The Emerging Role of the Gut Microbiome in the Cancer Response to Immune Checkpoint Inhibitors: A Narrative Review

ABSTRACT The discovery of immune checkpoint inhibitors (ICIs) has revolutionized the care of cancer patients. However, the response to ICI therapy exhibits substantial interindividual variability. Efforts have been directed to identify biomarkers that predict the clinical response to ICIs. In recent years, the gut microbiome has emerged as a critical player that influences the efficacy of immunotherapy. An increasing number of studies have suggested that the baseline composition of a patient's gut microbiota and its dysbiosis are correlated with the outcome of cancer immunotherapy. This review tackles the rapidly growing body of evidence evaluating the relationship between the gut microbiome and the response to ICI therapy. Additionally, this review highlights the impact of antibiotic-induced dysbiosis on ICI efficacy and discusses the possible therapeutic interventions to optimize the gut microbiota composition to augment immunotherapy efficacy.

Medication-Related Osteonecrosis of the Jaw in Patients Treated Concurrently with Antiresorptive and Antiangiogenic Agents: Systematic Review and Meta-Analysis

ABSTRACT Introduction Medication-related osteonecrosis of the jaws (MRONJ) is a known adverse event related to the use of antiresorptive (AR) drugs. More recently, an association between antiangiogenic (AA) drugs and MRONJ has been suggested. This review aimed to investigate the overall prevalence and relative risk of MRONJ in patients treated concurrently with AA and AR agents in comparison with a single AA or AR drug. Methods A review protocol was registered with PROSPERO (ID: CRD42020214244). A systematic literature search, study selection, quality assessment, and data extraction were carried out following PRISMA guidelines. Random-effects meta-analysis models were used to summarize relative estimates for the outcomes, namely prevalence and relative risk of MRONJ. Exposure variable included type of drug, specifically AA and AR agents administered either concurrently or individually. Results Eleven studies were included in the final qualitative and quantitative syntheses. The overall pooled weighted prevalence of MRONJ with concurrent AA-AR drugs was 6% (95% CI: 3–8%), compared with 0% (95% CI: 0–0%) for AA only and 5% (95% CI: 0–10%) for AR only. However, high heterogeneity was noted among included studies. Retrospective cohort studies showed a higher pooled prevalence of 13% (95% CI: 10–17%) for concurrent AA-AR therapy. The pooled risk ratio for MRONJ revealed a risk with concurrent AA-AR drugs 2.57 times as high as with AR only (95% CI: 0.84–7.87); however, this difference was not statistically significant. Concurrent AA-AR drugs had a risk for MRONJ 23.74 times as high as with AA only (95% CI: 3.71–151.92). Conclusions High-quality, representative studies are needed for accurate estimation of relative risk of MRONJ with concurrent AA and AR therapy.

A Wolf in Sheep's Clothing: Systemic Immune Activation Post Immunotherapy

ABSTRACT Introduction Immune checkpoint inhibitors (ICIs) are increasingly a standard of care for many cancers; these agents can result in immune-related adverse events (irAEs) including fever, which is common but can rarely be associated with systemic immune activation (SIA or acquired HLH). Methods All consecutive patients receiving ICIs in the Drug Development Unit of the Royal Marsden Hospital between May 2014 and November 2019 were retrospectively reviewed. Patients with fever ≥ 38°C or chills/rigors (without fever) ≤ 6 weeks of commencing ICIs were identified for clinical data collection. Results Three patients met diagnostic criteria for SIA/HLH with median time to onset of symptoms of 10 days. We describe the clinical evolution, treatment used, and outcomes for these patients. High-dose steroids are used first-line with other treatments, such as tocilizumab, immunoglobulin and therapeutic plasmapheresis can be considered for steroid-refractory SIA/HLH. Conclusion SIA/HLH post ICI is a rare but a potentially fatal irAE that presents with fever and a constellation of nonspecific symptoms. Early recognition and timely treatment are key to improving outcomes.

Case Report: Nivolumab-Induced Autoimmune Pancreatitis

ABSTRACT Nivolumab is an anti-programmed cell death protein 1 monoclonal antibody. While an effective treatment for a variety of tumors, immune checkpoint inhibitors (ICI) can cause immune-related adverse events such as ICI-pancreatic injury (ICI-PI). Here we present a case of a 60-year-old man with metastatic acral melanoma treated with nivolumab and ipilimumab who developed ICI-PI. Changes in positron emission tomography images preceded symptom onset. However, this case is unique in that the patient presented with cholestatic liver disease. Magnetic resonance cholangiopancreatography showed a dilated extrahepatic bile duct that resolved with steroid therapy, similar to the clinical course of autoimmune pancreatitis. ICI-PI has variable presentations including obstructive jaundice with a clinical course mimicking autoimmune pancreatitis and prompt awareness and treatment of ICI-PI is clinically significant given increasing use of ICIs.

Real-World Experiences of CAR T-Cell Therapy for Large B-Cell Lymphoma: How Similar Are They to the Prospective Studies?

ABSTRACT Chimeric antigen receptor (CAR) T cell therapy has emerged as a revolutionary treatment option for highly aggressive B cell malignancies. Clinical trials of CD19 CAR T cells for the management of relapsed and/or refractory non-Hodgkin lymphoma (NHL) have shown markedly improved survival and response rates. The goal of this review is to evaluate whether the results from these clinical trials are reflective of real-world practices through the analysis of published literature of the commercially available CAR T cell products. We have found that despite the significantly different patient characteristics, the adverse events and response rates of real-world patients were similar to those of the clinical trials. Of interest, several groups excluded from the clinical trials, such as patients with HIV infection, chronic viral hepatitis, and secondary CNS (central nervous system) lymphoma, had case reports of promising outcomes.

Immunotherapy in Special and Rare Situations: A Brief Review

ABSTRACT Immunotherapy has established itself as an important component of the treatment armamentarium against various solid as well as hematologic cancers. Immune checkpoint inhibitors (ICI) provide for a very well-tolerated and efficacious treatment option that has improved survival in several cancers. The approved ICIs mainly consist of antibodies targeting cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or its ligand, programmed cell death ligand 1 (PD-L1). However, most clinical trials of ICI have excluded patients from high-risk populations, such as those with autoimmune diseases, patients on chronic steroid intake for various reasons or preexisting HIV infections. The older adults are also an underrepresented section of the population enrolled into such trials, most probably due to the higher prevalence of comorbidities and frailty affecting their Eastern Co-Operative Oncology Group performance status, and thus the eligibility for clinical trial enrollment. This paper aimed to briefly review the available evidence and thus guide the decision-making process for use of ICI in such rare and special situations.