Anti-PD-1 and PD-L1 monoclonal antibodies (immune checkpoint inhibitors)

Introduction

The discovery of immune checkpoints and the subsequent development of monoclonal antibodies targeting them have revolutionized oncology. Among these, programmed death-1 (PD-1) receptor and its ligand PD-L1 represent one of the most important therapeutic axes.

• PD-1 is an inhibitory receptor expressed on activated T cells, B cells, and NK cells.

• PD-L1 (and PD-L2) are ligands expressed on tumor cells, antigen-presenting cells, and other tissues.

• Interaction of PD-1 with PD-L1 suppresses T-cell proliferation and cytokine production, leading to immune tolerance.

• Many cancers exploit the PD-1/PD-L1 pathway to escape immune surveillance.

Anti-PD-1 and anti-PD-L1 monoclonal antibodies (mAbs) block this interaction, thereby reactivating T cells to recognize and kill tumor cells. These drugs belong to the broader category of immune checkpoint inhibitors (ICIs) and are now standard treatments across a wide range of malignancies.

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Mechanism of Action

• PD-1 Receptor (on T cells): Binding of PD-1 to PD-L1/PD-L2 leads to recruitment of SHP-2 phosphatase, inhibition of TCR signaling, and T-cell exhaustion.

• Checkpoint Blockade:

  • Anti-PD-1 mAbs (e.g., nivolumab, pembrolizumab, cemiplimab, dostarlimab) bind to PD-1 receptors on T cells, preventing ligand binding.

  • Anti-PD-L1 mAbs (e.g., atezolizumab, durvalumab, avelumab) bind to PD-L1 on tumor and immune cells, preventing interaction with PD-1.

• Result: Restoration of T-cell proliferation, cytokine release, and cytotoxic activity against tumor cells.

Unlike cytotoxic chemotherapy, these drugs do not directly kill tumor cells—they release the brakes on the immune system.

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Approved Anti-PD-1 Monoclonal Antibodies

1. Nivolumab

• Brand name: Opdivo

• Indications:

  • Melanoma

  • Non-small cell lung cancer (NSCLC)

  • Renal cell carcinoma (RCC)

  • Hodgkin lymphoma

  • Head and neck squamous cell carcinoma (HNSCC)

  • Esophageal, gastric, bladder cancers, etc.

• Dose: 240 mg IV every 2 weeks or 480 mg IV every 4 weeks.

2. Pembrolizumab

• Brand name: Keytruda

• Indications:

  • Wide range including melanoma, NSCLC, HNSCC, classical Hodgkin lymphoma, urothelial carcinoma, MSI-high tumors, triple-negative breast cancer.

  • First PD-1 inhibitor approved for tumor-agnostic indication (MSI-H/dMMR solid tumors, TMB-high tumors).

• Dose: 200 mg IV every 3 weeks or 400 mg IV every 6 weeks.

3. Cemiplimab

• Brand name: Libtayo

• Indications:

  • Cutaneous squamous cell carcinoma (cSCC)

  • Basal cell carcinoma (BCC)

  • NSCLC, cervical cancer.

• Dose: 350 mg IV every 3 weeks.

4. Dostarlimab

• Brand name: Jemperli

• Indications:

  • dMMR/MSI-H recurrent or advanced endometrial cancer.

• Dose: 500 mg IV every 3 weeks × 4 doses, then 1000 mg every 6 weeks.

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Approved Anti-PD-L1 Monoclonal Antibodies

1. Atezolizumab

• Brand name: Tecentriq

• Indications:

  • NSCLC

  • Triple-negative breast cancer (TNBC)

  • Urothelial carcinoma

  • Hepatocellular carcinoma (HCC) in combination with bevacizumab.

• Dose: 1200 mg IV every 3 weeks.

2. Durvalumab

• Brand name: Imfinzi

• Indications:

  • Stage III NSCLC (post-chemoradiation).

  • Extensive-stage small cell lung cancer (ES-SCLC).

  • Biliary tract cancer (in combination).

• Dose: 10 mg/kg IV every 2 weeks or 1500 mg every 4 weeks.

3. Avelumab

• Brand name: Bavencio

• Indications:

  • Merkel cell carcinoma.

  • Urothelial carcinoma.

  • RCC (in combination with axitinib).

• Dose: 800 mg IV every 2 weeks.

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Adverse Effects

Checkpoint inhibitors cause immune-related adverse events (irAEs) due to generalized T-cell activation and loss of self-tolerance.

Common irAEs

• Skin: Rash, pruritus, vitiligo.

• GI: Colitis, diarrhea.

• Liver: Hepatitis (↑ transaminases).

• Endocrine: Hypothyroidism, hyperthyroidism, hypophysitis, adrenal insufficiency, diabetes mellitus.

• Lung: Pneumonitis (potentially fatal).

• Other: Nephritis, myocarditis, arthritis.

Management

• Mild: Supportive therapy.

• Moderate/severe: Withhold drug, start corticosteroids (prednisone 1–2 mg/kg/day).

• Refractory cases: Additional immunosuppressants (infliximab, mycophenolate).

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Contraindications

• Active autoimmune diseases (relative, case-dependent).

• Organ transplant recipients (risk of graft rejection).

• Severe, uncontrolled infections.

• Hypersensitivity to drug components.

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Precautions

• Monitor thyroid, liver, and kidney function regularly.

• Educate patients about early signs of irAEs.

• Pregnancy and breastfeeding: Not recommended (risk to fetus).

• Use with caution in elderly and immunocompromised patients.

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Drug Interactions

• Corticosteroids / immunosuppressants: May reduce efficacy, but required for management of irAEs.

• Live vaccines: Avoid during therapy.

• Other checkpoint inhibitors: Can be combined (e.g., nivolumab + ipilimumab) but increases toxicity.

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Clinical Efficacy

• Melanoma: Pembrolizumab and nivolumab significantly improve overall survival; now standard first-line therapy.

• NSCLC: PD-1/PD-L1 inhibitors improve survival vs chemotherapy, especially in tumors with high PD-L1 expression.

• MSI-H/dMMR tumors: Pembrolizumab demonstrated efficacy across multiple tumor types → first tumor-agnostic FDA approval.

• Combination regimens: Improved efficacy in many cancers (e.g., durvalumab post-CRT in NSCLC, atezolizumab + bevacizumab in HCC).

Limitations:

• Response rates vary (15–45% depending on cancer type).

• Some tumors exhibit primary resistance (lack of PD-L1 expression, immune desert tumors).

• Others develop acquired resistance during treatment.