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Immune checkpoint inhibitor (ICI) therapy is an increasingly used treatment modality across the various stages of hepatocellular cancer (HCC). There is currently no standard peri-operative therapy for HCC, despite a high probability of recurrence. Emerging studies in a variety of tumors demonstrate significant pathologic and immune responses to neoadjuvant immunotherapy. Unlike kinase inhibitors and other targeted therapies, which demonstrated no benefit in the adjuvant setting and fail to induce significant responses, ICIs can induce radiologically appreciable reduction in disease burden, which make ICI combinations an appealing downstaging strategy in patients early or locally advanced disease. Additionally, induction of anti-tumor immunity in the pre-operative setting may induce protracted T-cell response that, in the post-operative phase, may be capable of eliminating micro-metastatic disease and prevent future recurrence. In this review, we discuss the rationale and clinical hurdles that underlie optimal integration of immunotherapy in the pre-operative setting, highlighting the positive impact on surgical and oncological outcomes in patients with early-stage HCC.

Several studies have revealed that the hyper-inflammatory response induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major cause of disease severity and death. However, predictive biomarkers of pathogenic inflammation to help guide targetable immune pathways are critically lacking. We implemented a rapid multiplex cytokine assay to measure serum interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α and IL-1β in hospitalized patients with coronavirus disease 2019 (COVID-19) upon admission to the Mount Sinai Health System in New York. Patients (n = 1,484) were followed up to 41 d after admission (median, 8 d), and clinical information, laboratory test results and patient outcomes were collected. We found that high serum IL-6, IL-8 and TNF-α levels at the time of hospitalization were strong and independent predictors of patient survival (P

BackgroundHepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death. Immune checkpoint inhibitors targeting PD-1 have limited activity in HCC as monotherapy, with response rates ranging from 14–17%. Tumor neoantigens derived from tumor-specific mutations can be incorporated into personalized therapeutic cancer vaccines to generate tumor-specific T cell immunity, potentially priming the immune system for anti-PD1 therapy. DNA vaccines have been shown to elicit strong CD8 and CD4 T cell responses in preclinical and clinical trials. GNOS-PV02 is a personalized DNA vaccine, encoding up to 40 patient-specific neoantigens. In the GT-30 trial, it is used in combination with INO-9012 (plasmid-encoded IL-12) and pembrolizumab for the treatment of advanced HCC.MethodsGT-30 is a single-arm phase I/II clinical trial to assess the safety, immunogenicity, and preliminary efficacy of GNOS-PV02 in combination with INO-9012 and pembrolizumab in patients with advanced HCC. Twenty-four patients are anticipated to be enrolled. Patients are recruited upon diagnosis or during first-line treatment with tyrosine kinase inhibitors (TKI). Tumors are biopsied for exome and transcriptome sequencing, and peripheral blood collected for germline sequencing and histogenetics. The tumor specific vaccine is designed, optimized and manufactured during first-line therapy. Each vaccine encodes up to 40 neoantigens. After progression or intolerance with first-line therapy, patients commence concurrent personalized vaccine and pembrolizumab. GNOS-PV02 + INO-9012 are administered Q3w for the first 4 doses and Q9w thereafter. Pembrolizumab is delivered Q3w.ResultsWe performed a data cut-off on the first 12 patients. The median age was 66 years (range 55–75 years). GNOS-PV02 + INO-9012 with pembrolizumab has had no reported DLTs or drug related SAEs. The most common treatment-related AE were grade 1 fatigue (25%) and grade 1 injection site reactions (17%). By including up to 40 epitopes in the vaccine we were able to target all neoantigens present in 83% of the patients. The objective response rate was 25% (3/12 partial response, 5/12 stable disease, 4/12 progressive disease). Analysis of the TCR repertoire in peripheral blood and tumor tissue identified novel and significantly expanded T cell clones post-vaccination in all patients analyzed. Many of the novel peripheral T cell clones were also identified to have trafficked to the TME at week 9, potentially mediating the observed tumor regressions.ConclusionsThese data demonstrate the potential of GNOS-PV02 + INO-9012 with pembrolizumab to target multiple neoepitopes, and provide initial support for the safety and efficacy of this regimen in patients with advanced HCC.Trial RegistrationNCT04251117Ethics ApprovalThe study obtained IRB approval (IRB) and all patients signed informed consent prior to taking part in the clinical trial. NZCR EC: 20/NTA/6; JHU: IRB00227771; Mount Sinai: HS#: 20–00076

BackgroundImmune checkpoint inhibitors (ICIs) are approved by the U.S. Food&Drug Administration in over 17 tumor types. Older adult patients make up about a quarter of all cancer patients but are historically understudied in cancer clinical trials. ICIs are associated with immune-related adverse events (irAEs), which may be particularly morbid for older adult patients with underlying comorbidities and impaired functional status. In this study, we provide insight into the real-world safety and efficacy of ICIs among older adult patients (≥80 years) with cancer.MethodsThis is a multicenter, international retrospective study of tumor-agnostic older adult patients with cancer treated with single-agent ICIs between 2010–2019 from 18 academic centers in the U.S. and Europe. A cohort of 928 patients aged ≥80 years during treatment with ICI was assembled and analyzed to evaluate clinical outcomes and irAE patterns in older adult patients treated with single-agent ICIs.ResultsMedian age at ICI initiation was 83.0 years (range 75.8–97.0). Most patients (86.9%) were treated with anti-PD-1 therapy. Among the full cohort, the three most common tumors were non-small cell lung cancer (NSCLC, 37.2%,n=345), melanoma (35.5%,n=329), and genitourinary (GU) tumors (16.5%,n=153). Objective response rates for patients with NSCLC, melanoma, and GU tumors were 32.2%, 39.3%, and 26.2%, respectively. Median progression-free survival (PFS) was 6.7 months (95%CI, 5.2–8.6) for patients with NSCLC, 11.1 months (95%CI, 8.9–16.0) for patients with melanoma, and 6.0 months (95% CI, 5.0–10.7) for patients with GU malignancy. Median overall survival (OS) was 10.9 months (95%CI, 8.6–13.1) for patients with NSCLC, 30.0 months (95%CI, 23.6–46.4) for patients with melanoma, and 15.0 months (95%CI 9.1–25.4) for GU patients (Figure 1A-C). Within histology-specific cohorts (NSCLC, melanoma and GU), clinical outcomes were similar across age subgroups (90). Among all patients (N=928), 41.3% experienced ≥1 irAE(s), including 12.2% reported to be grade (G)3–4. No irAE-related deaths occurred. The median time to irAE onset was 9.8 weeks; 57% occurred within the first 3 months after ICI initiation. ICI was discontinued due to irAEs in 16.1% patients. There was no significant difference in the rate of irAEs among patients age ConclusionsICIs are effective and generally well-tolerated among older patients with cancer. However, ICI discontinuation due to irAE is more frequent with increasing age.

Predicting COVID-19 severity is difficult, and the biological pathways involved are not fully understood. To approach this problem, we measured 4,701 circulating human protein abundances in two independent cohorts totaling 986 individuals. We then trained prediction models including protein abundances and clinical risk factors to predict adverse COVID-19 outcomes in 417 subjects and tested these models in a separate cohort of 569 individuals. For severe COVID-19, a baseline model including age and sex provided an area under the receiver operator curve (AUC) of 65% in the test cohort. Selecting 92 proteins from the 4,701 unique protein abundances improved the AUC to 88% in the training cohort, which remained relatively stable in the testing cohort at 86%, suggesting good generalizability. Proteins selected from different adverse COVID-19 outcomes were enriched for cytokine and cytokine receptors, but more than half of the enriched pathways were not immune-related. Taken together, these findings suggest that circulating proteins measured at early stages of disease progression are reasonably accurate predictors of adverse COVID-19 outcomes. Further research is needed to understand how to incorporate protein measurement into clinical care.

Purpose The development of treatment-related adverse events (trAE) correlates favorably with clinical outcomes in multiple studies of patients receiving immune checkpoint inhibitors (ICI); however, this relationship is undefined in patients with hepatocellular carcinoma (HCC). Patients and methods We derived a cohort of 406 patients with unresectable/advanced HCC receiving ICI therapy as part of international clinical trials submitted to the US Food and Drug Administration (FDA) in support of marketing applications. We tested whether the development of clinically significant trAE (i.e. graded ≥2, trAE2) predicted improved overall survival (OS), progression-free survival (PFS), and objective response rates (ORR) following ICI. We established an international consortium of 10 tertiary-care referral centres located in Europe (n = 67), United States (US, n = 248) and Asia (n = 42) to validate this association. Results In the FDA dataset of 406 patients, 325 (80%) with Barcelona Clinic Liver Cancer (BCLC) stage C HCC mostly treated with ICI monotherapy (n = 258, 64%), trAE2 were reported in 228 patients (56.1%). Development of trAE2 was associated with longer OS (16.7 versus 11.2 months) and PFS (5.5 versus 2.2 months) and persisted as an independent predictor of outcome after adjusting for viral aetiology, gender, Child-Pugh class, BCLC stage, AFP levels, ECOG-PS, ICI regimen (mono/combination therapy) and receipt of corticosteroid therapy. In a multi-institutional cohort of 357 patients with similar characteristics mostly treated with ICI monotherapy (n = 304, 85%), the development of trAE2 was associated with longer OS (23.3 versus 12.1 months) and PFS (9.6 versus 3.9 months). TrAE2 were confirmed predictors of improved OS (HR 0.43; 95% CI:0.25–0.75) and PFS (HR 0.48; 95% CI: 0.31–0.75), with multivariable analyses confirming their association with outcome independent of clinicopathologic features of interest. Additional time-varying multivariable analyses also indicated that trAEs were associated with a decreased risk of progression (HR 0.56, 95% CI: 0.46–0.67) in the FDA dataset and death (HR 0.55; 95% CI: 0.32–0.95) in the multi-institutional dataset. Conclusion Development of trAE2 correlates with improved outcomes in patients with HCC receiving ICI in clinical trials and in routine practice. Prospective studies aimed at understanding the underlying immunologic foundations of such relationships are warranted to identify predictive biomarkers of toxicity and response.

Background CDX-1140 is an agonist anti-CD40 mAb selected to optimize systemic exposure and hence tumor microenvironment (TME) ingress. CDX-1140 activity may be enhanced by combining with CDX-301 (recombinant Flt3L), a dendritic cell growth factor, or with pembrolizumab, an anti-PD-1 mAb. Methods Patients with advanced solid or hematologic (Part 1 only) tumors are enrolled. Part 1 dose-escalation results have been presented (SITC 2019). In Part 2, CDX-1140 dose-escalation (0.09–1.5 mg/kg q4w) is in combination with CDX-301 (75 mcg/kg sc QD x 5 for 2 cycles). In Part 3, CDX-1140 dose-escalation (0.72–1.5 mg/kg q3w) is in combination with pembrolizumab 200 mg q3w. Part 1 and 2 expansion cohorts are dosed at the CDX-1140 MTD, 1.5 mg/kg q4w. Part 3 expansion cohorts are planned. Peripheral blood and tumor biomarkers analysis are ongoing. Results 92 patients have been treated (Part 1 n=57, Part 2 n=31, Part 3 n=4). Part 1 expansion cohorts in SCCHN (n=7) and RCC (n=5) are fully enrolled. Part 2 dose-escalation completed to the highest CDX-1140 dose and a SCCHN expansion cohort is ongoing. Part 3 dose-escalation recently initiated. Safety data is available for 23 and 10 patients at the MTD in Part 1 and 2, respectively. In general, the safety profiles were similar, with arthralgia (52% vs. 50%), pyrexia (44% vs 50%), fatigue (30% vs. 50%), chills (39% vs. 40%), vomiting (30% vs. 20%), nausea (26% vs 40%), myalgia (22% vs. 30%), increased ALT (22% vs. 20%), and increased AST (22% vs. 30%) being the most common drug related AEs at the MTD in Part 1 and 2, respectively. Most AEs were low grade. Across all cohorts, cytokine release syndrome (CRS) (G2 n=4, G3 n=2) occurred in 6 (Part 1 n=2; Part 2 n=4) and pneumonitis (G3) occurred in 5 (Part 1 n=4; Part 2 n=1) patients. Immune activation in the TME consistent with CD40 agonism and increases serum inflammatory cytokines were observed. Evidence of anti-tumor activity/clinical benefit include SD (n=13), tumor cavitation (n=2) and a uPR in solid tumors. A patient with follicular lymphoma has an ongoing durable complete metabolic response. Conclusions The CDX-1140 MTD dose of 1.5 mg/kg, a dose level expected to provide good systemic exposure and TME penetration, is generally well tolerated alone and with CDX-301. Transaminitis and CRS have generally been low grade and infrequent. A cohort combining CDX-1140 with chemotherapy will be initiated in patients with previously untreated metastatic pancreatic adenocarcinoma. Trial Registration NCT03329950 Ethics Approval The study was approved by the following: Providence St. Joseph Health IRB, approval number MOD2020001128; WIRB, approval number 1188814 (Hauke, Gabrail, Bordoni & Gordon); University of Pennsylvania IRB, approval number UPCC 18917; Mount Sinai School of Medicine IRB, approval number 18-00202; Memorial Sloan Kettering Cancer Center IRB, approval number 18-225A; Houston Methodist IRB, approval number MOD00000836

The impact of corticosteroid therapy (CT) on efficacy of immune checkpoint inhibitors (ICI) is undefined in hepatocellular carcinoma (HCC). We evaluated whether CT administered at baseline (bCT) or concurrently with ICI (cCT) influences overall (OS), progression-free survival (PFS) and overall response rates (ORR) in 341 patients collected across 3 continents. Of 304 eligible patients, 78 (26%) received >10 mg prednisone equivalent daily either as bCT (n=14, 5%) or cCT (n=64, 21%). Indications for CT included procedure/prophylaxis (n=37, 47%), management of immune-related adverse event (n=27, 35%), cancer-related symptoms (n=8, 10%) or comorbidities (n=6, 8%). Neither overall CT, bCT nor cCT predicted for worse OS, PFS nor ORR in univariable and multivariable analyses (p>0.05). CT for cancer-related indications predicted for shorter PFS (p

BackgroundNivolumab is Food and Drug Administration approved in sorafenib-experienced, advanced hepatocellular carcinoma (HCC). Post-registration data of treatment in a real-world setting is lacking.Patients and methodsWe performed an international, multicenter observational study to confirm safety and efficacy of nivolumab in 233 patients treated outside clinical trials from eight centers in North America, Europe and Asia.ResultsPatients received nivolumab for Barcelona Clinic Liver Cancer stage C (n=191, 92.0%) and Child-Pugh (CP) A (n=158, 67.8%) or B (n=75, 32.2%) HCC as first (n=85, 36.5%) or second to fourth systemic therapy line (n=148, 63.5%). Objective response rate (ORR) was 22.4% and disease control rate was 52.1%. Median overall survival (OS) was 12.2 months (95% CI 8.4 to 16.0) and median progression-free survival was 10.1 months (95% CI 6.1 to 14.2). Treatment-related adverse events of grade >2 occurred in 26 patients (11.2%). Efficacy and safety were similar across CP classes and therapy line. OS was shorter in CP-B than A (7.3 months vs 16.3 months, p=0.05). Achievement of an objective response predicted for improved OS (25.4 months vs 13.2 months, pConclusionsThis study confirms safety and efficacy of nivolumab in advanced HCC across various lines of therapy and degrees of liver dysfunction. Despite equal ORR and toxicity to nivolumab, patients with CP-B functional class have shorter survival than the patients with CP-A.

Immune checkpoint inhibitors (ICI) have shown positive results in patients with hepatocellular carcinoma (HCC). As liver function contributes to prognosis, its precise assessment is necessary for the safe prescribing and clinical development of ICI in HCC. We tested the accuracy of the albumin-bilirubin (ALBI) grade as an alternative prognostic biomarker to the Child-Turcotte-Pugh (CTP). In a prospectively maintained multi-centre dataset of HCC patients, we assessed safety and efficacy of ICI across varying levels of liver dysfunction described by CTP (A to C) and ALBI grade and evaluated uni- and multi-variable predictors of overall (OS) and post-immunotherapy survival (PIOS). We studied 341 patients treated with programmed-death pathway inhibitors (n = 290, 85%). Pre-treatment ALBI independently predicted for OS, with median OS of 22.5, 9.6, and 4.6 months across grades (p &lt, 0.001). ALBI was superior to CTP in predicting 90-days mortality with area under the curve values of 0.65 (95% CI 0.57&ndash, 0.74) versus 0.63 (95% CI 0.54&ndash, 0.72). ALBI grade at ICI cessation independently predicted for PIOS (p &lt, 0.001). Following adjustment for ICI regimen, neither ALBI nor CTP predicted for overall response rates or treatment-emerging adverse events (p &gt, 0.05). ALBI grade identifies a subset of patients with prolonged survival prior to and after ICI therapy, lending itself as an optimal stratifying biomarker to optimise sequencing of systemic therapies in advanced HCC.

The COVID-19 pandemic caused by infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to more than 100,000 deaths in the United States. Several studies have revealed that the hyper-inflammatory response induced by SARS-CoV-2 is a major cause of disease severity and death in infected patients. However, predictive biomarkers of pathogenic inflammation to help guide targetable immune pathways are critically lacking. We implemented a rapid multiplex cytokine assay to measure serum IL-6, IL-8, TNF-α, and IL-1β in hospitalized COVID-19 patients upon admission to the Mount Sinai Health System in New York. Patients (n=1484) were followed up to 41 days (median 8 days) and clinical information, laboratory test results and patient outcomes were collected. In 244 patients, cytokine measurements were repeated over time, and effect of drugs could be assessed. Kaplan-Meier methods were used to compare survival by cytokine strata, followed by Cox regression models to evaluate the independent predictive value of baseline cytokines. We found that high serum IL-6, IL-8, and TNF-α levels at the time of hospitalization were strong and independent predictors of patient survival. Importantly, when adjusting for disease severity score, common laboratory inflammation markers, hypoxia and other vitals, demographics, and a range of comorbidities, IL-6 and TNF-α serum levels remained independent and significant predictors of disease severity and death. We propose that serum IL-6 and TNF-α levels should be considered in the management and treatment of COVID-19 patients to stratify prospective clinical trials, guide resource allocation and inform therapeutic options. We also propose that patients with high IL-6 and TNF-α levels should be assessed for combinatorial blockade of pathogenic inflammation in this disease.

Purpose Lung cancer screening with low-dose computed tomography has been shown to significantly reduce lung cancer–related mortality in high-risk patients. However, patients diagnosed with lung cancer are typically older and often have multiple age- and smoking-related comorbidities. As a result, cancer screening in older adults remains a complex decision, requiring careful consideration of patients' risk characteristics and life expectancy to ensure that the benefits outweigh the risks of screening. In this review, we evaluate the evidence regarding lung cancer screening, with a focus on older patients. Methods PubMed was searched to identify relevant studies evaluating the clinical outcomes of lung cancer screening. The key words used in our search included non–small cell lung cancer (NSCLC), screening, older, comorbidities, computed tomography, and survival. While we primarily looked for articles specific to older patients, we also focused on subgroup analysis in older patients in larger studies. Finally, we reviewed all relevant guidelines regarding lung cancer screening. Findings Guidelines recommend that lung cancer screening be considered in adults aged 55 to 80 years who are at high risk based on smoking history (ie, 30-pack–year smoking history; having smoked within the past 15 years). Patients who fit these criteria have been shown to have a 20% reduction in lung cancer–related mortality with the use of low-dose computed tomography versus chest radiography. High rates of false-positive results and potential overdiagnoses were also observed. Therefore, screening is generally not recommended in adults with severe comorbidities or short life expectancy, who may experience limited benefit and higher risks with screening. However, several studies have shown a benefit with continued lung cancer screening with appropriate selection of older individuals at the highest risk and with the lowest comorbidities. Implications Older patients experience the highest risk for lung cancer incidence and mortality, and stand to be the most likely to benefit from lung cancer screening. However, careful consideration must be given to higher rates of false-positives and overdiagnosis in this population, as well as tolerability of surgery and competing risks for death from other causes. The appropriate selection of older individuals for lung cancer screening can be greatly optimized by using validated risk-based targeting.

IMPORTANCE: Geriatric (aged ≥80 years) patients are historically underrepresented in cancer clinical trials. Little is known about the efficacy of immune checkpoint inhibitors (ICIs) in geriatric patients. These agents are associated with immune-related adverse events (irAEs), which may be particularly associated with morbidity in this population. OBJECTIVE: To provide insight into the clinical outcomes and safety of ICIs among geriatric patients (aged ≥80 years) with cancer. DESIGN, SETTING, AND PARTICIPANTS: A Multicenter, international retrospective study of 928 geriatric patients with different tumors treated with single-agent ICIs between 2010 to 2019 from 18 academic centers in the US and Europe. Analyses were conducted from January 2021 to April 2021. MAIN OUTCOMES AND MEASURES: Clinical outcomes and irAE patterns in geriatric patients treated with single-agent ICIs. RESULTS: Median (range) age of the 928 patients at ICI initiation was 83.0 (75.8-97.0) years. Most patients (806 [86.9%]) were treated with anti–programmed cell death 1 therapy. Among the full cohort, the 3 most common tumors were non–small cell lung cancer (NSCLC, 345 [37.2%]), melanoma (329 [35.5%]), and genitourinary (GU) tumors (153 [16.5%]). Objective response rates for patients with NSCLC, melanoma, and GU tumors were 32.2%, 39.3%, and 26.2%, respectively. Median PFS and OS, respectively, were 6.7 and 10.9 months (NSCLC), 11.1 and 30.0 months (melanoma), and 6.0 and 15.0 months (GU). Within histologically specific subgroups (NSCLC, melanoma, and GU), clinical outcomes were similar across age subgroups (aged

BackgroundProgrammed cell death protein 1 (PD-1) inhibitors as monotherapy or in combination with chemotherapy have become a standard of care first-line therapy for Stage IIIB/IV non-small cell lung cancer (NSCLC). However, many patients experience disease progression and require subsequent therapy within the first year of treatment.1 For patients requiring salvage chemotherapy, prognosis is poor, with a median progression-free survival (PFS) and overall survival (OS) of 4.0 and 8.5 months, respectively.2 Combinations of PD-1 blockade using sasanlimab (PF-06801591) and other immune and/or targeted therapies may be able to achieve clinical response in patients who have progressed on standard chemoimmunotherapy.MethodsLANDSCAPE 1011 (NCT04585815) is a prospective, open-label, multi-center, parallel group, phase 1b/2 umbrella study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of sasanlimab in combination with other therapies, in patients with Stage IIIB/IV NSCLC. The study is expected to enrol ~375 patients age 18 years or older diagnosed with stage IIIB/IV NSCLC. During phase 1b, the safety of each sub-study combination with subcutaneous sasanlimab will be assessed and the recommended phase 2 dose determined for each combination. Phase 2 will further evaluate safety and anti-tumor activity of each combination using the respective recommended phase 2 dose (figure 1). Up to 5 parallel sub-studies are planned. Currently, 2 sub-studies are ongoing. Sub-Study A will investigate sasanlimab, encorafenib (a BRAF inhibitor), and binimetinib (a MEK inhibitor) in patients with BRAF^V600E mutations (only including treatment-naïve patients in phase 2). Sub-Study B will investigate sasanlimab, axitinib (a vascular endothelial growth factor receptor inhibitor), and SEA-TGT (an anti-TIGIT antibody). In phase 2, this will involve treatment-naïve patients without oncogene drivers who have PD ligand 1-positive tumors or whose disease has progressed on prior immune checkpoint inhibitor-containing regimens. The primary phase 1b endpoint is the dose-limiting toxicity during the first cycle (28 days). The primary phase 2 endpoint in Sub-Study A is durable objective response (OR) defined as confirmed complete response or partial response lasting 10 or more months; and in Sub-Study B, OR defined as confirmed complete response or partial response, according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints include adverse events and laboratory abnormalities, duration of response, time to tumor response, PFS, OS, OR by PD-L1 expression at baseline, pharmacokinetic parameters, incidence of anti-drug antibodies and neutralizing antibodies, and health-related quality of life. The first patient was enrolled in November 2020.Abstract 456 Figure 1LANDSCAPE 1011 study overviewAcknowledgementsThis study was sponsored by Pfizer. Medical writing and editorial support was provided by Simon Stones at Engage Scientific Solutions, and funded by Pfizer. The authors would like to acknowledge the late Aron Thall, who was highly devoted to the execution and success of this study.Trial RegistrationClinicalTrials.gov NCT04585815ReferencesGandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:2078–92.Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016;387:1540–50.Ethics ApprovalThe study is approved at each study site according to local regulations.

BackgroundIntratumoral (IT) cancer therapies may enhance T cell activation and tumor infiltration when combined with systemic checkpoint blockade. This approach may improve treatment of advanced breast cancer, which is commonly resistant to immune therapy.MethodsA multicenter basket-style trial (NCT02643303) was performed in patients with advanced solid tumors, who received polyICLC IT 1mg x 6, then intramuscular (IM) x 3, combined with intravenous (IV) durvalumab 1500 mg q4W. Most were assigned to cohorts also receiving tremelimumab: 10 mg IT or 75 mg IV. Goals were to assess tolerability and clinical activity. Treated tumors were evaluated for immune infiltrates on days (d) 0, 15, and 29 by multiparameter immunofluorescence histology. A strong signal for clinical response was in breast cancer patients; thus, an expansion cohort was enrolled. We report analysis of that breast cancer subgroup.ResultsNineteen participants with treatment-refractory recurrent breast cancer with median 4 prior lines of therapy were enrolled and treated with IV durvalumab and IT/IM polyICLC. Seventeen also received tremelimumab (15 IT, 2 IV). Common treatment-related AEs were fatigue, injection site pain, and chills. There was one dose-limiting toxicity in a participant who received tremelimumab IV, and died with severe hyponatremia (DLT) and progressive disease. Objective clinical responses (1 complete; 4 partial (1 unconfirmed)) were observed in 5 (26%), including 2/9 patients with triple-negative breast cancer (TNBC) and 3/10 with non-TNBC. Median OS was longer for those with CR, PR, or SD (not reached) vs. those with PD or not evaluable (5 months): two responders remain alive at 34+ and 40+ months. In injected tumors, there were significant increases from d0 to d29 in numbers/mm2 of CD8+ T cells, CD20+ B cells, mature dendritic cells (DC), macrophages, and CD56+ NK cells, and in CD8+ cells with antigen-experience (CD45RO), cytotoxic function (granzyme B), activation (ICOS1), or proliferation (Ki67). CD8+ cells expressing LAG3 and TIM3 increased, as did PDL1+ tumor cells and stromal cells. There were no differences in cells expressing IDO, ARG1, CD39, or CD73. Among patients with objective response, vs. all others, proportions of intratumoral CD8+ cells expressing Ki67 increased (p < 0.04).ConclusionsIT tremelimumab and polyICLC plus systemic durvalumab is safe and has clinical activity in patients with advanced TNBC and non-TNBC. The therapy enhances intratumoral immune effectors and markers of T cell function in hypothesis-generating data that warrant confirmatory studies. Clinical response was associated with longer survival and increased CD8 T cell proliferation.Trial RegistrationNCT02643303Ethics ApprovalThe study has been performed with approval of the institutional review boards of each participating institution (Roswell Park Cancer Institute: STUDY 00000121/I291016; Mount Sinai School of Medicine: IRB-17-01692; University of Virginia: IRB # 19276; Cleveland Clinic: 18-694; Toledo: 300176; Dartmouth: STUDY00031630; Emory: IRB00099445). All participants give informed consent before enrolling and participating. The study was also performed with approval from the FDA

Introduction: Hepatic resection is the accepted treatment of early-stage hepatocellular carcinoma (HCC), however, the majority of tumors recur despite surgery and no perioperative intervention has demonstrated a survival advantage. Neoadjuvant immunotherapy has shown success in inducing pathological responses alongside induction of immune memory in multiple tumor types and is being evaluated to determine its potential in HCC. Methods: We recently completed accrual into a trial of perioperative cemiplimab (anti-PD-1) for resectable HCC (NCT03916627, Cohort B). This trial enrolled 21 patients to receive 2 cycles of neoadjuvant cemiplimab (350 mg Q3W) followed by surgical resection and an additional 8 adjuvant cycles. The primary endpoint was significant tumor necrosis, defined as >70% necrosis of the resected tumor. Secondary endpoints included delay of surgery, overall response rate, adverse events (AEs), and change in lymphocyte infiltration. Patients underwent pre-treatment biopsies and regular blood collection throughout treatment to enable exploratory analyses including multiplex IHC and single-cell proteomic and transcriptomic analysis. The final patient enrolled underwent resection on December 28, 2020. Results: Over the course of 18 months, 21 patients were enrolled. All patients received 2 cycles of preoperative cemiplimab, and all but 1 patient underwent successful resection; 1 patient was found to have metastatic disease at the time of surgery and resection was aborted. Cemiplimab demonstrated an acceptable risk-benefit profile: 90.5% of patients experienced any treatment-emergent AE (TEAE) of any grade during the neoadjuvant treatment period through the perioperative period; 28.6% of patients experienced any Grade 3 TEAE. One patient experienced Grade 3 pneumonitis during neoadjuvant therapy and surgery was delayed by 2 weeks past protocol defined surgical window. Of the 20 patients with resected tumors, 4 (20%) met the predefined endpoint of >70% tumor necrosis and 7 (35%) had ≥50% tumor necrosis. Three (15%) of the 4 patients with >70% tumor necrosis had a pathological complete response, defined as 100% tumor necrosis. We observed similar patterns of change in degree of necrosis on pathological assessment and 3D MRI at baseline and following completion of immunotherapy. Initial pathological assessment suggests an association between immune cell infiltration and tumor response. Tissue analysis is ongoing and multiplex IHC relating myeloid and lymphoid infiltration patterns with response to cemiplimab will be presented at the meeting. Conclusion: This is the largest trial reported to date of neoadjuvant PD-1 targeted monotherapy in HCC. Pathological response data support larger trials to identify optimal clinical endpoints that correlate with improvement in survival, and to establish the utility and safety of perioperative PD-1 blockade. Citation Format: Thomas Urban Marron, Ganesh Gunasekaran, Parissa Tabrizian, Edward Kim, Maria Isabel Fiel, Stephen Ward, Zhen Zhao, Deborah Doroshow, Meredith Legg, Ashley Hammad, Paul Kennedy, Guray Akturk, Pauline Hamon, Antoinette Bonaccorso, Daniel Labow, Sacha Gnjatic, Bachir Taouli, Elizabeth Miller, Pradeep Thanigaimani, Nathalie Fiaschi, Jennifer Sims, Jayakumar Mani, Nicola James, Sara Hamon, Vladimir Jankovic, Siyu Li, Hung Kam Cheung, Gavin Thurston, Israel Lowy, Myron Schwartz, Miriam Merad. Neoadjuvant cemiplimab demonstrates complete pathological responses in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT182.

Background: The majority of novel cancer immunotherapies rely on adequate priming of T cells to tumor-specific neoantigens, which is believed to be lacking in patients who do not respond to therapy. We developed a personalized genomic vaccine (PGV-001) in which patient-specific synthetic neoantigen peptides (25 mer),are formulated and administered to patients with multiple cancer types in the adjuvant setting (NCT02721043). Methods: This trial enrolled patients whom had undergone curative-intent surgery (solid tumor patients) or autologous stem cell transplant (multiple myeloma patients), and for whom there was >30% chance of recurrence. Sequencing of tumor and germline DNA and RNA was performed and the OpenVax custom computation pipeline was used to identify candidate neoantigens; this platform ranks transcribed mutations using predicted MHC-I binding affinity and neoantigen abundance. A maximum of 10 peptides were synthesized per patient. Peptides were administered over the course of 27 weeks with poly-ICLC and a tetanus helper peptide. Primary objectives were to determine the safety and tolerability of vaccination, feasibility of vaccine production and administration, and immunogenicity. Results: Within 15 patients enrolled, the OpenVax pipeline identified an average of 67.1 neoantigens/patient (range 8-193), only two patients did not have adequate number of neoantigens identified to synthesize 10 peptides. 13 of the 15 patients received PGV-001, including 10 patients with solid tumor diagnoses and 3 patients with multiple myeloma, 11 of whom received all 10 doses, while 1 experienced progression of disease while on treatment. The vaccine was well tolerated, with grade 1 injection site reactions in 31% of patients, and grade 1 fever in one patient; there were no other significant adverse events. While one patient was lost to follow-up, of the remaining 12 patients the median progression-free survival from the time of their surgery or transplant of 618 days. With a mean follow-up of 925 days, 4 patients remain without evidence of disease, 4 patients are receiving subsequent lines of therapy, and 4 patients have died, though notably only two with documented recurrence of their malignancy. Initial analysis of the patient samples analyzed confirms immunogenicity. T cell responses were measured using ex vivo ELISpot and intracellular cytokine staining following expansion with neoantigen peptide libraries, both demonstrating induction of IFN-gamma, TNF-alpha and IL-2. Notably, robust T cell reactivity was only seen at the completion of all 10 vaccines, supporting the need for a prolonged schedule. Conclusions: PGV-001 was successfully synthesized for 15 patients and administered successfully to 13 patients without significant adverse events. Immune monitoring of immunogenicity is ongoing, with initial analysis demonstrating induction of neoantigen-specific CD4 and CD8 T cell expansion. Citation Format: Thomas Urban Marron, Mansi Saxena, Nina Bhardwaj, Marcia Meseck, Alex Rubinsteyn, John Finnigan, Julia Kodysh, Ana Blazquez, Tim O'Donnel, Mathew Galsky, Deborah Doroshow, Brett Miles, Krysztof Misiukiewicz, Hanna Irie, Amy Tiersten, Samir Parekh, Marshall Posner, Andrea Wolf, John Mandeli, Rachel Brody, Sacha Gnjatic, Eric Schadt, Philip Friedlander, Jeffrey Hammerbacher. An adjuvant personalized neoantigen peptide vaccine for the treatment of malignancies (PGV-001) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB048.

Background: Immune checkpoint inhibition (ICI) is an expanding option in hepatocellular carcinoma (HCC). Antibiotics (ATB) have been shown to reduce response and survival after ICI in other cancers. Methods: Efficacy of ICI is described in patients (pt) from 11 centres (246 USA, 100 Asia, 68 Europe), with median overall (OS), progression-free survival (PFS) and best response (RECIST 1.1) compared between pt with and without ATB exposure in the early immunotherapy period (EIOP) of 30 days before and after ICI initiation. Results: Most of our 414 pt were cirrhotic (297, 71.7%) due to hepatitis C (162, 391.1%) with Barcelona Clinic Stage C (294, 71.0%), Child-Pugh class (CP) A (313, 76.3%) and AFP>400 IU/mL (158, 39.3%). OS was 15.4 mo (95%CI 13.1-17.7) and PFS was 5.3 months (95% CI 4.5-6.0). Most ICI was anti-PD-1 monotherapy (358, 86.5%) and given as 1st (173, 41.8%) or 2nd line (208, 50.2%). Best response to ICI was complete response in 27 pt (6.5%), partial response in 45 (10.9%), stable disease (SD) in 160 (38.6%) and progressive disease (PD) in 161 (38.9%). ATB was given to 167 pt (40.3%), prior to or early after (30 d) ICI initiation (EIOP, 157, 38.0%) or beyond 30 days (21, 5.1%), mostly as beta-lactams (27, 10.9%) or quinolones (26, 10.5%). ATB use was independent of CP class (p=0.76), ECOG performance status (p=0.58) and BCLC stage (p=0.60). mOS in the EIOP+ group was similar to the EIOP- group (13.1 vs 15.5 mo, p=0.92). mPFS in the EIOP+ group was significantly longer than the EIOP- group (7.9 vs 4.2 mo, p=0.004). Observations persisted when stratified by CP class (p=0.42) and ICI type (p=0.92). Partial response rate was higher in the EIOP+ group (17.3% vs 8.6%, p=0.01), although overall objective response and disease control rates were similar between EIOP groups (ORR: 22.7% vs 15.9%, p=0.10; DCR: 64.0% vs 56.6%, p=0.15). Pt in the EIOP+ group were not more likely to experience gastrointestinal AE (EIOP +/- 9.2%/5.4%, p=0.12) or hepatic AE (EIOP +/-, 17.9%/16.5%, p=0.92) of any grade, while severe liver AE (grade 2 or above) were less common in the EIOP+ group (EIOP+/- 2.8%/9.5%, p=0.01). Conclusions: ATB in the 30 d before or after ICI initiation in HCC is associated with prolonged PFS. This is contrary to findings in other solid tumors. Evaluation of the immune-microbiologic determinants of response to ICI in HCC a key research question. Citation Format: Petros Fessas, Muntaha Naeem, Thomas U. Marron, David Szafron, Elad Sharon, Anwar Saeed, Tomi Jun, Sirish Dharmapuri, Abdul R. Naqash, Thoetchai Peeraphatdit, Anuhya Gampa, Yinghong Wang, Uqba Khan, Mahvish Muzaffar, Musharraf Navaid, ChiehJu Lee, Pei-Chang Lee, Anushi Bulumulle, Bo Yu, Sonal Paul, Neil Nimkar, Dominik Bettinger, Hannah Hildebrand, Yehia I. Abugabal, Tiziana Pressiani, Nicola Personeni, Naoshi Nishida, Masatoshi Kudo, Ahmed Kaseb, Yi-Hsiang Huang, Celina Ang, Anjana Pillai, Lorenza Rimassa, David J. Pinato. Early antibiotic exposure delays disease progression following immune checkpoint inhibitor therapy for hepatocellular carcinoma: Evidence from an observational study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 485.

4085 Background: The development of treatment-related adverse events (trAE) correlates favorably with clinical outcomes in multiple studies of patients receiving immune checkpoint inhibitors (ICI), however, this relationship is undefined in patients with hepatocellular carcinoma (HCC). This retrospective multi-center study aimed to examine whether trAEs are prognostic in HCC. Methods: We established an international consortium of 10 tertiary-care referral centers located in Europe (n = 67), United States (US, n = 248) and Asia (n = 42) to test whether the development of clinically significant trAE (i.e. graded >2, trAE2) predicted for improved overall (OS), progression-free survival (PFS), and overall response rates (ORR) following ICI, and subsequently validated this association in a separate cohort of 406 HCC patients receiving ICI therapy as part of international clinical trials submitted to the US Food and Drug Administration (FDA) in support of marketing applications. Results: In a multi-institutional cohort of 357 patients, 274 (77%) with Barcelona Clinic Liver Cancer (BCLC) stage C HCC mostly treated with ICI monotherapy (n = 304, 85%), trAE were reported in 146 patients (41%). Development of trAE2 were associated with longer OS (23.3 versus 12.2 months) and PFS (8.6 months versus 3.7 months). After adjusting for viral aetiology, gender, presence of cirrhosis, Child-Pugh class, BCLC stage, AFP levels, ECOG-PS, ICI regimen (mono/combination therapy) and receipt of corticosteroid therapy, trAE2 were confirmed predictors of improved OS (HR 0.55; 95%CI:0.34-0.88) and PFS (HR 0.51; 95%CI: 0.35-0.74). TrAE2 were associated with higher ORR (27% versus 16%) from ICI. The association between trAE2 and patients’ OS (HR 0.49; 95%CI:0.34-0.70) and PFS (HR 0.43; 95%CI:0.32-0.59) was also observed in the FDA dataset. After a 6-weeks landmark selection, trAE2 were confirmed to be associated with improved PFS (HR 0.59; 95%CI:0.39-0.87); the additional analysis adjusted for tumour response and duration of treatment within the FDA cohort further confirmed the association with longer PFS (HR 0.67; 95%CI: 0.47-0.94). Conclusions: Development of trAE2 may correlate with response and survival in patients with HCC receiving ICI, a clinical setting where the lack of biomarkers still represents an unmet need. Prospective studies aimed at understanding the underlying immunologic foundations of such relationship are warranted to identify predictive biomarkers of toxicity and response.

Throughout the field of oncology, immunotherapy is moving further towards the first-line setting, and there is encouraging data for the use of these novel therapies in the management of lymphomas, utilizing treatments approved for both solid and hematologic malignancies. Herein, we review promising advances in this rapidly moving field from the past year.In the last year, we have seen promising clinical data on engineered antibody therapies for the treatment of lymphomas, as well as further optimization of engineered antibody fragments fused onto linkers or chimeric T cell receptors, both of the modalities capable of transforming non-specific T cells into tumor-specific, serial killer cells. Here we will review the promising data on these advances in antibody-based therapies, as well as some of the immunomodulators and checkpoint-blocking therapies that shown to have promising results in the treatment of lymphomas within the past year.

Immune checkpoint inhibitors (ICIs) have improved overall survival for cancer patients, however, optimal duration of ICI therapy has yet to be defined. Given ICIs were first used to treat patients with metastatic melanoma, a condition that at the time was incurable, little attention was initially paid to how much therapy would be needed for a durable response. As the early immunotherapy trials have matured past 10 years, a significant per cent of patients have demonstrated durable responses; it is now time to determine whether patients have been overtreated, and if durable remissions can still be achieved with less therapy, limiting the physical and financial toxicity associated with years of treatment. Well-designed trials are needed to identify optimal duration of therapy, and to define biomarkers to predict who would benefit from shorter courses of immunotherapy. Here, we outline key questions related to health, financial and societal toxicities of over treating with ICI and present four unique clinical trials aimed at exposing criteria for early cessation of ICI. Taken together, there is a serious liability to overtreating patients with ICI and future work is warranted to determine when it is safe to stop ICI.

Purpose To assess the safety of locoregional treatment (LRT) combined with nivolumab for intermediate and advanced hepatocellular carcinoma (HCC). Materials and Methods A single-center retrospective review included 29 patients undergoing 41 LRTs—transarterial chemoembolization or yttrium-90 transarterial radioembolization—60 days before or concurrently with nivolumab. Demographic, clinical, and laboratory values and adverse events were reviewed before and after nivolumab initiation and after each LRT. Treatment response and time to progression were assessed using Modified Response Evaluation Criteria in Solid Tumors. Clinical events, including nivolumab termination, death, and time of last follow-up, were assessed. Results Over a median nivolumab course of 8.1 months (range, 1.0–30) with a median of 14.2 2-week cycles (range, 1–53), predominantly Child–Pugh A (22/29) patients—12 Barcelona Clinic Liver Cancer (BCLC) B and 17 BCLC C—underwent 20 transarterial chemoembolization and 21 transarterial radioembolization LRTs at a median of 67 days (range, 48–609) after nivolumab initiation. Ten patients underwent multiple LRTs. During a median follow-up of 11.5 months (range, 1.8–35.1), no grade III/IV adverse events attributable to nivolumab were observed. There were five instances of grade III/IV hypoalbuminemia or hyperbilirubinemia within 3 months after LRT. There were no nivolumab-related deaths, and 30-day mortality after LRT was 0%. Conclusions LRTs performed concurrently with nivolumab immunotherapy demonstrate an acceptable safety profile in patients with intermediate and advanced HCC.

Background: Mutation-derived tumor antigens (MTAs) arise as a result of somatic mutations, such as nucleotide substitutions and small insertions/deletions. MTAs can serve as specific targets for antitumor therapy, including neoantigen vaccines. The goal of neoantigen vaccination is to help prime T cells to recognize such tumor-specific mutations. Here we describe a phase I trial testing a personalized genomic vaccine (PGV-001) in multiple histologies in the adjuvant setting (NCT02721043). Methods: This trial included patients with histologic diagnosis of solid malignancies or multiple myeloma with a >30% risk of recurrence but no measurable disease at the time of first vaccination. For each patient, HLA typing was performed, and the patient's tumor and germline DNA and tumor RNA were sequenced. Mutated peptides containing predicted neoantigens were selected using the OpenVax computational pipeline, which prioritizes somatic mutations by expression of the mutant allele in the tumor RNA and predicted MHC class I epitope binding for the patient's HLA type. A maximum of 10 peptides was included in each patient's personalized vaccine. The vaccine was administered over the course of 6 months, given in combination with poly-ICLC as the adjuvant. The primary objectives were to determine safety and tolerability, feasibility, and immunogenicity of the PGV-001 neoantigen vaccine. Results: The neoantigen vaccine was successfully administered to 13 patients, spanning 5 different tumor types. For each patient, an average of 1730 somatic mutations were identified (range 521-5106), of which 349 were coding variants (range 68-1493), 88 were coding and expressed in the tumor RNA (range 9-233), and 71 were coding, expressed and resulted in predicted MHC class I ligands (range 8-193). The urothelial, head & neck, and lung tumors resulted in larger numbers of predicted neoantigens than in the cases of multiple myeloma or breast tumors. Despite this difference, each of the 13 patient tumor samples showed enough of a neoantigen load to enable vaccination. We have also initiated analysis of immunogenicity, and early reports demonstrate neoantigen-specific CD4 and CD8 T-cell responses. Conclusions: The PGV-001 personalized neoantigen vaccine was successfully administered to 13 patients, where each patient's neoantigen load was adequate for vaccine synthesis. While we have demonstrated the computational feasibility of identification of neoantigens for inclusion in the PGV-001 genomic vaccine, clinical outcomes will be reported separately. Citation Format: Julia Kodysh, Thomas Marron, Alex Rubinsteyn, Tim O'Donnell, John Finnigan, Ana Blazquez, Mansi Saxena, Marcia Meseck, Philip Friedlander, Nina Bhardwaj. PGV-001: A phase I trial of a multipeptide personalized neoantigen vaccine in the adjuvant setting [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT173.

e16677 Background: Nivo is FDA-approved in sorafenib-experienced, advanced HCC. Post-registration data to portray treatment in a real-world setting is lacking. Methods: We describe safety and efficacy of nivo in patients (pts) from 8 centres (USA n = 181, Asia n = 47, Europe n = 5), documenting overall (OS), progression-free survival (PFS), overall response (ORR) and disease control rates (DCR) (RECIST). Results: We analysed 233 pts, mostly cirrhotic (n = 176, 75%) due to hepatitis C (n = 95, 54.0%) with Barcelona Clinic Stage (BCLC) C HCC (n = 178, 76.4%), Child-Pugh class (CP) A (n = 158, 67.8%) or B (n = 75, 32.2%), and AFP > 400 IU/mL (n = 132, 56.7%). Nivo was given as first (1L, n = 85, 36.5%), second line (2L, n = 130, 55.8%) or > 2L (n = 18, 7.7%), after local (n = 191, 82%) and systemic therapy (n = 148, 63.5%), mostly sorafenib (n = 142, 60.9%). Median duration of nivo was 6.0 months (mo, interquartile range [IQR] 2.6-11.9) and stopped due to progression (n = 109, 46.8%) or toxicity (n = 8, 3.4%). After median follow up of 7 mo (IQR 3.0-12.3), ORR was 22.4% and DCR was 52.1%. Best responses (n = 219, 94%) included complete and partial responses in 18 (7.7%) and 31 (13.3%) pts respectively, stable disease in 65 (27.9%) and progressive disease in 105 (45.1%), not dissimilar by CP (p = 0.26). Median OS was 12.2 mo (95%CI 8.4-16.0) and predicted by CP (CPA 16.3 mo 95%CI 11.7-20.8; CPB 7.3 mo 95%CI 4.2-10.4; hazard ratio [HR] 1.9, p = 0.01), nivo line (1L 16.3 mo 95%CI 8.0-24.5; > 1L 10.4 mo 95%CI 7.4-13.5; HR 0.68, p = 0.05), and PVT (PVT- 13.8 mo 95%CI 11.7-16.0; PVT+ 10.4 mo 95%CI 7.8-13.0; HR 1.8, p = 0.015) but not cirrhosis, AFP, BCLC or steroid use (p > 0.05). Median PFS was 10.1 mo (95%CI 6.1-14.2), predicted by BCLC (A-B 19.0 mo 95%CI 7.1-30.8; C 8.2 mo 95%CI 4.9-11.4; HR 2.8, p = 0.002) and line (1L 18.2 mo 95%CI 10.4-25.9; > 1L 8.2 mo 95% CI 6.2-10.2; HR 0.60, p = 0.021), but not cirrhosis, AFP, or steroid use (p > 0.05). 26 pts (11.2%) suffered > = Grade 2 toxicities, most commonly fatigue (n = 29, 24.7%). Conclusions: Real-world use of nivo in advanced HCC across line of therapy suggests reproducible clinical efficacy and safety compared to prospective trials.

531 Background: The impact of corticosteroid treatment (CT) on the efficacy of immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) is undefined. We evaluated whether CT administered at baseline (bCT) or concurrently to ICI (cCT) influences clinical outcomes of HCC patients treated with ICI. Methods: This retrospective, multi-center observational study was conducted across 9 tertiary academic referral centers collected 341 HCC patients who received ICI across 3 continents between January 1, 2016 and April 1, 2019. Outcome measures included overall (OS) and progression-free survival (PFS) calculated from time of ICI commencement and overall response rates (ORR) defined by Response Evaluation Criteria in Solid Tumors (v1.1) on 6-8 weekly periodic restaging. Results: Of 331 eligible patients, 254 (76%) had BCLC-C stage HCC and received mostly PD(L)-1 ICI monotherapy (n=250, 85%). Median OS was 12.1 months (95%CI 9.2-15.0 months) and median PFS was 8.1 months (95%CI 6.3-10 months). In total 81 patients (24%) received >10 mg prednisone equivalent daily either as bCT (n=15, 4%) or cCT (n=66, 20%). Indications for CT included procedure/prophylaxis (n=37, 45%), management of irAE (n=31, 37%), cancer-related symptoms (n=5, 2%) or comorbidities (n=8, 3%). Neither overall CT, bCT nor cCT predicted for worse OS, PFS nor ORR in uni- and multi-variable analyses (p>0.05). CT for cancer-related indications predicted for shorter PFS (2.4 vs. 11.3 months, p=0.01), OS (4.5 vs. 12.8 months, p=0.05) and reduced ORR (p=0.03) compared to cancer-unrelated indications. Conclusions: This is the first study to demonstrate that neither bCT nor cCT appear to influence response and OS following ICI in HCC. Worse survival and ORR in CT recipients for cancer-related indications appears driven by the poor prognosis associated with symptomatic HCC.

Multiple myeloma involvement of the central nervous system is rare, portends a poor prognosis, and requires rapid clinical intervention. The gold standard for diagnosis is cytology, which is highly insensitive. Abnormal free light chain detection in cerebrospinal fluid was more reliably concordant with clinical diagnosis of central nervous system multiple myeloma than cytology. Free light chain levels in cerebrospinal fluid dynamically correlated with response to therapy. Assessment of free light chains in cerebrospinal fluid can be included in the diagnostic algorithm to diagnose central nervous system multiple myeloma and monitor response to therapy.

O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1

Common variable immunodeficiency (CVID) is characterized by low levels of immune globulins and lack of antibody. Mutations in transmembrane activator and calcium-modulating cyclophilin ligand (TACI), are found in 8-10%, associated with autoimmunity and splenomegaly. Some patients with mutations had increased serum levels of TACI. Because of this, and the prevalence of autoimmunity, splenomegaly, and lymphadenopathy, we quantitated levels of TACI ligands, a proliferation inducing ligand (APRIL) and B cell activating factor (BAFF) and TACI in serum of 77 patients. CVID subjects had markedly increased serum levels of BAFF (p

Background: Lymphomas are the 5th most common cancer in the United States, 40% of these are cases are indolent non-Hodgkin's lymphoma (iNHL) and are incurable with standard therapy. A previous trial of in situ vaccination in iNHLs, in which intratumoral CpG, the TLR9 agonist, was combined with low dose radiation to induce a systemic immune response against tumor. In this trial induction of tumor-specific CD8 T cell responses and durable clinical remissions of patients’ untreated sites of disease was seen in some patients. One limitation in this previous trial may have been the scarcity of intratumoral dendritic cells (DC) and the suppressive tumor microenvironment. DC are uniquely able to endocytose dying (e.g. irradiated) tumor cells for cross-presentation to anti-tumor CD8 T cells. In this new iteration of in situ vaccine, Flt3L is added as a priming step to increase the presence of intratumoral DCs ahead of vaccination. Fms-like tyrosin kinase 3 ligand (Flt3L) induces tumor leukocyte infiltration and regression in lymphoma tumors in pre-clinical trials, and CDX-301- a formulation of Flt3L - was shown to mobilize BDCA-1 and BDCA-3 myeloid DC subsets in an early phase trial. These DC subsets respond to several TLR agonists and cross-present antigens more effectively than plasmacytoid DCs. While pDCs are high expressors of TLR9, responsive to CpG, myeloid dendritic cells express a wider array of TLRs, including high levels of TLR3. Methods: This Phase I/II trial tests the hypothesis that this novel in situ vaccination will induce clinical remissions at distant (untreated) tumor sites in two cohorts of patients with either previously untreated or relapsed/refractory iNHL (n = 15 per group). Intratumoral CDX-301 25ug/kg is injected into a palpable lymph node for 9 days, followed 2Gy local radiotherapy on day 9 and 10 to the target lymph node. On day 10, following radiation therapy, intratumoral poly-ICLC 2mg is injected to activate local DCs. Poly-ICLC 2mg is then injected on day 14, day 17 (1 week after initial dose) and weekly thereafter for a total of 9 treatments over 8 weeks. Response is assessed with CT scans every three months as per the Revised Response Criteria for Malignant Lymphoma, also known as the Cheson criteria, and leukemic phase of lymphoma monitored by peripheral blood flow cytometry. The trial started accrual in January 2014 and is ongoing, 11 have been enrolled including 8 untreated patients and 3 with refractory disease. To perform correlative studies during the clinical trial we perform excisional biopsy of a distal lymph node before starting trial to assess baseline immunomodulatory or immunosuppressive characteristics of a patients tumor microenvironment. Fine needle aspirate (FNA) of the target tumor (site of Flt3L, Radiation and poly-ICLC administration) treatment at weeks 0, 2, 4 and 6, after which target tumor is significantly smaller and biopsy not typically possible. Blood is collected for immune monitoring at weeks 0, 2, 4, 6, 8, 12 to assess for transient enrichment of DC populations, and monitoring for tumor-specific effector T cell populations. Citation Format: Thomas U. Marron, Nina Bhardwaj, Linda Hammerich, Seunghee Kim-Schulze, Tibor Keler, Tom Davis, Elizabeth Crowley, Andres M. Salazar, Joshua Brody. In situ vaccination of low-grade lymphoma with intratumoral Flt3L and poly-ICLC with low-dose radiotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-081.

Background: Lymphomas are the 5th most common cancer in the U.S. and most are incurable with standard therapy. Previously, we completed three trials of ‘in situ vaccination’ - combining low-dose radiotherapy (XRT) with intratumoral administration of TLR9 agonist (CpG). We demonstrated induction of anti-tumor CD8 T cell responses and clinical remissions of patients' non-irradiated sites of disease, lasting up to 4+ years. One limitation may have been the paucity of intratumoral dendritic cells (DC). DC are uniquely able to endocytose dying (e.g. irradiated) tumor cells for cross-presentation to anti-tumor CD8 T cells. Methods: Flt3L – the predominant DC differentiation factor– induces tumor leukocyte infiltration and regression of lymphoma tumors pre-clinically and a new formulation of this cytokine -CDX-301- was shown to mobilize BDCA-1 and BDCA-3 DC subsets in an early phase trial. These DC subsets respond to several TLR agonists and cross-present antigens more effectively than plasmacytoid DC (the CpG-responsive DC subset). We initiated a phase I/II study of a new iteration of the in situ vaccine, adding Flt3L-priming and replacing the prior TLR9 agonist with the TLR3 agonist poly-ICLC (Fig 1A). The vaccine consists of: intratumoral Flt3L administration to increase DC within the tumorlow-dose XRT to induce immunogenic tumor cell death and release tumor-associated antigens, andintratumoral poly-ICLC administration to activate tumor antigen-loaded DC. Results: Six patients have been enrolled, two patients have completed therapy. Treated patients had 2-200-fold increases in BDCA1 and BDCA3 intratumoral DC after Flt3L administration and marked DC activation after XRT and poly-ICLC. Both treated patients have had partial remissions of untreated sites per Cheson criteria, persisting or improving for >6 months after vaccination. These include regressions of bulky lymph nodes (Fig 1B), as well as peripheral blood (Fig1C) and bone marrow disease. A patient with significant peripheral blood tumor burden experienced >10-fold decrease in malignant B cells with concurrent increase in non-tumor B cells, suggesting a degree of cell specificity in the tumor-killing mechanism. Conclusions: Preliminary results suggest that the Flt3L-primed in situ vaccine is feasible, safe and immunologically and clinically effective, warranting further study. Research supported by: Damon Runyon Cancer Research Foundation Clinical Investigator Award Lymphoma Research Foundation Clinical Research Mentorship Program Citation Format: Thomas Marron, Nina Bhardwaj, Elizabeth Crowley, Tibor Keler, Thomas Davis, Andres Salazar, Joshua Brody. Turning a tumor into a vaccine factory: In situ vaccination for low-grade lymphoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA03.

TPS3105 Background: Lymphomas are the 5th most incident cancer in the U.S. and indolent non-Hodgkin's lymphoma (iNHL) are incurable with standard therapy. We previously completed three trials of ‘i...