What are the recommended cellular therapies, such as CAR-T (Chimeric Antigen Receptor T) cell therapy or tumor-infiltrating lymphocyte therapy, for patients with cancer, including leukemia and lymphoma?

Cellular Therapies in Cancer

Primary Recommendation

For patients with relapsed/refractory hematologic malignancies, CAR-T cell therapy targeting CD19 (for B-cell leukemias and lymphomas) or BCMA (for multiple myeloma) represents the standard of care after ≥2 prior lines of therapy, while tumor-infiltrating lymphocyte (TIL) therapy with lifileucel is now FDA-approved for advanced melanoma after progression on immune checkpoint inhibitors. 1, 2, 3

CAR-T Cell Therapy: Indications and Target Selection

FDA-Approved Hematologic Malignancies

CD19-Targeted CAR-T Products (tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel):

• B-cell acute lymphoblastic leukemia (B-ALL): Pediatric and young adult patients with relapsed/refractory disease achieve 83% complete remission rates with MRD-negative responses 3
• Large B-cell lymphoma: Improves 4-year overall survival to 54.6% versus 46.0% with standard chemotherapy followed by stem cell transplant 4
• Follicular lymphoma: Approved after ≥2 prior systemic therapies, particularly for transformed disease 1
• Mantle cell lymphoma: Indicated after prior chemoimmunotherapy 2
• Chronic lymphocytic leukemia: For relapsed/refractory disease 4

BCMA-Targeted CAR-T Products (idecabtagene vicleucel, ciltacabtagene autoleucel):

• Multiple myeloma: After 1-4 prior lines of therapy, prolongs progression-free survival to 13.3 months versus 4.4 months with standard therapy 4
• BCMA is expressed on mature B cells and plasma cells but not naïve B cells, making it an ideal target with elevated serum levels in myeloma patients 1, 3

Specific Timing Criteria

CAR-T therapy should be administered after ≥2 prior chemoimmunotherapy regimens for the specific disease indication 1. For transformed follicular lymphoma, CAR-T is appropriate after ≥2 prior regimens for either indolent or transformed disease 1.

TIL Cell Therapy: The Solid Tumor Breakthrough

FDA-Approved Indication

Lifileucel is approved for unresectable or metastatic melanoma after progression on immune checkpoint inhibitors and targeted therapies (if BRAF-mutated) 1:

• Achieves 31.4% objective response rate with median duration of response not reached at 36.5 months median follow-up 1
• Phase 3 data shows significant improvement in progression-free survival (7.2 vs 3.1 months; HR 0.50) and higher ORR (49% vs 21%) compared to ipilimumab 1

Mechanistic Advantage Over CAR-T

TIL therapy differs fundamentally from CAR-T by its polyclonality and ability to recognize multiple patient-specific tumor neoantigens, as TILs are obtained directly from resected tumor tissue rather than engineered to target a single antigen 1.

Manufacturing Process and Pre-Treatment Requirements

CAR-T Cell Production

The multi-week process involves 1, 2, 3:

1. Leukapheresis to collect white blood cells including T cells
2. T-cell isolation, activation, and genetic modification using viral vectors (lentiviral or retroviral) to express the CAR transgene
3. Ex vivo expansion over several days to weeks
4. Cryopreservation and quality control testing

TIL Cell Production

The process requires 1:

1. Direct surgical resection of tumor tissue
2. Prosection and ex vivo expansion of TILs, which reverses their dysfunctional state acquired in the tumor microenvironment
3. Centralized manufacturing has increased access to this therapy

Lymphodepletion Chemotherapy

All patients must undergo non-myeloablative lymphodepletion (typically fludarabine and cyclophosphamide) prior to cell infusion to prevent immunologic rejection and maximize cell expansion and persistence 1, 2, 3.

Critical Toxicity Management

Cytokine Release Syndrome (CRS)

CRS occurs in 40-95% of CAR-T patients, manifesting as early as hours to 10-15 days post-infusion (typical duration 7-8 days) 1:

• Clinical features: Fever, hypotension, tachycardia, hypoxia, chills, with potential cardiac, hepatic, and renal dysfunction 1
• Management: Tocilizumab 8 mg/kg IV over 1 hour is the cornerstone therapy, repeatable every 8 hours if no improvement (maximum 3 doses) 3
• Monitoring: Rapidly rising ferritin >5000 ng/mL with cytopenias suggests hemophagocytic lymphohistiocytosis/macrophage-activation syndrome 1

Neurologic Toxicity (ICANS)

Neurotoxicity occurs in 15-65% of patients, typically 1-2 weeks post-infusion but can occur up to one month later 1, 2:

• Manifestations: Encephalopathy, delirium, aphasia, lethargy, headache, tremor, myoclonus, seizures, and potentially fatal cerebral edema 1
• Monitoring requirement: Neurological evaluations at least twice daily during the acute period 2
• Safety precaution: Patients must refrain from driving or hazardous activities for at least 8 weeks following infusion 2

Infection Risk

Patients remain at increased risk of infections for weeks to months after infusion 1:

• Prophylaxis required: Vesicular stomatitis virus/herpes simplex virus reactivation and Pneumocystis jirovecii pneumonia prophylaxis for several months 1
• IVIG replacement: Consider monthly 400-500 mg/kg IVIG for patients with hypogammaglobulinemia (IgG <400-600 mg/dL) AND serious or recurrent bacterial infections after anti-CD19 CAR-T therapy 1

Patient Monitoring Protocol

Acute Phase (First 4 Weeks)

All patients require close monitoring with hospitalization typically recommended for adults 2:

• Laboratory monitoring: Complete blood count, comprehensive metabolic panel, C-reactive protein, ferritin levels 2
• Vital signs: Assessment at least every 8 hours during and immediately after infusion 2
• Neurological assessment: At least twice daily 2

Long-Term Sequelae

• Cytopenias: May persist for weeks to months following lymphodepleting chemotherapy and cell infusion 1
• B-cell aplasia and hypogammaglobulinemia: Can occur in patients achieving complete remission after anti-CD19 CAR-T therapy 1

Patient Selection and Contraindications

Acceptable Prior Therapies

• Prior allogeneic hematopoietic stem cell transplant: Not a contraindication when patients are off immunosuppression, though may increase toxicity risk in ALL 3
• Prior bispecific antibodies or prior CAR-T: Not contraindications, but antigen-negative escape must be excluded at relapse before proceeding 3
• Active infections: Require deferral until controlled; latent infections (HIV, HBV, HCV) can proceed with prophylactic antiviral treatment 3

Re-Treatment Considerations

A second infusion of anti-CD19 CAR-T cells can induce remission in a subset of patients; in multiple myeloma, re-treatment with anti-BCMA CAR-T is possible 3.

Post-CAR-T Transplant Considerations

Critical caveat: HDT/ASCR is not recommended after CAR-T therapy; allogeneic HCT could be considered but remains investigational, as data on transplant efficacy after CAR-T are not available 1.

Emerging Strategies and Future Directions

CRISPR-Cas9 Enhancement of CAR-T

Genome editing with CRISPR-Cas9 can create next-generation CAR-T cells by 1:

• Knocking out endogenous TCR genes to enable "off-the-shelf" universal donor CAR-T cells and prevent graft-versus-host disease 1
• Eliminating T cell inhibitory receptors (CTLA4, PD1) to boost CAR-T efficacy 1
• Decreasing histocompatibility antigen expression to prevent host rejection 1

Allogeneic CAR-T Development

Allogeneic "off-the-shelf" CAR-T products are under development to reduce manufacturing time and costs, potentially addressing current logistical barriers and making therapy more economically favorable compared to antibody-based checkpoint inhibitors 1, 2, 3.

Common Pitfalls to Avoid

1. Do not delay CAR-T referral: Manufacturing takes several weeks; refer early when patients meet eligibility criteria after second-line therapy failure
2. Do not underestimate infection risk: Prophylaxis is mandatory, not optional, and must continue for months post-infusion
3. Do not discharge patients prematurely: The 4-week monitoring period is critical as CRS and neurotoxicity can occur late
4. Do not proceed with CAR-T without excluding antigen-negative escape in patients with prior bispecific antibody or CAR-T exposure
5. Do not plan HDT/ASCR after CAR-T therapy: This sequence is not recommended based on current evidence