Immune checkpoint inhibitors in challenging populations

Abstract

Immune checkpoint inhibitors, including those targeting the PD-1/PD-L1 and CTLA-4 pathways, are revolutionizing cancer therapeutics. Both activity and toxicities largely stem from unleashing tumor- or host-specific cytotoxic T cells. Many patients seen in routine clinical practice did not qualify for, or were seriously underrepresented in immune checkpoint inhibitor clinical trials. Thus, a major gap in knowledge regarding the safety and efficacy of these agents persists in many populations, even following regulatory approval. To address this challenge, we aggregated and synthesized the available pre-clinical and clinical data surrounding immune checkpoint inhibitor therapy in challenging clinical populations to assist treatment decision making for both academic and community oncologists. Specifically, we focus on the safety and activity of immune checkpoint inhibitors in patients with autoimmune disorders, post-organ transplant, chronic viral infections, ongoing immunosuppressant use, organ dysfunction, pregnancy, brain metastases, extremes of age, and impaired functional status.

To treat or not to treat: Patient exclusion in immune oncology clinical trials due to preexisting autoimmune disease

“…8 Therefore, effective management depends on early recognition and prompt intervention. 4,8 Treatment-related deaths occur in up to 2% of patients. 9 A recent meta-analysis has found that anti-CTLA-4 treatment causes highgrade irAEs in approximately 20% to 30% of patients.…”

“…For example, cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a cell-surface receptor that normally inhibits T-cell activation. 4 2 Similarly, programmed cell death protein 1 (PD-1) is another cell-surface receptor that hinders T-cell activation upon ligand binding with programmed death ligand 1 (PD-L1) or PD-L2.…”

T cell immunotherapy in hepatitis B Virus related hepatocellular carcinoma

“…This is particularly important in patients with HCC recurrence post liver transplantation. In these patients, immunosuppressive agents are given to control graft rejection, but the very same enhanced anti-tumour response due to checkpoint inhibitors could also lead to uncontrolled inflammation and even graft rejection [22,23] , which is why the use of checkpoint inhibitors is at the moment not indicated for liver transplanted patients.…”

When to Consider Alternatives to Front-Line Immune Therapies in Metastatic Melanoma

“…As patients with autoimmune diseases have been excluded from most immune therapy trials, these patients have not been studied prospectively. Retrospective studies have suggested that either PD-1 or CTLA-4 inhibitors are safe and efficacious in many patients with pre-existing autoimmune disorders, with manageable and reversible autoimmune flares or conventional immune-related adverse events [10][11][12]. Despite this, a careful discussion regarding the risks, benefits and alternative therapies with patients with severe autoimmune disease is required.…”

“…Despite this, a careful discussion regarding the risks, benefits and alternative therapies with patients with severe autoimmune disease is required. Another key comorbidity that may limit immune therapy is a history of organ transplant, which may induce graft rejection [12]. Other patient characteristics and comorbidities not directly addressed in prospective trials include age and organ dysfunction.…”