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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.

e21578 Background: Both immunotherapy (IO) and targeted therapy (TT) are approved as adjuvant (Adj) treatment for stage III melanoma, as they have proven to significantly decrease disease recurrence. While there is evidence to suggest overall survival (OS) benefit with TT, data demonstrating OS advantage with Adj IO is lacking. There are no prospective head-to-head trials to date comparing these two treatment modalities. Our aim is to determine whether Adj IO equally improves outcomes compared to Adj TT. Methods: We retrospectively analyzed 104 patients (pts) with resected stage III melanoma who received Adj IO or TT from 1/2016 - 12/2021. Relapse free survival (RFS), distant metastasis free survival (DMFS) and OS rates were assessed between the 2 groups. Results: Of 104 pts, 78 received IO (91% nivolumab, 7% pembrolizumab, 2% other) and 26 pts TT (100% dabrafenib/trametinib). Median follow up was 21 months. At data cutoff, among the 26 pts who received TT, 50% completed 1 year of planned therapy, whereas 50% discontinued TT prematurely (42% due to adverse events [AEs], 8% due to disease relapse). Among the 78 pts who received IO, 70% completed 1 year of planned treatment or continued to receive IO at the end of the study, whereas 30% discontinued IO prematurely (18% due to disease relapse, 12% due to AEs). Relapsed disease was noted in 6/26 (23%) and 27/78 (34.6%) pts of the TT and IO groups, respectively. With regards to location of recurrence, in the TT group 2/6 pts relapsed locally and 4/6 distally, whereas in the IO group 14/27 pts relapsed locally and 13/27 distally. The estimated median RFS of the TT vs IO groups was not reached (NA) (95% Cl: 17 months, NA) vs. 30 months (95% CI: 17 months, NA) respectively, which was not statistically significant (p = 0.49). Comparison of DMFS rate was found not to be statistically significant between the 2 groups (p = 0.86). Finally, median OS was NA in either group. At the end of the study 91% and 90.5% of the pts in the TT and IO arms, respectively, were still alive. The most common AEs in the TT group were fatigue (23%), fever (23%), nausea/vomiting (19%), whereas in the IO group were fatigue (22%), hypothyroidism (14%), diarrhea/colitis (10%), pruritic rash (9%). Conclusions: Both TT and IO appear to equally decrease disease recurrence, locally or distally, when given as Adj therapy for stage III melanoma. Prospective, randomized control trials with longer follow up and larger sample size are warranted to determine any difference in potential OS benefit.[Table: see text]

e14008 Background: For patients with melanoma brain metastasis (MBM) treated with stereotactic radiosurgery (SRS), 5-6.5% develop radiation necrosis of the brain (RNB), which is commonly treated with corticosteroids (CS). Nonetheless, high-dose CS may reduce efficacy of immunotherapy (IO). Bevacizumab (BV) has been shown to reduce symptoms and peritumoral edema associated with RNB. However, data on the efficacy and toxicity of BV in patients with MBM who also receive IO is limited. We aimed to describe clinical features and outcomes of patients with MBM who received BV and were also treated with IO. Methods: Under an IRB-approved protocol, patients with MBM who developed RNB or steroid-refractory edema (SRE) and were treated with BV were identified. The selection criteria were as follows: (1) one or more MBM; (2) prior SRS for MBM; (3) development of RNB or SRE detected radiographically or based on expert opinion; (4) treatment with one or more cycles of BV; (5) treatment with IO for metastatic melanoma. Results: In this single-center retrospective series, 8 patients received IO and BV: 4 concurrently and 4 patients received IO immediately prior to or after BV. IO therapy included ipilimumab-nivolumab, nivolumab alone or pembrolizumab. Median number of MBM was 3.6 (range, 1-8) and median number of RNB/SRE foci were 1.125 (range, 1-2). Median time from diagnosis of RNB/SRE to initiation of BV was 1.4 months (range, 0.5-3 months). BV dosing regimen was 5 mg/kg every 2 weeks, 7.5 mg/kg every 3 weeks or 10 mg/kg every 2 weeks. 71% (5 of 7) patients who required CS for RNB/peritumoral edema symptoms at the time of starting BV were able to taper CS after receiving BV or stop CS completely. This allowed for 4 of these patients to subsequently start or resume IO. 28% (2 of 7) patients had increasing neurological symptoms during CS taper and required an increase in CS dosing. Only 1 patient was not on CS at the time of BV initiation. 75% (6 of 8) cases attained intracranial radiologic response, with documented decreased edema or tumor size, or resolution of enhancement on MRI; 1 patient had stable disease after BV; and 1 patient had continued clinical deterioration despite BV. 62.5% (5 of 8) patients had no adverse events from BV, but 37.5% (3 of 8) had DVT/PE, 1 requiring a thrombectomy, and 1 additionally had perforated diverticulitis. Median follow-up time from BV administration was 17.94 months (range, 1-58 months), with 75% (6 of 8) patients with survival > 10 months. Conclusions: Treatment of RNB/SRE with BV in patients with MBM receiving IO appears to be effective and relatively well tolerated, though with occasional serious adverse events. BV led to improvement of symptoms and allowed for CS taper in a substantial proportion of patients. By reducing CS requirement, BV may permit continuation of IO, which leads to durable survival in a large proportion of patients.

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.