Category:Immunomodulators

An immunomodulator is a medicine that modifies the immune response, broadly construed. The category is intentionally inclusive and covers both medicines that suppress immune responses (the immunosuppressants proper, used in transplantation and autoimmune disease) and medicines that augment or redirect immune responses (the interferons in viral hepatitis and multiple sclerosis, the interleukins in selected oncologic indications, the immune-checkpoint inhibitors that unmask antitumour immunity, the cellular therapies including chimeric antigen receptor T cells, and the immunoglobulin preparations used in primary and secondary immunodeficiency). The unifying clinical feature is intervention at the immune system rather than at the disease's downstream pathology.

The first immunomodulator in clinical use was the Bacillus Calmette-Guérin (BCG) preparation, derived by Albert Calmette and Camille Guérin at the Pasteur Institute from a 1908 isolate of Mycobacterium bovis attenuated by serial passage on glycerol-bile potato medium. BCG was introduced as a tuberculosis vaccine in 1921 and has continued in routine immunisation programmes across much of the world; its second indication, intravesical BCG for high-grade non-muscle-invasive bladder cancer, was reported by Alvaro Morales of Kingston, Ontario, in 1976 and has remained a foundational treatment of intermediate-to-high-risk bladder cancer for fifty years.^[1]

The interferons are the prototype cytokine medicines. The phenomenon of viral interference (the resistance of cells to a second viral infection after exposure to the first) was described in 1957 by the British virologist Alick Isaacs and the Swiss virologist Jean Lindenmann at the National Institute for Medical Research in London, who named the responsible secreted protein interferon.^[2] Clinical development took thirty years (the molecule was difficult to purify in quantity), and the recombinant interferon-alpha (Intron A, Schering 1986; Roferon-A, Roche 1986) became the first approved cytokine medicine, used initially in hairy cell leukemia and then extended to chronic hepatitis B and C, melanoma, renal cell carcinoma, Kaposi sarcoma, and several other indications. The pegylated formulations (PEG-Intron 2001, Pegasys 2002) extended the dosing interval. Interferon-beta (Betaseron 1993; Avonex 1996; Rebif 1998) entered multiple sclerosis as the first disease-modifying therapy for that disease. Interferon-gamma (Actimmune 1990) is used in chronic granulomatous disease and in severe malignant osteopetrosis.

The interleukin-2 story is briefly told. Recombinant human IL-2 (aldesleukin, Proleukin) was approved in 1992 for metastatic renal cell carcinoma and in 1998 for metastatic melanoma; its substantial systemic toxicity (capillary leak syndrome, severe hypotension, multi-organ dysfunction) limited it to inpatient administration in a small number of specialised centres, and it has largely been displaced by the immune-checkpoint inhibitors in both indications. The interleukin-2 mechanism, however, has been re-explored in the chimeric-antigen-receptor T-cell therapies, where infused engineered T cells produce IL-2 endogenously to support their expansion.

The intravenous immunoglobulin (IVIg) preparations occupy a distinct sub-category. Pooled human polyclonal IgG from thousands of donors, given intravenously or subcutaneously, is used as replacement therapy in primary and secondary immunodeficiencies (X-linked agammaglobulinaemia, common variable immunodeficiency) and as immunomodulator therapy in a long list of autoimmune and inflammatory conditions (Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis crisis, immune thrombocytopenia, Kawasaki disease, and many others). The mechanism in the immunomodulator indications is incompletely characterised, involving Fc-receptor saturation, neutralisation of pathogenic autoantibodies, modulation of complement activation, and induction of regulatory T cells. The newer Fc-targeted medicines (the FcRn inhibitor efgartigimod, approved in 2021 for myasthenia gravis; the C1-esterase inhibitor and the anti-C5 monoclonal eculizumab, used in paroxysmal nocturnal hemoglobinuria and atypical haemolytic uraemic syndrome) act on related mechanisms more selectively.

The transformative immunomodulator class of the past fifteen years is the immune-checkpoint inhibitor, the central event of contemporary medical oncology (described in detail under antineoplastics). The CTLA-4 antibody ipilimumab (2011), the PD-1 antibodies pembrolizumab and nivolumab (2014), the PD-L1 antibodies atezolizumab, durvalumab, and avelumab, and the LAG-3 antibody relatlimab block the inhibitory checkpoint signals that limit antitumour T-cell activity; the autoimmune adverse-effect profile (rash, colitis, hepatitis, pneumonitis, endocrinopathy) reflects the same disinhibition mechanism. Allison and Honjo shared the 2018 Nobel Prize for the work that led to this class.

The chimeric antigen receptor T-cell therapies (tisagenlecleucel 2017 for paediatric ALL, axicabtagene ciloleucel 2017 for lymphoma, brexucabtagene autoleucel, lisocabtagene maraleucel, idecabtagene vicleucel and ciltacabtagene autoleucel for multiple myeloma) and the bispecific T-cell engagers (blinatumomab for ALL, teclistamab and elranatamab for myeloma) are cellular and protein immunomodulators that physically redirect T cells against tumour antigens. Their adverse-effect profile (cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome) has produced a distinct intensive-care subspecialty and the routine use of the IL-6 receptor antagonist tocilizumab for management.

The classical disease-modifying medicines for multiple sclerosis (interferon-beta, glatiramer acetate, the oral fumarate-derivative dimethyl fumarate, the S1P-receptor modulators fingolimod and siponimod and ozanimod and ponesimod, the antibody-mediated lymphocyte-depleting agents alemtuzumab and natalizumab and the more recent ocrelizumab, ofatumumab, and ublituximab targeting CD20 B cells) are immunomodulators by indication and are collected separately in detail at disease-modifying therapy for MS pages; they overlap with the immunosuppressant category in mechanism.

By approach:

• Immunosuppressants (cross-indexed; transplantation and autoimmune): the systemic glucocorticoids, the antimetabolites, the calcineurin and mTOR inhibitors, the biologics including the TNF inhibitors, the IL-6 and IL-1 and IL-17 and IL-23 antagonists, the JAK inhibitors, and the lymphocyte-depleting agents
• Interferons: interferon-alfa-2a and -2b, pegylated interferon-alfa-2a and -2b, interferon-beta-1a and -1b, interferon-gamma-1b
• Interleukins: aldesleukin (IL-2), oprelvekin (IL-11, for chemotherapy-induced thrombocytopenia)
• BCG and other mycobacterial-based: intravesical BCG for bladder cancer
• Pooled human immunoglobulin: intravenous (IVIg) and subcutaneous (SCIg) immunoglobulin preparations
• Selective Fc-related and complement-related medicines:
  • Efgartigimod (FcRn inhibitor; myasthenia gravis)
  • Eculizumab, ravulizumab (anti-C5; paroxysmal nocturnal hemoglobinuria, atypical HUS, generalised myasthenia gravis, neuromyelitis optica)
  • C1-esterase inhibitor (hereditary angioedema)
  • Lanadelumab, berotralstat (hereditary angioedema)
• Immune-checkpoint inhibitors (cross-indexed under antineoplastics):
  • Ipilimumab (anti-CTLA-4), pembrolizumab and nivolumab (anti-PD-1), atezolizumab and durvalumab and avelumab (anti-PD-L1), relatlimab (anti-LAG-3), tislelizumab and others
• CAR-T and other cellular immunotherapy:
  • Tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene, lisocabtagene maraleucel, idecabtagene vicleucel, ciltacabtagene autoleucel
• Bispecific T-cell engagers:
  • Blinatumomab (CD19xCD3, B-ALL), teclistamab and elranatamab (BCMAxCD3, myeloma), tarlatamab (DLL3xCD3, small-cell lung cancer)
• Multiple-sclerosis-specific:
  • Glatiramer acetate, dimethyl fumarate and diroximel fumarate, the S1P-receptor modulators (fingolimod, siponimod, ozanimod, ponesimod), natalizumab, alemtuzumab, the anti-CD20 monoclonals (ocrelizumab, ofatumumab, ublituximab), cladribine, mitoxantrone (historical)
• Thalidomide derivatives (multiple myeloma, leprosy ENL):
  • Thalidomide, lenalidomide, pomalidomide

The boundary of this category is "medicine prescribed to modify the immune response." The anti-infectives act on the pathogen rather than on the immune response and are collected separately, although vaccines (described under biologics) are functionally immunomodulators in the prophylactic direction. The antineoplastics in their cytotoxic actions are not immunomodulators in this category sense, although several specific antineoplastics (the immune-checkpoint inhibitors, the CAR-T cell products, the BCG-based therapy for bladder cancer) are cross-listed here. The systemic glucocorticoids are immunomodulators across the suppression-stimulation spectrum but their primary classification follows the broader steroid pharmacology.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.