Immunotherapy of autoimmunity and cancer: the penalty for success

Abstract

Advances in our understanding of autoimmunity and tumour immunity have led to improvements in immunotherapy for these diseases. Ironically, effective tumour immunity requires the induction of the same responses that underlie autoimmunity, whereas autoimmunity is driven by dysregulation of the same mechanisms that are involved in host defence and immune surveillance. Therefore, as we manipulate the immune system to treat cancer or autoimmunity, we inevitably unbalance the vital mechanisms that regulate self tolerance and antimicrobial resistance. This Science and Society article aims to dissect the conundrum that is inherent to the concept of immunotherapy and highlights the need for new and more specific therapeutic approaches.

Figure 1. A simplified model of common immune responses following adoptive immunotherapy

Tumour-infiltrating lymphocytes (TILs) are expanded in vitro in the presence of excised tumour cells and interleukin-2 (IL-2). CD8⁺ cytotoxic T lymphocytes (CTLs) are activated and expanded. These cells are then infused back into the patient, where they home not only to the tumour to mediate tumour regression, but also to healthy tissues that express melanin, such as the skin and eye, to cause autoimmune inflammation.

Figure 2. Severe vitiligo and uveitis induced by adoptive immunotherapy for melanoma

A | Extensive vitiligo in a patient who received cytoreductive therapy followed by infusion of autologous, in vitro-expanded CD8⁺ T cells. B | The images show the occurrence of uveitis in a patient with melanoma who was treated with monoclonal antibody that was specific for CTLA4 (cytotoxic T-lymphocyte antigen 4). The clinical picture is similar to that seen in patients who have been treated with cytoreductive therapy and tumour-infiltrating lymphocytes. The images are a slit-lamp photograph of the patient’s left eye, showing inflammation and an irregular pupil (iris adheres to lens) (Ba) and a slit-lamp photograph of the right eye (after pupil dilation), showing iris pigment epithelium and fibrin (indicated by arrows) that has adhered to the surface of the lens (Bb). Images are reproduced from REF. (A) and REF. (B).