What is peptide therapy and how is it used in medical treatment?

Understanding Peptide Therapy

Peptide therapy is a molecularly targeted treatment approach that uses synthetic or naturally-derived peptides—short chains of amino acids—to bind specific cellular receptors or proteins, thereby modulating biological pathways to treat disease, with the most established clinical application being peptide receptor radionuclide therapy (PRRNT) for neuroendocrine tumors. 1

Core Mechanism of Action

PRRNT involves systemic administration of radiolabeled peptides (β-emitting radionuclides chelated to peptides) that target cell surface receptors overexpressed on tumors, delivering cytotoxic radiation with high specificity. 1 The oligopeptides are designed to bind cellular proteins—most commonly somatostatin receptor subtype 2 (sstr2)—which undergoes receptor-mediated internalization after binding, concentrating the radioactive payload inside tumor cells. 1

Specific Radiopharmaceuticals in Clinical Use

• ¹⁷⁷Lu-DOTATATE is a β- and γ-emitting radionuclide with physical half-life of 162 hours, maximum β-particle energy of 0.498 MeV, and soft-tissue penetration depth of 1.7 mm maximum (0.23 mm mean), allowing post-treatment imaging and dosimetry. 1

• ⁹⁰Y-DOTATOC is a pure β-emitting isotope with physical half-life of 64 hours, maximum β-particle energy of 2.28 MeV, and deeper soft-tissue penetration of 11 mm maximum (3.9 mm mean). 1

Primary Clinical Application: Neuroendocrine Tumors

PRRNT is indicated for metastatic or inoperable neuroendocrine tumors expressing somatostatin receptor subtype 2, confirmed by positive somatostatin receptor imaging (68Ga-DOTATOC/DOTATATE PET/CT or 111In-pentetreotide). 1, 2

Treatment Outcomes and Efficacy

• Objective tumor responses (partial or complete) occur in up to 30% of treated patients, with patients showing high tumor receptor expression achieving significantly longer survival and improved quality of life. 1

• ⁹⁰Y-DOTATOC achieves objective response rates of 9-33% by WHO/RECIST criteria, with median time to progression of 29 months and overall survival of 36.7 months from treatment. 1

• ⁹⁰Y-DOTATATE produces partial responses in 23% of patients with progressive disease, with the remaining 77% achieving stable disease. 1

• Symptom response rates of 40-60% are reported after repeated ¹³¹I-mIBG therapy, with 10-15% partial objective responses and actuarial survival improvement of 22% at 5 years. 1

Dosing Protocols

Administer ⁹⁰Y-DOTATOC or ⁹⁰Y-DOTATATE at activities of 3-6 GBq at 6-8 week intervals, to cumulative activity of 12-18 GBq, with most patients reporting subjective benefit within two treatment cycles. 1

Toxicity Profile and Management

Side effects primarily affect kidneys and bone marrow but are typically mild with adequate protective measures, specifically amino acid co-administration for renal protection. 1

Specific Adverse Effects

• Temporary myelosuppression occurs 4-6 weeks after therapy and is cumulative, potentially dose-limiting after repeated cycles, particularly in patients with bone marrow infiltration or prior chemotherapy. 1

• Radiation nephritis risk is mitigated by prophylactic amino acid infusion during treatment. 1

• Nausea and vomiting during and immediately after treatment are partly attributed to amino acid co-administration and are managed with prophylactic antiemetics. 1

• Pain from temporary radiation edema may occur in patients with bulky tumors, managed with corticosteroids and analgesics. 1

Patient Selection Criteria

Eligibility requires demonstration of superior radiopharmaceutical uptake at all tumor sites compared to normal tissues on diagnostic imaging, reasonable bone marrow reserve, and adequate renal function. 1

Absolute Contraindications

• Pregnancy and breastfeeding 1
• Patients who are not continent or self-caring (to minimize radiation risk to nursing staff) 1

Broader Peptide Therapy Applications Beyond PRRNT

Peptides function as anticancer agents through multiple mechanisms: direct cytotoxicity via membrane disruption and necrosis, apoptosis induction, tumor angiogenesis inhibition, immune regulation, disruption of cell signaling pathways, cell cycle regulation, and interference with DNA repair pathways. 3, 4

Advantages of Peptide Therapeutics

• Smaller molecular size, high target specificity, low immunogenicity, good in vivo biocompatibility, convenient synthesis, amenable to sequence modification, and no limitation on cargo type. 4

• High specificity for targets with ability to target almost any protein of interest, including proteins lacking small-molecule drugs, making them valuable for personalized cancer medicine. 5

Current Limitations Requiring Mitigation

• Short half-lives in systemic circulation, easy degradation by plasma and cellular proteases, rapid clearance by reticuloendothelial system, and potential immunogenicity. 5

• Chemical modifications to enhance stability include cyclization, substitution with D-amino acids, peptoid formation, N-methylation, and side-chain halogenation. 6

• Macromolecular peptide delivery systems and tumor-targeting agents overcome bioavailability obstacles. 5

Regulatory Status

PRRNT remains investigational in most jurisdictions and must comply with national legislation and ethical guidelines for human therapeutic investigations. 1

In the USA, these radiopharmaceuticals are not FDA-approved and must be administered only by physicians enrolled in investigational protocols under valid Investigational New Drug applications or Radioactive Drug Research Committee approval, with institutional review board oversight. 1

Treatment Sequencing in Multimodal Management

Surgery with curative intent should always be performed when feasible; PRRNT may serve as neoadjuvant therapy to render patients accessible to surgery in selected cases within multidisciplinary approach. 1

Somatostatin analogues (octreotide LAR 30 mg IM monthly or lanreotide 120 mg deep SC monthly) represent first-line therapy for receptor-positive, low-grade tumors, providing both antisecretory effects (controlling hormonal symptoms in 40-90% of patients) and antiproliferative effects. 1, 2

After somatostatin analogue failure in receptor-positive G1/G2 tumors, PRRT with ¹⁷⁷Lu-DOTATATE, everolimus, sunitinib, or chemotherapy (CAP-TEM) are recommended second-line options. 2