Is CAR (Chimeric Antigen Receptor) T-cell therapy effective for low-grade neuroendocrine tumors (NETs)?

CAR T-Cell Therapy for Low-Grade Neuroendocrine Tumors

CAR T-cell therapy is not currently recommended for low-grade neuroendocrine tumors (NETs) as there are no FDA-approved CAR T-cell products for this indication, and established treatment options with proven efficacy should be prioritized. 1

Current Treatment Landscape for Low-Grade NETs

First-Line Treatment Options

• Surgery: Treatment of choice for localized disease with curative intent 1
• Somatostatin analogs (SSAs):
  • Octreotide or lanreotide are first-line systemic therapy for unresectable, somatostatin receptor-positive low-grade NETs 1
  • Particularly effective for controlling hormonal symptoms and providing antiproliferative effects 1

Second-Line and Beyond Options

• Everolimus: Recommended for progressive disease, particularly for intermediate-grade NETs 1
• Peptide Receptor Radionuclide Therapy (PRRT): 177Lu-dotatate for somatostatin receptor-positive NETs that progress on SSAs 1
• Locoregional therapies: For liver-predominant disease 1
• Chemotherapy: Limited efficacy in well-differentiated NETs but may be considered for pancreatic NETs or progressive disease 1
  • Streptozotocin-based combinations for pancreatic NETs
  • Temozolomide-based regimens showing promise

Status of CAR T-Cell Therapy for NETs

Current Evidence

• CAR T-cell therapy is FDA-approved for several hematologic malignancies but not for any solid tumors, including NETs 2
• Preclinical research has shown potential for CAR T-cells targeting CDH17 (a cell surface adhesion protein) in NETs, with promising results in animal models 3
• NETs generally have low tumor mutational burden, which may limit immunotherapy response 4

Challenges for CAR T-Cell Therapy in Solid Tumors

• Limited efficacy in solid tumors due to barriers including:
  • Poor T-cell trafficking to tumor sites
  • Immunosuppressive tumor microenvironment
  • Heterogeneous antigen expression
  • Limited persistence of CAR T-cells 5, 6

Clinical Decision-Making Algorithm

1. Confirm diagnosis and grade of NET

   • Low-grade (G1) and intermediate-grade (G2) NETs have different treatment approaches than high-grade (G3) NETs

2. Assess disease extent and somatostatin receptor status

   • Perform somatostatin receptor imaging (e.g., 68Ga-DOTATATE PET/CT)
   • Evaluate for presence of symptoms, tumor burden, and growth rate

3. For localized disease: Consider surgical resection with curative intent

4. For unresectable or metastatic low-grade NET:

   • If somatostatin receptor-positive: Start with SSAs (octreotide or lanreotide) 1
   • If asymptomatic with low tumor burden: "Watch and wait" approach may be appropriate in select cases 1

5. For progressive disease despite SSAs:

   • Consider PRRT with 177Lu-dotatate (if somatostatin receptor-positive) 1
   • Consider everolimus 1
   • Consider locoregional therapies for liver-predominant disease
   • Consider chemotherapy for selected cases, especially pancreatic NETs 1

6. Clinical trials: Consider enrollment in clinical trials, including emerging immunotherapy approaches

Important Caveats

• CAR T-cell therapy remains investigational for NETs and should only be considered within clinical trials
• The heterogeneity of NETs requires individualized treatment decisions based on tumor site, grade, and receptor status
• Severe toxicities associated with CAR T-cell therapy (cytokine release syndrome, neurotoxicity) must be weighed against potential benefits 1
• Molecular targeted therapies like everolimus and sunitinib have demonstrated efficacy in NETs with more established safety profiles 1

Given the current evidence, patients with low-grade NETs should receive established treatments with proven efficacy and safety profiles rather than experimental CAR T-cell therapy outside of clinical trials.