Opportunistic Autoimmune Disorders Potentiated by Immune-Checkpoint Inhibitors Anti-CTLA-4 and Anti-PD-1

Abstract

To improve the efficacy of immunotherapy for cancer and autoimmune diseases, recent ongoing and completed clinical trials have focused on specific targets to redirect the immune network toward eradicating a variety of tumors and ameliorating the self-destructive process. In a previous review, both systemic immunomodulators and monoclonal antibodies (mAbs), anti-CTLA-4, and anti-CD52, were discussed regarding therapeutics and autoimmune sequelae, as well as predisposing factors known to exacerbate immune-related adverse events (irAEs). This review will focus on immune-checkpoint inhibitors, and the data from most clinical trials involve blockade with anti-CTLA-4 such as ipilimumab. However, despite the mild to severe irAEs observed with ipilimumab in ~60% of patients, overall survival (OS) averaged ~22–25% at 3–5 years. To boost OS, other mAbs targeting programed death-1 and its ligand are undergoing clinical trials as monotherapy or dual therapy with anti-CTLA-4. Therapeutic combinations may generate different spectrum of opportunistic autoimmune disorders. To simulate clinical scenarios, we have applied regulatory T cell perturbation to murine models combined to examine the balance between thyroid autoimmunity and tumor-specific immunity.

The Contained Self-Reactive Peripheral T Cell Repertoire: Size, Diversity, and Cellular Composition

“…Yet, the majority of cancer patients receiving immune-checkpoint blockade inhibitor therapy will develop autoimmune complications (15). In line with the findings reported in this article, these opportunistic autoimmune diseases seem to differ from classic organ-specific autoimmune diseases in their broader range of affected organs.…”

“…In fact, recent clinical trials with anti-CTLA-4 and anti-PD1 Abs uncovered that T cell reactivity against self is unleashed by these treatments. This now constitutes a major limitation for therapies that interfere with tolerance and immune homeostasis (15).…”

Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes

“…Additionally, recent studies demonstrate that immune checkpoint inhibitors can generate and/ or amplify an immune response against mutated antigens (37)(38)(39)(40). As a result of their systemic nature, these treatments can lead to severe autoimmune toxicities (41,42). The occurrence of severe autoimmune toxicities following treatment with an approach that targets neoantigens using MHC tetramer-sorted lymphocytes or cells engineered to express mutated epitope-specific TCRs is unlikely, however, as expression of these antigens is strictly limited to tumor cells.…”

Immune checkpoint-targeted therapy: cancer and autoimmune diseases represent two sides of the same coin

“…The frequency and type of irAE symptoms varied in clinical trials, depending on the nature of the target molecule and the patient cohort, the type and amount of Ab, as well as the particular protocol, and involved a range of tissues and organs. These symptoms led to dermatitis, enterocolitis, hepatitis, and wide spread endocrinopathies (hypophysitis, thyroiditis, adrenal insufficiency), with less frequent symptoms of uveitis, nephritis, arthritis, and inflammatory myopathy [6,34,35].…”