Immune Checkpoint Inhibitors (Checkpoints): Pembrolizumab, Nivolumab and Ipilimumab

Mechanism

Pharmacological Class and Group

Humanized and human monoclonal antibodies of immunobiological class IgG4 (Pembrolizumab and Nivolumab) and IgG1 (Ipilimumab), selective modulators of immune checkpoints of T lymphocytes.

Mechanism of Action

The tumor is able to actively evade the surveillance of CD8+ cytotoxic T lymphocytes by activating down-modulating receptors expressed on its cell surface:

• Pembrolizumab and Nivolumab (Anti-PD-1): They selectively and specifically bind to the programmed cell death 1 (PD-1) receptor expressed on exhausted effector T lymphocytes in the periphery. By blocking the receptor, they physically prevent its coupling with the suppressive ligands secreted by the tumor: PD-L1 (B7-H1) and PD-L2 (B7-DC). By silencing the receptor, activation of the blocked T cell receptor (TCR) is restored, robustly promoting cellular reactivation of clonal antitumor cytotoxic T cells against the tumor.
• Ipilimumab (Anti-CTLA-4): It physically and potently couples to the cytotoxic T lymphocyte antigen 4 (CTLA-4) receptor, which acts as a physiological negative competitor of the immune costimulatory signal expressed at the early draining lymph node synapse. By blocking CTLA-4, the costimulatory ligand CD80/CD86 expressed on antigen-presenting cells can freely bind to the activating lymphocyte receptor CD28, broadly restimulating the early recruitment of naïve T cell clones.

Blockade of the Tumor Immunosuppressive Pathway by Anti-PD-1

By Pembrolizumab or Nivolumab binding to PD-1 receptors expressed on the lipid membrane of infiltrating intratumoral effector T lymphocytes, the negative intracellular cellular signal mediated by SHP-1/2 phosphatases is abolished:

Anti-PD-1 Blockade of PD-1/PD-L1 Axis Inactivation of SHP-1/2 Restoration of CD8^{+ Lymphocyte TCR}

This allows the T cell to resume active lysosomal degranulation of perforins and granzymes, inducing selective T cell-mediated cytotoxic destruction against malignant tumor cells.

Pharmacokinetics

High Resolution Pharmacokinetics

• Distribution and Metabolism: Very low peripheral volume of distribution confined to the lymphatic tissue bed. Clearance is carried out by nonspecific intracellular proteolytic degradation after molecular internalization mediated by cellular receptors. They do not interfere with nor are they eliminated by phase I hepatic or direct capillary filtration renal routes.
• Half-life (t_1/2): The elimination half-life is long, approximately 22 to 27 days for Pembrolizumab and Nivolumab, and 15 days for Ipilimumab, which facilitates dosing regimens spaced every 2, 3, 4 or 6 weeks.

Indicators and dose

Clinical Indications and Frequent Regimens

• Pembrolizumab: Advanced or metastatic melanoma, first-line treatment of non-small-cell lung cancer (according to tumor PD-L1 expression measured by TPS ≥ 50% for monotherapy, or irrespective of TPS when combined with chemotherapy), and solid tumors with a phenotype of high microsatellite instability (MSI-H) or DNA mismatch repair deficiency (dMMR).
• Nivolumab: Metastatic melanoma, previously treated advanced renal cell carcinoma, recurrent classical Hodgkin lymphoma.
• Ipilimumab: Advanced metastatic melanoma, often administered in synergistic combination with nivolumab to activate both initial and peripheral immune checkpoints.

Dosage and Clinical Adjustment

• Pembrolizumab IV: 200 mg every 3 weeks or 400 mg every 6 weeks as a short, 30-minute intravenous infusion, continued over time.
• Nivolumab IV: 240 mg every 2 weeks or 480 mg every 4 weeks as a 30-minute infusion, continued over time.
• Ipilimumab IV: 3 mg/kg every 3 weeks for a total of 4 consecutive combination doses.
• Dose adjustments are not suggested for mild-moderate renal or hepatic impairment.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Severe hypersensitivity to the active ingredient or biological excipients.
• Severe active systemic autoimmune disease with an uncontrolled basis (Lupus, Rheumatoid Arthritis or Ulcerative Colitis with an active progressive course, due to extreme risk of fatal exacerbation).

Relative Contraindications

• Previous mild or asymptomatic interstitial lung dysfunction.
• History of basic allogeneic solid organ transplantation.

Adverse Effects (ADR) and Specific Toxicity

• Immune-Related Adverse Events (irAEs): Inflammatory toxicity secondary to loss of peripheral tissue self-tolerance induced by generalized lymphocyte overactivation:
  • Autoimmune colitis: Severe watery diarrhea with mucus or fresh blood, potentially progressing to colonic perforation.
  • Autoimmune pneumonitis: Dry cough, progressive exertional dyspnea and diffuse patchy CT infiltrates causing dose-limiting toxicity.
  • Autoimmune endocrinopathies: Diffuse hypophysitis (with combined hormonal deficiencies), subacute thyroiditis, hypothyroidism or new-onset type I diabetes mellitus.
  • Autoimmune hepatitis: Marked transaminase elevation without obvious cholestasis.

Critical Management of irAEs: Severity Classification and Steroid Treatment

The appearance of autoimmune inflammatory toxicities requires an early treatment protocol to avoid patient death due to generalized inflammatory dysregulation:

• Grade 1 Toxicity (Mild): Continue immunotherapy with close monitoring of symptoms and laboratory tests every two weeks.
• Grade 2 Toxicity (Moderate): Immediately withhold the immunotherapy temporarily. Start systemic oral corticosteroids (Prednisone 0.5 - 1.0 mg/kg/day), continuing until resolution to grade ≤ 1 to reduce the autoimmune response.
• Grade 3 or 4 toxicity (Serious/Fatal): Permanently discontinue the immunotherapy. Hospitalize the patient urgently and immediately start high-dose intravenous corticosteroids (Methylprednisolone 1.0 - 2.0 mg/kg/day):

irAEs Grade 3/4 Methylprednisolone IV 48h resistance Infliximab 5 mg/kg

• Refractory: In autoimmune colitis refractory to corticosteroids after 48 hours of treatment, promptly coadminister the immunosuppressive monoclonal antibody Infliximab (5 mg/kg IV as a single infusion) to induce remission of colonic mucosal inflammation.