (Tecartus)

• Indications:
  • Mantle cell lymphoma: Adults with relapsed or refractory disease
  • B-ALL: Adults with relapsed or refractory disease

Lisocabtagene Maraleucel (Breyanzi)

• Indications: 2
  • Large B-cell lymphoma (LBCL): Adults with:
    • Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line therapy
    • Refractory disease to first-line chemoimmunotherapy or relapse after first-line therapy and not eligible for HSCT due to comorbidities or age
    • Relapsed or refractory disease after 2 or more lines of systemic therapy
  • Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL): Adults with relapsed or refractory disease who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor
  • Follicular lymphoma (FL): Adults with relapsed or refractory disease who have received 2 or more prior lines of systemic therapy
  • Mantle cell lymphoma (MCL): Adults with relapsed or refractory disease who have received at least 2 prior lines of therapy, including a BTK inhibitor

BCMA-Directed CAR-T Cell Therapies

Idecabtagene Vicleucel (Abecma)

• Indications:
  • Multiple myeloma: Adults with relapsed or refractory disease after four or more prior lines of therapy 1

Ciltacabtagene Autoleucel (Carvykti)

• Indications:
  • Multiple myeloma: Adults with relapsed or refractory disease after four or more prior lines of therapy 3

Efficacy Outcomes

• B-cell malignancies: CAR-T cell therapies have shown remarkable efficacy with response rates up to 90% in some pediatric and young adult populations 3
• Large B-cell lymphoma: Compared with standard chemotherapy followed by stem cell transplant, CAR-T cells improved 4-year overall survival (54.6% vs 46.0%) 3
• Multiple myeloma: CAR-T cell therapy prolonged treatment-free remissions compared with standard treatments (progression-free survival of 13.3 months vs 4.4 months) 3

Common Toxicities

1. Cytokine Release Syndrome (CRS): 1

   • Occurs in approximately 40-95% of patients
   • Characterized by fever, hypotension, hypoxia, and multi-organ dysfunction
   • Management includes tocilizumab (anti-IL-6) and corticosteroids

2. Neurologic Toxicity (ICANS/CRES): 1

   • Occurs in approximately 15-65% of patients
   • Characterized by encephalopathy, delirium, seizures, and rarely cerebral edema
   • Can occur concurrently with CRS or independently

3. Cytopenias: 2

   • May persist for several weeks following infusion
   • Regular monitoring of complete blood counts is essential

4. B-cell aplasia and hypogammaglobulinemia: 1

   • Long-term complication requiring monitoring of immunoglobulin levels
   • May require IVIG replacement therapy

Important Considerations for Patient Selection

• Performance status: ECOG <2, Karnofsky >60% or Lansky >60% 1
• Life expectancy: >6-8 weeks 1
• Infection status: Active infections should be controlled before proceeding 1
• Prior treatments: Previous targeted therapies against the same antigen may affect efficacy but are not absolute contraindications 1
• Immunosuppressive medications: Relative contraindication as they may impair CAR-T efficacy 1

Future Directions

• Development of "off-the-shelf" allogeneic CAR-T cells to increase accessibility and reduce manufacturing time 1
• Use of gene editing technologies like CRISPR-Cas9 to enhance CAR-T cell efficacy and reduce toxicity 1
• Expansion of CAR-T therapy to solid tumors (currently no FDA-approved CAR-T products for solid tumors) 3
• Dual-targeting CAR-T cells (e.g., CD19/22) to reduce antigen escape and improve durability of response 4

CAR-T cell therapy represents a significant advancement in cancer treatment, particularly for hematologic malignancies that have failed conventional therapies. The specific product selection should be based on the disease type, prior treatments, patient characteristics, and institutional experience with each product.