Toxicities of Immunotherapy for the Practitioner

Abstract

The toxicities of immunotherapy for cancer are as diverse as the type of treatments that have been devised. These range from cytokine therapies that induce capillary leakage to vaccines associated with low levels of autoimmunity to cell therapies that can induce damaging cross-reactivity with normal tissue to checkpoint protein inhibitors that induce immune-related adverse events that are autoinflammatory in nature. The thread that ties these toxicities together is their mechanism-based immune nature and the T-cell–mediated adverse events seen. The basis for the majority of these adverse events is a hyperactivated T-cell response with reactivity directed against normal tissue, resulting in the generation of high levels of CD4 T-helper cell cytokines or increased migration of cytolytic CD8 T cells within normal tissues. The T-cell immune response is not tissue specific and may reflect a diffuse expansion of the T-cell repertoire that induces cross-reactivity with normal tissue, effectively breaking tolerance that is active with cytokines, vaccines, and checkpoint protein inhibitors and passive in the case of adoptive cell therapy. Cytokines seem to generate diffuse and nonspecific T-cell reactivity, whereas checkpoint protein inhibition, vaccines, and adoptive cell therapy seem to activate more specific T cells that interact directly with normal tissues, potentially causing specific organ damage. In this review, we summarize the toxicities that are unique to immunotherapies, emphasizing the need to familiarize the oncology practitioner with the spectrum of adverse events seen with newly approved and emerging modalities.

Is autoimmunity the Achilles' heel of cancer immunotherapy?

“…In humans, autoimmune manifestations caused by drugs targeting the CTLA-4 and PD-1 pathways seem to be dependent on the pathway(s) targeted 5,10,28,29 . For example, the most commonly reported endocrine irAE following therapy with the CTLA-4-blocking antibody ipilimumab is hypophysitis, an event that is rarely observed after PD-1-antibody therapy.…”

Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials

“…Common treatment‐related adverse events (TRAEs) with anti–PD‐L1/PD‐1 agents include low‐grade fatigue, pruritus, and rash 2, 3. In addition, potentially serious immune‐related AEs (irAEs), such as high‐grade pneumonitis or autoimmune‐like side effects, occur in a minority of patients 2, 3. To the best of our knowledge, the mechanisms underlying toxicities related to ICIs are not fully understood, and agents targeting PD‐L1 or PD‐1 may have differing safety profiles 2…”

HSP90 Inhibition Enhances the Anti-Tumor Efficacy of Combination Chemo Immunotherapy Targeting DNA Repair Proteins

“…Such analyses will be pursued in future studies extended to include alternate genotoxic agents (including DOX known to promote tumor "immunogenic cell death" [36]) and additional inhibitors of HSP90 (including alternate in-clinic HSP90i that affect ATP-binding [37]), as well as, HDACi known to alter the acetylation of regulatory lysine residues in the HSP90 protein leading to its dysfunction [38][39][40]. Although we failed to observe any evidence for pathologic autoimmunity in our ACT modeling, it will be important to monitor mice vaccinated against DNA-RP in future experiments for deleterious autoimmune sequelae, particularly in combination approaches designed to promote strong inflammatory responses [3][4][5][41][42][43].…”