4.3.3 Targeting the CTLA-4 Pathway: Lessons from t...
Targeting the CD28/CTLA-4 pathway using antibodies and fusion proteins is of considerable interest in the treatment of cancer and autoimmune diseases.Since CTLA-4 limits immune responses to self-tissues, augmenting this pathway represents a treatment option for autoimmunity whereas suppressing this has the potential to stimulate anti-self-responses towards tumors.The potential for the immunological rejection of cancer by harnessing immune responses was first realized using anti-CTLA-4 antibodies, and has resulted in exponential activity in this area [21].
Initially, murine cancer models demonstrated that anti-CTLA-4 antibody treatment resulted in tumor regression and relative resistance to re-inoculation with cancer.Less immunogenic cancers were, however, unresponsive to anti-CTLA-4 therapy unless GM-CSF producing vaccines were co-administered.Importantly, enhanced anti-tumor responses following CTLA-4 blockade were associated with autoimmunity.This was illustrated by CD8 T cell mediated depigmentation in melanoma models, immune-mediated prostatitis following vaccination against prostate cancer-specific antigens and the generation of anti-double stranded DNA antibodies.Based upon the efficacy of CTLA-4 blockade in animal models anti-CTLA-4 antibodies were developed for clinical use.Ipilimumab, a recombinant human immunoglobulin (Ig) G1 monoclonal antibody, and tremelimumab, a human IgG2 monoclonal antibody (previously known as ticilimumab) have both been trialed in a range of advanced stage cancers.It is clear that ipilimumab potently blocks the interaction of CTLA-4 with its ligands by binding to the MYPPPY motif, which is critical for this interaction.Reports from human trials in melanoma, non-small cell lung cancer, mesothelioma,prostate, ovarian, breast and urothelial cancer treatment have shown efficacy.Alongside the benefits in tumor control, these trials nonetheless demonstrate a broad range of immune related adverse events (irAEs) occurring in 60%-65% of patients.irEAs most commonly effect the skin,gastrointestinal (GI) tract, liver and endocrine organs.Additionally, autoimmunity has been reported in almost all other organs including the liver, eyes, nervous system, lungs, heart, kidneys,and joints.The breadth of irAEs is therefore consistent with the biological role of CTLA-4 in the maintenance of polyclonal immune self-tolerance [10, 22].
Further evidence for a role of CTLA-4 in the control of polyclonal auto-reactive T cells has come from examining the circulating TCR repertoire following anti-CTLA-4 therapy.Increased diversity of the TCR repertoire occurs following treatment, is associated with irAE frequency and polyclonal T cell expansion predates and predicts irAEs.This data is consistent with the idea that CTLA-4 blockade allows the expansion and activation of new T cell clones and fits with the idea that self-reactive T cells are present in healthy individuals and are prevented from expanding by CTLA-4-mediated control of CD80/CD86 [23].(https://www.daowen.com)
The fact that CTLA-4 blockade enables immune responses to cancers and healthy self-tissues indicates that significant recognition of self-antigens exists within our immune repertoire.This is supported by data from heterozygous loss-of-function mutations in the CTLA-4 gene.Individuals with these mutations present with an autosomal dominant syndrome of complex autoimmunity and immunodeficiency.This phenotype has many similarities to anti-CTLA-4 antibody treatment and includes enteropathy, autoimmune cytopenias, haemolytic anaemia, thyroid disease, arthritis,psoriasis, granulomatous lung disease and lymphocytic infiltration of non-immune organs.Furthermore, a second CTLA-4 deficiency syndrome caused by autosomal recessive mutations in the LRBA gene is associated with an earlier onset, but phenotypically similar autoimmune syndrome, consistent with the role played by LRBA in the trafficking of CTLA-4.The similarities in wide-ranging autoimmunity between genetic deficiency in the CTLA-4 pathway and the impact of anti-CTLA-4 treatments are striking and reaffirm the central role for CTLA-4 in the maintenance of self-tolerance seen in animal studies [24].
The concept that CTLA-4 deficiency leads to a CD28 driven disease is also supported in humans by the effect of treatment with the CTLA-4-Ig fusion protein, abatacept.This drug has an established role in the treatment of autoimmune disorders, including rheumatoid arthritis, where it is viewed through the lens of blocking the CD28 co-stimulation pathway.In contrast, in CTLA-4 deficiency syndromes, abatacept is viewed as a CTLA-4 replacement therapy.Nonetheless, the functional effects are the same in that CD80 and CD86 ligand availability is diminished.The fact that CTLA-4- and LRBA-deficient patients respond to abatacept is consistent with the concept that these diseases are driven by excessive CD28 co-stimulation and in agreement with the fundamental biology of CTLA-4, as described above [25].
Individuals with a mutation in a single allele of CTLA-4 are highly susceptible to autoimmunity,raising the possibility that more subtle variations in the level of CTLA-4 in the general population may influence responses to treatment.Indeed, non-pathogenic polymorphisms in CTLA-4 that alter the expression of CTLA-4 influence an individual’s lifetime risk for the development of cancer and autoimmune disorders.Taken together these findings illustrate that CTLA-4 expression has a pivotal role in balancing immune responses against self-tissues, and therefore in regulating both autoimmune and anti-cancer responses [10].