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Cancer immunotherapies, including checkpoint inhibitors and adoptive cell therapy, manipulate the immune system to recognize and attack cancer cells. These therapies have the potential to induce durable responses in multiple solid and hematologic malignancies and thus have transformed treatment algorithms for numerous tumor types. Cancer immunotherapies lead to unique toxicity profiles distinct from the toxicities of other cancer therapies, depending on their mechanism of action. These toxicities often require specific management, which can include steroids and immune-modulating therapy and for which consensus guidelines have been published. This review will focus on the toxicities of checkpoint inhibitors and chimeric antigen receptor T cells, including pathophysiology, diagnosis, and management.

Immune checkpoint inhibitors (ICI) predispose patients to immune-related adverse events (irAEs). Although hepatitis is a potentially lethal toxicity, the timing and outcomes have not been well described. In this retrospective study, patients from six international institutions were included if they were treated with ICIs and developed immune-related hepatitis. Patient and tumor characteristics, and hepatitis management and outcomes were evaluated. Of the 164 patients included, most were male (53.7%) with a median age of 63.0 years. Most patients had melanoma (83.5%) and stage IV disease (86.0%). Median follow-up was 585 days; median OS and PFS were not reached. The initial grade of hepatitis was most often grade 2 (30.5%) or 3 (45.7%) with a median time to onset of 61 days. Patients were most commonly asymptomatic (46.2%), but flu-like symptoms, including fatigue/anorexia (17.1%), nausea/emesis (14.0%), abdominal/back pain (11.6%), and arthralgias/myalgias (8.5%) occurred. Most patients received glucocorticoids (92.1%); the median time to improvement by one grade was 13.0 days, and the median time to complete resolution was 52.0 days. Second-line immunosuppression was required in 37 patients (22.6%), and steroid-dose re-escalation in 45 patients (27.4%). Five patients (3%) died of ICI-hepatitis or complications of hepatitis treatment. Ninety-one patients (58.6%) did not resume ICI; of 66 patients (40 grade 1/2, 26 grade 3/4) that were rechallenged, only 25.8% (n = 17) had recurrence. In this multi-institutional cohort, immune-related hepatitis was associated with excellent outcomes but frequently required therapy discontinuation, high-dose steroids, and second-line immunosuppression. Rechallenge was associated with a modest rate of hepatitis recurrence.

Background MBM have a unique molecular profile compared to ECM. Methods We analyzed a previously published dataset from MD Anderson Cancer Center, including RNA-seq on surgically resected, FFPE MBM and ECM from the same patients. STAR pipeline was used to estimate mRNA abundance. DESeq2 package was used to perform differential gene expression (DGE) analyses. Pathway analysis was performed using Gene Set Enrichment Analysis (GSEA). Paired DGE and GSEA compared MBM vs. lymph node (LN) metastases (n = 16) and MBM vs. skin mets (n = 10). CIBERSORTx estimated relative abundance of immune cell types in MBM and ECM. GATK Mutect2 pipeline was used to call somatic mutations using paired normal tumor samples. Mutations were annotated using the Ensembl Variant Effect Predictor and visualized using the Maftools package in R. RNA-seq was available on 54 human primary cutaneous melanomas (CM). Gene Ontology or KEGG Pathway analysis was performed using goana function of limma package in R. Results Paired GSEA found that autophagy pathways may be up-regulated in MBM vs. LN and MBM vs. skin mets. On a single-gene level, the most strongly up-regulated genes in autophagy pathways were GFAP and HBB. Fold changes in other autophagy-related genes were low and did not reach significance. Comparison between CM which recurred in brain vs. CM which did not recur identified up-regulation of autophagy pathways. CIBERSORTx identified an increased proportion of immune suppressive M2 macrophages compared to tumor suppressive M1 macrophages in MBMs and ECMs. Conclusion Up-regulation of autophagy pathways was observed in patient-matched MBM vs. LN and skin mets. This finding was driven by up-regulation of GFAP and HBB, which could reflect changes in the tumor microenvironment. Higher M2:M1 ratio may contribute to an immune suppressive tumor microenvironment and may be targetable. Validation of our findings in an independent Duke dataset is ongoing.

9521 Background: Previous work has shown that MBM have a unique molecular profile compared to ECM. Description of the biology of MBM will facilitate the design of rational therapies for patients (pts) with MBM. Methods: We analyzed a previously published dataset from MD Anderson Cancer Center, which includes RNA-seq on surgically resected FFPE MBM (88 tumors from 74 pts) and surgically resected ECM from the same pts (50 from 34 pts). WES on 18 matched pairs of MBM and ECM was available. The STAR pipeline was used to estimate mRNA abundance. The DESeq2 package was used to perform differential gene expression (DGE) analyses. Pathway analysis was performed using Gene Set Enrichment Analysis (GSEA). Paired DGE and GSEA analyses comparing MBM vs. lymph node metastases (LN mets, n = 16) and MBM vs. skin mets (n = 10) were performed. CIBERSORT estimated relative abundance of immune cell types in MBM and ECM. The GATK Mutect2 pipeline was used to call somatic mutations using paired normal tumor samples. Mutations were annotated using the Ensembl Variant Effect Predictor and visualized using the Maftools package in R. RNA-seq was available on 54 primary cutaneous melanoma (CM) pt samples, including 19 CM which did not recur, 19 CM which recurred as MBM, and 16 CM which recurred as ECM. Gene Ontology or KEGG Pathway analysis was performed using goana function of limma package in R. Results: Comparing MBM vs. LN and MBM vs. skin mets, paired DGE identified 136 and 89 up-regulated genes with a fold change > 2 and false-discovery rate (FDR) q-value < 0.05. Moreover, 308 and 659 down-regulated genes with a fold change < 0.5 were identified in MBM vs. LN and MBM vs. skin mets, respectively (q < 0.05). Paired GSEA found that autophagy signaling pathways may be up-regulated in MBM vs. LN and MBM vs. skin mets. On a single-gene level, comparing both MBM vs. LN and skin mets, the most strongly up-regulated genes in autophagy pathways were GFAP and HBB, whereas fold changes in the majority of other autophagy-related genes were low and did not reach significance. Comparison between CM which recurred in brain vs. CM which did not recur identified up-regulation of autophagy pathways. No difference in autophagy pathway expression was observed comparing between CM with any recurrence vs. without recurrence. CIBERSORT identified an increased proportion of immune suppressive M2 macrophages compared to tumor suppressive M1 macrophages in both MBMs and ECMs. Conclusions: Up-regulation of autophagy pathways was observed in pt-matched MBM vs. LN and skin mets. This finding seemed to be driven by up-regulation of GFAP and HBB, which could reflect changes in the tumor microenvironment (TME). Future studies using single-cell RNA-seq or spatial transcriptomic technology will dissect the TME. A higher M2:M1 ratio may contribute to an immune suppressive tumor microenvironment in MBM and ECM and is targetable. Validation of our findings in an independent Duke dataset is ongoing.

Recipients of hematopoietic cell transplantation (HCT) are at risk for potentially preventable infectious complications because of defects in humoral and cell-mediated immunity. Studies of vaccine immunogenicity in HCT recipients have shown that antibody response rates depend on age, type of vaccine, and presence or absence of graft-versus-host disease. However, few large-scale studies have assessed the immune response to vaccination in HCT recipients. Additionally, HCT recipients have much higher rates of potentially preventable infections compared with the general population even after vaccination. This review evaluates the available studies and our view on the measurement of specific antibody titers, definition of an immune response, and durability of response in HCT recipients in both inactivated and live attenuated vaccines.