New therapeutic perspectives to manage refractory immune checkpoint-related toxicities

Abstract

Immune-checkpoint inhibitors (ICIs) are reshaping the prognosis of many cancer types and are progressively becoming a standard of care for many of them. Cancer immunotherapy has started a revolution in the oncology therapeutic landscape, bringing new hope to patients but also a whole new spectrum of toxicities for practitioners to manage. Oncologists and specialists involved in the pluridisciplinary management of immune-related adverse events (irAEs) are increasingly confronted with the therapeutic challenge of severe and/or refractory cases. In this personal view, we summarize the therapeutic strategies reported to manage them. Based on current knowledge of irAE pathogenesis and our immunological expertise, we also transpose the use of new biologic and non-biologic immunosuppressive agents, used to treat primary autoimmune disorders (AIDs), in the context of severe and/or steroid refractory irAE management. Depending on the immune-type predominant infiltrate, we propose a personalized treatment algorithm beyond corticosteroids. A shut-off strategy, intended to treat severe or steroid-refractory irAEs, based on the efficient inhibition of key inflammatory components involved in their pathophysiological processes, and limit potential adverse effects of drug immunosuppression on tumor response is proposed. This approach goes beyond current guidelines, challenging the step-by-step increase in drug immunosuppression proposed so far.

A review of cancer immunotherapy toxicity

“…A retrospective series that included 298 patients who received ipilimumab for melanoma found that 35% of patients required steroids for an irAE and 10% of patients required additional systemic immunosuppression, highlighting the importance of optimizing treatment algorithms for patients with refractory irAEs. Data to inform the management of refractory irAEs are often drawn from case reports, small series, and expert opinions given a lack of prospective data . A recent review of emerging strategies to manage refractory irAEs suggests that biologic therapy for refractory irAEs could be selected based on the pathophysiology of the specific irAE .…”

“…The most common irAEs treated with tocilizumab were pneumonitis and serum sickness/systemic inflammatory response syndrome, and clinical improvement was observed in 27 of 34 patients. IL‐6 expression has been shown to promote tumor growth and metastasis; therefore, IL‐6 blockade may offer the potential for the effective treatment of refractory irAEs and maintenance of immunotherapy efficacy …”

“…31 A recent review of emerging strategies to manage refractory irAEs suggests that biologic therapy for refractory irAEs could be selected based on the pathophysiology of the specific irAE. 31 Some authors have proposed a strategy of the standard use of IL-6 receptor blockade with tocilizumab in refractory irAEs. For instance, a retrospective, single-center series, in which tocilizumab was used as second-line therapy for high-grade irAEs, reported the use of tocilizumab in 34 of 87 patients who were treated with nivolumab for multiple solid tumor types.…”

“…IL-6 expression has been shown to promote tumor growth and metastasis; therefore, IL-6 blockade may offer the potential for the effective treatment of refractory irAEs and maintenance of immunotherapy efficacy. 31…”

Immune checkpoint inhibitors‐induced neuromuscular toxicity: From pathogenesis to treatment

“…Additionally, CTLA‐4 blockade seems to increase the availability of ligands for CD28 permitting the activation of potentially self‐reactive T cells . This hypothesis leads to a series of therapeutic proposals in severe steroid‐resistant irAEs . Furthermore, the role of infectious agents has been proposed, suggesting a similarity with immune reconstitution syndrome in human immunodeficiency virus (HIV) and pathogen‐induced immune response .…”