Is CAR (Chimeric Antigen Receptor) T cell treatment targeting B7H3 effective for 90% esophageal squamous cell carcinoma (ESCC)?

CAR T-Cell Therapy for B7H3-Positive Esophageal Squamous Cell Carcinoma

B7H3-targeted CAR T-cell therapy is an investigational approach for esophageal squamous cell carcinoma (ESCC) that shows promise in preclinical studies but currently lacks sufficient clinical evidence to recommend as standard treatment for patients with 90% B7H3-expressing ESCC.

Current Standard Treatment for ESCC

Esophageal squamous cell carcinoma treatment depends on disease stage and patient factors:

For Locally Advanced ESCC:

• First-line approach: Preoperative chemoradiotherapy followed by surgery OR definitive chemoradiotherapy with close surveillance and salvage surgery for local tumor persistence/progression [I, A] 1
• Standard chemoradiotherapy regimens include:
  • Weekly carboplatin-paclitaxel with radiotherapy (CROSS regimen)
  • Cisplatin-5-FU with radiotherapy

For Advanced/Metastatic ESCC:

• First-line treatment options:

  • Pembrolizumab plus chemotherapy (platinum/fluoropyrimidine) - greatest benefit in PD-L1 CPS ≥10 [I, A] 1
  • Nivolumab plus chemotherapy for tumors with PD-L1 TPS ≥1% [I, A] 1
  • Nivolumab-ipilimumab (with caution due to lower response rates) [I, B] 1

• Second-line treatment:

  • Nivolumab monotherapy [I, A] 1
  • Pembrolizumab for PD-L1 CPS ≥10 (where approved) [I, A] 1
  • Taxane or irinotecan-based chemotherapy [II, B] 1

B7H3 CAR T-Cell Therapy for ESCC

Current Evidence:

• B7H3 (also known as CD276) is overexpressed in approximately 90% of ESCC cases, making it a potential target for immunotherapy 2
• Preclinical studies have demonstrated that B7H3-targeted CAR T-cells can kill ESCC cells in laboratory settings 2
• A novel microenvironment regulated system CAR-T (MRS.B7H3.CAR-T) has shown promising anti-tumor activity against ESCC in preclinical models 2

Limitations and Challenges:

• No completed clinical trials specifically for B7H3 CAR T-cell therapy in ESCC
• CAR T-cell therapy for solid tumors faces several challenges:
  • Limited tumor infiltration
  • Immunosuppressive tumor microenvironment
  • On-target/off-tumor toxicity due to antigen expression on normal tissues
  • High levels of TGF-β in tumor areas may hinder CAR T-cell efficacy 3

Safety Considerations:

• CAR T-cell therapy can cause significant toxicities requiring specialized management:
  • Cytokine release syndrome (CRS)
  • CAR T-cell-related encephalopathy syndrome (CRES)
  • Need for intensive monitoring and potentially critical care support 1

Practical Recommendations

1. For patients with 90% B7H3-positive ESCC:

   • Follow standard of care treatment based on disease stage as outlined above
   • Consider B7H3 CAR T-cell therapy only within the context of a clinical trial

2. Clinical trial participation:

   • Patients should be evaluated for eligibility in clinical trials investigating B7H3-targeted immunotherapies
   • Trials may be available at specialized cancer centers with CAR T-cell expertise

3. Biomarker testing:

   • Comprehensive molecular profiling is recommended, including:
     • PD-L1 expression (CPS and TPS)
     • HER2 status
     • MSI status
   • These biomarkers can guide approved immunotherapy and targeted therapy options 1

Future Directions

• Ongoing development of next-generation CAR T-cells with enhanced tumor-targeting capabilities
• Combination strategies with checkpoint inhibitors or other immunomodulatory agents
• Local delivery methods to improve CAR T-cell infiltration into solid tumors
• Alternative CAR-based approaches such as CAR-NK cells are also being investigated for ESCC 4

While B7H3 CAR T-cell therapy shows promise in preclinical studies, patients with ESCC should currently receive established standard-of-care treatments with proven survival benefits while research continues to advance this potentially promising approach.