CTLA-4 antibodies are a type of immunotherapy used to treat cancer by targeting the CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) pathway, a crucial checkpoint in the immune system. CTLA-4 is a receptor on T cells that downregulates immune responses by competing with CD28 for binding to the B7 molecules (CD80/CD86) on antigen-presenting cells. Blocking this interaction enhances T cell activation and proliferation, promoting anti-tumor responses.

Mechanism of Action

• CTLA-4 antibodies block CTLA-4 from binding to B7 molecules.
• This blockade enhances T cell activation by allowing CD28 to bind to B7 molecules without competition.
• Increased T cell activation boosts the immune response against cancer cells.

Approved CTLA-4 Antibodies

• Ipilimumab (Yervoy): Used for melanoma, renal cell carcinoma (RCC), and in combination with nivolumab for several other cancers.

Clinical Applications

• CTLA-4 antibodies are often used in combination with other immune checkpoint inhibitors, such as PD-1 antibodies, to enhance efficacy.
• Effective in treating cancers that are less responsive to single-agent immunotherapy.

Adverse Effects

• Immune-related adverse events (irAEs) are common due to increased immune activation:
  • Dermatologic: Rash, pruritus.
  • Gastrointestinal: Colitis, diarrhea.
  • Hepatic: Hepatitis.
  • Endocrine: Hypophysitis, thyroid dysfunction.
  • Pulmonary: Pneumonitis.

Biomarkers for Response

• Unlike PD-1/PD-L1 antibodies, there are no well-established biomarkers for predicting response to CTLA-4 blockade.
• Ongoing research aims to identify biomarkers that could predict efficacy and manage adverse effects.

Resistance Mechanisms

• Primary resistance: Tumor-intrinsic factors or immune environment factors that prevent initial response.
• Acquired resistance: Changes in the tumor microenvironment or immune evasion mechanisms that develop after initial response.

Future Directions

• Research on combination therapies to improve response rates and overcome resistance.
• Development of new strategies to manage irAEs more effectively.
• Exploration of CTLA-4 antibodies in treating other diseases involving immune regulation.