What are the indications and procedures for Chimeric Antigen Receptor T (CART) cell therapy?

CAR-T Cell Therapy: Indications and Procedures

Primary Indications

CAR-T cell therapy is indicated for relapsed/refractory hematologic malignancies, specifically B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma, and multiple myeloma, with CD19-targeted products for B-cell malignancies and BCMA-targeted products for multiple myeloma. 1, 2, 3

FDA-Approved Products and Targets

• CD19-targeted therapies include tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, and lisocabtagene maraleucel for B-cell malignancies 4, 1
• BCMA-targeted therapy idecabtagene vicleucel is approved for multiple myeloma patients who have received ≥4 prior therapies including an anti-CD38 monoclonal antibody, proteasome inhibitor, and immunomodulatory drug 2
• Ciltacabtagene autoleucel (BCMA-targeted) is approved for relapsed/refractory multiple myeloma after ≥4 prior lines, demonstrating superior response rates (97% ORR vs 73% for idecabtagene vicleucel) 2

Patient Eligibility Criteria

Performance Status and Life Expectancy

• ECOG <2, Karnofsky >60%, or Lansky >60% is required, though patients with ECOG >1 treated outside trials showed significantly decreased overall survival and progression-free survival 4
• Life expectancy >6-8 weeks minimum 4

Age Considerations

• No absolute age limit exists—decision should be based on physical condition rather than chronological age 4
• Real-world data shows 5.9% of B-ALL patients were <3 years old and 53.5% of NHL patients were >65 years old, with comparable complete response rates 4
• Ability to collect sufficient cells by apheresis can be limiting in infants and small children 4

Absolute Contraindications

• Active bacterial or fungal infection requires treatment and stability before leukapheresis 4
• Active viremia mandates deferral until infection is controlled 4
• Active malignancy requiring treatment (except non-melanoma skin cancer or carcinoma in situ) 4
• Systemic immunosuppressive treatment impairs CAR-T efficacy (topical, inhaled, or intranasal corticosteroids are permitted) 4

Relative Contraindications Requiring Risk-Benefit Assessment

• High tumor burden in B-ALL and DLBCL increases risk of treatment failure and greater toxicity 4
• CNS involvement requires careful consideration—active CNS pathology was excluded in pivotal trials (ZUMA-1, JULIET, ELIANA), though emerging real-world evidence suggests tolerability in controlled CNS disease 4
• Prior allogeneic HCT is not a contraindication when off immunosuppression, but in ALL may increase CAR-T-associated toxicity risk 4, 3

Prior Targeted Therapy Considerations

• Prior bispecific antibodies or prior CAR-T is not a contraindication, but antigen-negative escape must be excluded at relapse before proceeding, especially in B-cell ALL 4, 3
• Prior treatment with blinatumomab may impair anti-CD19 CAR-T efficacy 4
• Second infusion of anti-CD19 CAR-T cells can induce remission in a subset of patients, though efficacy is limited by poor CAR-T expansion and antigen modulation 4, 5

Latent Viral Infections

• HIV, HBV, or HCV are contraindications for some (but not all) commercial products 4
• When proceeding with latent infections, prophylactic antiviral treatment is required 4, 3
• Asymptomatic COVID-19 positive patients may proceed at physician's discretion after checking feasibility with manufacturer 4

Manufacturing Process

Step 1: Leukapheresis

• Absolute lymphocyte count (ALC) threshold of 0.2 x 10⁹/L is generally recommended, though emerging evidence supports leukapheresis in patients with low ALC 4, 1
• Infectious disease markers must be tested on peripheral blood within 30 days of leukapheresis with results available on day of shipment 4
• Presence of leukemic blasts is acceptable to manufacturers 4

Step 2: T-Cell Modification

• T cells are isolated, activated, and transduced with a CAR transgene typically delivered via lentiviral or retroviral vector 4, 1
• The CAR structure includes an extracellular antigen recognition domain, hinge region, transmembrane domain, and intracellular signaling domains (CD3 zeta plus costimulatory domains like CD28 or 4-1BB) 1, 3

Step 3: Expansion and Cryopreservation

• Transduced T cells are expanded over several days to weeks, harvested, and prepared for infusion 1, 3
• The entire manufacturing process takes several weeks to complete 2

Bridging Therapy During Manufacturing

Acceptable Bridging Regimens

• Vincristine, dexamethasone, doxorubicin (vAD): vincristine 1.5 mg/m² IV weekly for 4 doses, dexamethasone 6 mg/m² daily for 5 days, doxorubicin 50 mg/m² IV single dose 4
• Continuous daily 6-mercaptopurine at 50 mg/m² orally 4
• Hydroxyurea 15-50 mg/kg per day orally (dose titrated) 4
• Cyclophosphamide 1,000 mg/m² IV single dose plus cytarabine 75 mg/m² IV daily for 4 days 4
• Tyrosine kinase inhibitors (monotherapy or with chemotherapy) for Philadelphia chromosome-positive or Ph-like ALL 4

Timing of Treatment Discontinuation Before Infusion

• TKIs and hydroxyurea: stop ≥72 hours before infusion 4
• Vincristine, 6-mercaptopurine, methotrexate ≤25 mg/m², cytarabine ≤100 mg/m², non-pegylated asparaginase: stop ≥1 week before infusion 4
• Clofarabine, cytarabine >100 mg/m², anthracyclines, cyclophosphamide, methotrexate ≥25 mg/m²: stop ≥2 weeks before infusion 4
• Pegylated asparaginase: stop ≥4 weeks before infusion 4
• CNS prophylaxis treatment: stop ≥1 week before infusion 4

Lymphodepletion Chemotherapy

Standard Regimens

• Cyclophosphamide 900 mg/m² single dose plus fludarabine 25 mg/m² daily for 3 days 4
• Cyclophosphamide 30-60 mg/kg single dose plus fludarabine 25 mg/m² daily for 3-5 days 4
• Cyclophosphamide 500 mg/m² daily for 2 days plus fludarabine 30 mg/m² daily for 4 days 4

Intensified Lymphodepletion

• Fludarabine 120 mg/m² plus cyclophosphamide 1200 mg/m² may augment CAR-T expansion compared to standard dosing (fludarabine 75 mg/m², cyclophosphamide 900 mg/m²) 5
• Intensified lymphodepletion corresponded with higher CAR-T expansion in patients receiving second CAR-T infusion (p=0.029) 5

Rationale

• Lymphodepletion prevents immunologic rejection of infused CAR-T cells and maximizes their expansion and persistence 4, 1, 3

Post-Infusion Monitoring

Hospitalization and Duration

• Hospitalization typically recommended for adult patients for at least the initial post-infusion period 1
• Close monitoring required for at least 4 weeks post-infusion 1

Vital Signs and Cardiac Monitoring

• Continuous cardiac monitoring and telemetry should be strongly considered beginning on day of infusion and continuing for minimum number of days based on peak incidence of CRS and neurotoxicity 4
• Vital signs assessment at least every 8 hours during and after infusion 1

Laboratory Monitoring

• Complete blood count, comprehensive metabolic panel, coagulation testing, serum ferritin, and C-reactive protein should be measured frequently during the high-risk period for CRS 4, 1

Neurological Assessment

• Neurological evaluations at least twice daily to detect early signs of CAR-T cell-related encephalopathy syndrome 1
• Baseline assessment of heart rate, blood pressure, mood, cognition, and developmental status should be documented 4

Activity Restrictions

• Patients should refrain from driving or hazardous activities for at least 8 weeks following infusion 1

Major Toxicities and Management

Cytokine Release Syndrome (CRS)

CRS occurs in 84-95% of patients, characterized by fever, hypotension, and potentially life-threatening organ dysfunction, typically within the first 2 days after infusion. 4, 2, 3

Grade 1 CRS Management

• Fever ≥38°C is the defining feature 4
• For prolonged CRS (>3 days) in symptomatic patients, elderly patients, or those with comorbidities, consider tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg) 4
• Sepsis screen and empiric broad-spectrum antibiotics; consider G-CSF if neutropenic 4, 2

Grade 2 CRS Management

• Tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg/dose), repeat in 8 hours if no improvement 4, 2
• Manage as Grade 3 if no improvement within 24 hours 2

Grade 3 CRS Management

• Tocilizumab as per Grade 2 plus dexamethasone 10 mg IV every 6 hours 4, 2
• Transfer to ICU for hemodynamic monitoring 2

Grade 4 CRS Management

• Tocilizumab as per Grade 2 plus dexamethasone 10 mg IV every 6 hours 4, 2
• Maximum of 3 doses of tocilizumab 3

Neurotoxicity (CAR-T Cell-Related Encephalopathy Syndrome)

• Occurs 1-2 weeks post-infusion, with late onset possible up to a month later 1
• Requires close neurological monitoring and prompt intervention 4, 1

Hematologic Toxicities

• Grade 3-4 neutropenia (89-95%), anemia (60-70%), thrombocytopenia (52-63%) are common 2, 6
• Cytopenias are now considered a related side effect reported in all pivotal clinical trials 6

Infectious Complications

• Grade 3-4 infections occur in 44.8-69% of patients, requiring aggressive prophylaxis and monitoring 2

Long-Term B-Cell Aplasia

• Long-term B-cell aplasia and hypogammaglobulinemia can occur in patients with complete remission after anti-CD19 CAR-T therapy 4
• Consider monthly IVIG replacement 400-500 mg/kg for patients with serum IgG <400-600 mg/dL AND serious or recurrent bacterial infections 4
• Continue IVIG until serum IgG levels normalize and infections resolve 4

Common Pitfalls and Caveats

Antigen Escape

• Emergence of antigen-negative/dim disease occurs in approximately 33% of patients following second CAR-T infusion, contributing to lack of complete response 5
• Serial monitoring of antigen expression is warranted to detect antigen modulation 5

Diminished CAR-T Expansion on Re-treatment

• Peripheral blood CAR-T expansion is significantly lower with second infusion compared to first infusion (p=0.03) 5
• Up to 60% of DLBCL patients ultimately progress or relapse following CAR-T therapy 7

Manufacturing Failures

• The manufacturing process remains complex and logistically challenging, with potential for manufacturing failure 1, 3
• Financial counseling should occur rapidly after patient identification to avoid delays related to insurance pre-authorizations 4