What are immunomodulators?

Immunomodulators: Definition, Types, and Clinical Applications

Immunomodulators are substances that modify the immune response by either enhancing (immunostimulants) or suppressing (immunosuppressants) immune function, used to treat various autoimmune, inflammatory, and malignant conditions.

Types of Immunomodulators

Corticosteroids

• Primary mainstay of treatment for most high-grade immune-related adverse events (irAEs) 1
• Short-term use to treat irAEs has not been shown to reduce antitumor efficacy
• Require appropriate duration and careful tapering to prevent recurrence of immune-related adverse events

TNF Inhibitors

• Block inflammatory effects of tumor necrosis factor in autoimmune diseases 1
• Infliximab is a monoclonal anti-TNF-α antibody used for treating:
  • Crohn's disease
  • Ulcerative colitis
  • Rheumatoid and psoriatic arthritis
  • Psoriasis
• Mechanism: Blocks TNF-α receptor interaction, inhibiting proinflammatory cytokines (IL-1, IL-6) and modulating immune effector cells 1
• Particularly effective for immune-related colitis and inflammatory arthritis
• May increase risk of serious infections and reactivation of latent infections 2

Thiopurines

• Include azathioprine and 6-mercaptopurine
• Associated with increased risk of viral infections 1
• Can cause severe bone marrow suppression, particularly in patients with TPMT or NUDT15 deficiency 3
• Increase risk of lymphomas, particularly when used in combination with TNF inhibitors 3

Integrin Antagonists

• Vedolizumab binds to α4β7 integrin, blocking interaction with mucosal addressin cell adhesion molecule-1 1
• Inhibits T-cell migration across endothelium into inflamed GI tissues
• Indicated for treating GI inflammation in ulcerative colitis and Crohn's disease
• May provide more specific immune suppression for inflamed GI mucosa with less systemic immunosuppression 1

Mycophenolate Compounds

• Available as mycophenolic acid or mycophenolate mofetil
• Used for preventing organ rejection after transplantation
• Multiple immunosuppressive actions 1

JAK Inhibitors

• Promising in treating certain immune-mediated conditions 1
• Examples include baricitinib and tofacitinib
• Beneficial in COVID-19 cases requiring oxygen therapy 1

Emerging Immunomodulatory Approaches

Checkpoint Inhibitors

• Target immune checkpoints beyond PD-L1 1
• Examples include drugs targeting:
  • Co-stimulatory signals (OX40, CD40, CD70, ICOS, CD137)
  • Co-inhibitory signaling (LAG3, TIM3, TIGIT, STAT3)
  • NK cell immune checkpoints (NKG2A)

Microenvironment Modulators

• Target the "immune-metabolism" of the tumor microenvironment 1
• Examples include IDO and CD73 inhibitors
• Aim to modulate compounds that limit T-cell activity (tryptophan, adenosine)

Immune Response Enhancers

• Improve immune response against tumor-associated antigens 1
• Approaches include:
  • Targeting DNA repair pathways
  • New generations of vaccines (DC vaccines, peptide vaccines, DNA/RNA vaccines)
  • Oncolytic viruses

Engineered T-Cell Therapies

• Involve ex vivo manipulation, expansion, and reinfusion of T cells 1
• Examples include CAR-T cells and tumor antigen-specific TCRs
• Promising for oncogene-addicted tumors and specific targets

Clinical Applications

Autoimmune Diseases

• Used to modulate aberrant immune responses in conditions like:
  • Inflammatory bowel disease
  • Rheumatoid arthritis
  • Psoriasis
  • Autoimmune retinopathy 4

Cancer Immunotherapy

• Manage immune-related adverse events from checkpoint inhibitors 1
• Combination therapies to enhance anti-tumor immune responses 1

Infectious Diseases

• Novel approaches for treatment of infectious diseases with increasing pathogen resistance 5
• Target host immune response rather than the pathogen directly

Transplantation

• Prevent organ rejection after transplantation 1

Considerations and Risks

Infection Risk

• Patients treated with immunomodulators are at increased risk for bacterial, viral, fungal, protozoal, and opportunistic infections 3
• Risk of reactivation of latent infections
• Progressive multifocal leukoencephalopathy (PML) has been reported with some immunomodulators 3

Malignancy Risk

• Increased risk of lymphomas, particularly with thiopurines 3
• Hepatosplenic T-cell lymphoma reported in young males with inflammatory bowel disease on azathioprine and TNF inhibitors 3

Monitoring

• Regular monitoring of complete blood counts recommended with many immunomodulators 3
• Prompt dose reduction or temporary withdrawal may be necessary with evidence of bone marrow depression

Pregnancy Considerations

• Many immunomodulators can cause fetal harm when administered during pregnancy 3
• Careful risk-benefit assessment required before use in patients of reproductive potential

Immunomodulatory therapies continue to evolve with our growing understanding of the immune system, offering novel approaches for treating a wide range of conditions while requiring careful monitoring for potential adverse effects.