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Acinar cell carcinoma (ACC) is a very rare tumor of the exocrine pancreas, representing less than 1% of all pancreatic malignancies. The majority of data regarding ACC are limited to small case series.This is a retrospective study conducted at a large healthcare system from 1996 to 2019. Patients with pathologically confirmed ACC were included, and demographic data, tumor characteristics, and treatment outcomes were abstracted by chart review. Survival curves were obtained by using the Kaplan-Meier method and compared using the log-rank test.Sixty-six patients with ACC were identified. The median patient age at diagnosis was 64, and 42% presented with metastatic disease. The majority presented with abdominal pain or pancreatitis (69%), and laboratory parameters did not correlate with tumor size, metastatic disease, or survival. Several somatic abnormalities were noted in tumors (BRCA2, TP53, and mismatch-repair genes). In patients with localized disease that underwent resection, the median time to develop metastatic lesions was 13 months. The median overall survival (OS) was 24.7 months from diagnosis, with a survival difference based on metastatic disease at diagnosis (median 15 vs 38 mos). Surgery was associated with improved survival in non-metastatic cases (p = 0.006) but not metastatic cases (p = 0.22), and chemotherapy showed OS benefit in metastatic disease (p 0.01). Patients with metastatic ACC treated after 2010 utilized more platinum-based agents, and there was a OS benefit to FOLFOX or FOLFIRINOX chemotherapy compared to gemcitabine or capecitabine-based regimens (p = 0.006).Pancreatic ACC patients often present with advanced disease. Surgery was associated with survival benefit among patients presenting with localized disease. The use of FOLFOX or FOLFIRINOX chemotherapy regimens was associated with improved OS in metastatic patients. These data add to our knowledge in this rare malignancy, and improves understanding about the genomic underpinnings, prognosis and treatment for acinar cancers.

Background Programmed cell death receptor ligand 1 (PD-L1) inhibitors are immune checkpoint inhibitors (ICIs) with a side effect profile that may differ from other classes of ICIs such as those directed against cytotoxic T-lymphocyte−associated protein 4 (CTLA-4) and programmed cell death 1 receptor (PD-1). Being the more recently approved class of checkpoint inhibitors, there are no studies investigating the frequency, etiology and predictors of acute kidney injury (AKI) in patients receiving PD-L1 inhibitors. Methods This was a retrospective cohort study of patients who received PD-L1 inhibitors during 2017 to 2018 in our healthcare system. AKI was defined by a ≥1.5-fold rise in serum creatinine from baseline. The etiology of all cases of sustained AKI (lasting >48 hours) and clinical course were determined by review of electronic health records. Results The final analysis included 599 patients. Within 12 months of ICI initiation, 104 patients (17%) experienced AKI, and 36 (6%) experienced sustained AKI; however, only 5 (, Graphical abstract

PURPOSE: Enterocolitis is among the leading adverse events associated with immune checkpoint inhibitors (ICIs). There are limited retrospective data regarding the safety of ICIs in patients with inflammatory bowel disease (IBD; ulcerative colitis, Crohn’s disease) because they have been generally excluded from clinical trials testing ICIs. Furthermore, there are no outcome data available in patients with microscopic colitis, a leading cause of chronic diarrhea. We aimed to study the safety of ICIs in patients with cancer with pre-existing IBD or microscopic colitis. METHODS: We retrospectively reviewed the records of patients with cancer treated at our institution who received at least 1 dose of either a programmed cell death-1 (PD-1)/ PD-1 ligand inhibitor, cytotoxic T-lymphocyte-associated antigen 4 inhibitor, or both between 2011 and 2018. We identified patients with pre-existing IBD or microscopic colitis. RESULTS: Of 548 patients with solid tumor treated with an ICI, we identified 25 with pre-existing colitis (21 IBD; 4 microscopic colitis). An enterocolitis flare occurred in 7 patients (28%): 3 of 4 patients (75%) with microscopic colitis and 4 of 21 (19%) with IBD. All were treated with systemic corticosteroids, 2 required an anti–tumor necrosis factor agent, and one required an anti-integrin agent and colectomy for treatment of refractory colitis. ICI therapy was discontinued in all patients who experienced an enterocolitis flare. CONCLUSION: In our cohort, exacerbation of enterocolitis occurred in a notable percentage of patients with IBD and a majority of patients with microscopic colitis, leading to discontinuation of ICIs. Although these data suggest that patients with cancer with pre-existing IBD/microscopic colitis may be treated with ICIs, additional studies are needed to validate our results.

Immune checkpoint inhibitors (ICI) have improved outcomes in patients with various malignancies; however, they can cause immune-related hepatitis and enterocolitis. Patients on ICI may also develop upper gastrointestinal symptoms and undergo measurement of gastric emptying. Our aim was to review records of patients with gastroparesis following ICI therapy at two medical centers. We performed a retrospective review of all patients at Mayo Clinic and Brigham and Women’s/Dana-Farber Cancer Center (BWH/DFCC) who underwent gastric scintigraphy for the assessment of symptoms of gastroparesis following ICI treatment up to January 2020. Clinical presentation, medical history, laboratory evaluation, imaging, treatment, and outcomes were retrieved from the records. Gastroparesis was diagnosed as delayed gastric emptying (GE) measured by gastric scintigraphy. At Mayo Clinic, 2 patients (median age 59 years, 1 male [M], 1 female [F]) had delayed GE, while 4 patients (median age 53 years, 3M, 1F) had normal GE following ICI use. Of those with delayed GE (diagnosed after 38 and 2 months of ICI initiation), 1 patient was treated for non-Hodgkin’s lymphoma and melanoma with ipilimumab; a second patient with breast cancer was treated with pembrolizumab. At BWH/DFCC, 2 patients (median age 56 years, 1M, 1F) had normal GE after ICI treatment, while a 62-year-old female with non-small cell lung cancer developed gastroparesis 3 months following initiation of nivolumab. This report documents gastroparesis as a potential adverse effect of ICI. Further studies should explore the potential for ICI therapy to damage anti-inflammatory macrophages that preserve the enteric neurons.

Background There is a lack of predictive markers informing on the risk of colitis in patients treated with immune checkpoint inhibitors (ICIs). The aim of this study was to identify potential factors associated with development of ICI colitis. Methods We performed a retrospective analysis of melanoma patients at Dana-Farber Cancer Institute who received PD-1, CTLA-4, or combination ICIs between May 2011 to October 2017. Clinical and laboratory characteristics associated with pathologically confirmed ICI colitis were evaluated using multivariable logistic regression analyses. External confirmation was performed on an independent cohort from Massachusetts General Hospital. Results The discovery cohort included 213 patients of whom 37 developed ICI colitis (17%). Vitamin D use was recorded in 66/213 patients (31%) before starting ICIs. In multivariable regression analysis, vitamin D use conferred significantly reduced odds of developing ICI colitis (OR 0.35, 95% CI 0.1-0.9). These results were also demonstrated in the confirmatory cohort (OR 0.46, 95% CI 0.2-0.9) of 169 patients of whom 49 developed ICI colitis (29%). Pre-treatment neutrophil-to-lymphocyte ratio (NLR) ≥5 predicted reduced odds of colitis (OR 0.34, 95% CI 0.1-0.9) only in the discovery cohort. Conclusions This is the first study to report that among patients treated with ICIs, vitamin D intake is associated with reduced risk for ICI colitis. This finding is consistent with prior reports of prophylactic use of vitamin D in ulcerative colitis and graft-versus-host-disease. This observation should be validated prospectively in future studies.

Locoregional therapies (LRTs) including radiofrequency ablation, surgical resection, and TACE, play a pivotal role in the treatment of early stage/locally advanced hepatocellular carcinoma (HCC). Besides their direct effect on tumor cells, LRTs also play an essential role in the immunomodulation of the tumor microenvironment which is of interest in the current era of cancer immunotherapy. In this review, we describe the HCC immune microenvironment and how it is affected by LRTs as described in multiple pre-clinical and clinical studies and provide the rationale for combining LRTs with immunotherapy.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer, improving outcomes in patients with advanced malignancies. The use of ICIs in clinical practice, and the number of ICI clinical trials, are rapidly increasing. The use of ICIs in combination with other forms of cancer therapy, such as chemotherapy, radiotherapy, or targeted therapy, is also expanding. However, immune-related adverse events (irAEs) can be serious in up to a third of patients. Critical questions remain surrounding the characteristics and outcomes of irAEs, and how they may affect the overall risk–benefit relationship for combination therapies. This article proposes a framework for irAE classification and reporting, and identifies limitations in the capture and sharing of data on irAEs from current clinical trial and real-world data. We outline key gaps and suggestions for clinicians, clinical investigators, drug sponsors, patients, and other stakeholders to make these critical data more available to researchers for pooled analysis, to advance contemporary understanding of irAEs, and ultimately improve the efficacy of ICIs.

Immune checkpoint inhibitors (ICIs) are widely used for various malignancies. However, their safety and efficacy in patients with a kidney transplant have not been defined. To delineate this, we conducted a multicenter retrospective study of 69 patients with a kidney transplant receiving ICIs between January 2010 and May 2020. For safety, we assessed the incidence, timing, and risk factors of acute graft rejection. For efficacy, objective response rate and overall survival were assessed in cutaneous squamous cell carcinoma and melanoma, the most common cancers in our cohort, and compared with stage-matched 23 patients with squamous cell carcinoma and 14 with melanoma with a kidney transplant not receiving ICIs. Following ICI treatment, 29 out of 69 (42%) patients developed acute rejection, 19 of whom lost their allograft, compared with an acute rejection rate of 5.4% in the non-ICI cohort. Median time from ICI initiation to rejection was 24 days. Factors associated with a lower risk of rejection were mTOR inhibitor use (odds ratio 0.26; 95% confidence interval, 0.09-0.72) and triple-agent immunosuppression (0.67, 0.48-0.92). The objective response ratio was 36.4% and 40% in the squamous cell carcinoma and melanoma subgroups, respectively. In the squamous cell carcinoma subgroup, overall survival was significantly longer in patients treated with ICIs (median overall survival 19.8 months vs. 10.6 months), whereas in the melanoma subgroup, overall survival did not differ between groups. Thus, ICIs were associated with a high risk of rejection in patients with kidney transplants but may lead to improved cancer outcomes. Prospective studies are needed to determine optimal immunosuppression strategies to improve patient outcomes. ispartof: KIDNEY INTERNATIONAL vol:100 issue:1 pages:196-205 ispartof: location:United States status: published

Both immune checkpoint inhibitors (ICI) and antiangiogenesis agents have changed the landscape of cancer treatment in the modern era. While antiangiogenesis agents have demonstrated activities in tumors with high vascularization, including renal cell carcinoma and colorectal cancer, the effect of ICIs has been seen mainly in immunologically recognized tumors, with highly immune-infiltrative lymphocytes. The main challenge in the drug development of ICIs is moving their activities to noninflamed tumors and overcoming resistance that is driven, in part, by the immune-suppressive microenvironment. Angiogenesis factors drive immune suppression by directly suppressing the antigen-presenting cells as well as immune effector cells or through augmenting the effect of regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and tumor-associated macrophages (TAM). Those suppressive immune cells can also drive angiogenesis, creating a vicious cycle of impaired immune activation. The combination of bevacizumab and ipilimumab was the first to show the promising effect of antiangiogenesis and ICIs. A plethora of similar combinations has entered the clinic since then, confirming the promising effects of such approach.

Safe use of immune checkpoint blockade in patients with cancer and autoimmune disorders requires a better understanding of the pathophysiology of immunologic activation. We describe the immune correlates of reactivation of granulomatosis with polyangiitis (GPA)—an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis—in a patient with metastatic urothelial carcinoma treated with pembrolizumab. After PD-1 blockade, an inflammatory pulmonary nodule demonstrated a granulomatous, CD4+ T-cell infiltrate, correlating with increased CD4+ and CD8+ naïve memory cells in the peripheral blood without changes in other immune checkpoint receptors. Placed within the context of the existing literature on GPA and disease control, our findings suggest a key role for PD-1 in GPA self-tolerance and that selective strategies for immunotherapy may be needed in patients with certain autoimmune disorders. We further summarize the current literature regarding reactivation of autoimmune disorders in patients undergoing immune checkpoint blockade, as well as potential immunosuppressive strategies to minimize the risks of further vasculitic reactivation upon rechallenge with anti-PD-1 blockade. Key Points Nonspecific imaging findings in patients with cancer and rheumatological disorders may require biopsy to distinguish underlying pathology. Patients with rheumatologic disorders have increased risk of reactivation with PD-(L)1 immune checkpoint blockade, requiring assessment of disease status before starting treatment. Further study is needed to evaluate the efficacy of treatment regimens in preventing and controlling disease reactivation.

Immune checkpoint inhibitors (ICPis) are a novel class of immunotherapeutic agents that have revolutionized the treatment of cancer; however, these drugs can also cause a unique spectrum of autoimmune toxicity. Autoimmune hemolytic anemia (AIHA) is a rare, but often severe, complication of ICPis. We identified 14 patients from nine institutions across the United States who developed ICPi-AIHA. The median interval from ICPi initiation to development of AIHA was 55 days (interquartile range [IQR], 22-110 days). Results from the direct antiglobulin test (DAT) were available for 13 of 14 patients: 8 patients (62%) had a positive DAT and 5 (38%) had a negative DAT. The median pretreatment and nadir hemoglobin concentrations were 11.8 g/dL (IQR, 10.2-12.9 g/dL) and 6.3 g/dL (IQR, 6.1-8.0 g/dL), respectively. Four patients (29%) had a preexisting lymphoproliferative disorder, and two (14%) had a positive DAT prior to initiation of ICPi therapy. All patients were treated with glucocorticoids, with three requiring additional immunosuppressive therapy. Complete and partial recoveries of hemoglobin were achieved in 12 (86%) and 2 (14%) patients, respectively. Seven patients (50%) were rechallenged with ICPis, and one (14%) developed recurrent AIHA. Clinical and laboratory features of ICPi-AIHA were similar in DAT positive and negative patients. ICPi-AIHA shares many clinical features with primary AIHA; however, a unique aspect of ICPi-AIHA is a high incidence of DAT negativity. Glucocorticoids are an effective first-line treatment in the majority of patients with ICPi-AIHA, and most patients who are rechallenged with an ICPi do not appear to develop recurrence of AIHA.

Therapeutic radiation has conflicting immune effects: radiation therapy (RT)-induced immunogenic cell death can contribute to immune response, but lymphocytes are also sensitive to RT. It is unknown whether palliative RT leads to lymphopenia in patients treated with immune checkpoint inhibitors (ICIs) and whether this affects outcomes. As such, we sought to assess the impact of palliative RT on circulating lymphocyte count and neutrophil-to-lymphocyte ratio in patients being treated with PD-1-directed ICI and associations with survival.We identified patients from 5 radiation oncology centers, treated with palliative RT and either pembrolizumab or nivolumab with non-small cell lung cancer, metastatic melanoma, and renal cell carcinoma. Patients who received intervening cytotoxic chemotherapy were excluded. We recorded absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio before and after palliative RT and at the start of ICI. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazard models.One hundred ten patients received 225 courses of palliative RT. Median change in ALC after RT was -161 cells/mL. Decreases in ALC were greater with RT to the spine, lung/mediastinum, and chest wall compared with the brain, extremity, or abdomen/pelvis (P = .002) and after courses5 fractions (P = .003). Extracranial and5-fraction RT was associated with increased odds of severe lymphopenia (ALC500) at the end of RT (odds ratio [OR], 3.7; P = .001; and OR, 3.9; P = .001, respectively). Patients who developed RT-induced severe lymphopenia were more likely to have severe lymphopenia when ICI was initiated (OR, 6.4; P = .0001), particularly when RT was administered in the previous 3 months (OR, 189; P .0001). Severe lymphopenia at onset of ICI therapy was associated with increased mortality on multivariable analysis (hazard ratio, 2.1; P = .03).Extracranial or prolonged courses of RT increase the risk of severe lymphopenia, which is associated with poorer survival in patients treated with ICI.

Summary Background Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalimab) with gemcitabine plus nab-paclitaxel, with and without nivolumab, in patients with pancreatic adenocarcinoma to establish the recommended phase 2 dose. Methods This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0–1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m2 intravenous gemcitabine and 125 mg/m2 intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov , NCT03214250 and is ongoing. Findings Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0–19·4; cohort B1 22·0 months [21·4–22·7], cohort B2 18·2 months [17·0–18·9], cohort C1 17·9 months [14·3–19·7], cohort C2 15·9 months [12·7–16·1]). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3–4 treatment-related adverse events were lymphocyte count decreased (20 [67%]; five in B1, seven in B2, four in C1, four in C2), anaemia (11 [37%]; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine [30%]; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (four each in B1, B2, C1; two in C2) had a treatment-related serious adverse event. The most common serious adverse event was pyrexia (six [20%] of 30; one in B2, three in C1, two in C2). There were two chemotherapy-related deaths due to adverse events: one sepsis in B1 and one septic shock in C1. The recommended phase 2 dose of APX005M was 0·3 mg/kg. Responses were observed in 14 (58%) of 24 DLT-evaluable patients (four each in B1, C1, C2; two in B2). Interpretation APX005M and gemcitabine plus nab-paclitaxel, with or without nivolumab, is tolerable in metastatic pancreatic adenocarcinoma and shows clinical activity. If confirmed in later phase trials, this treatment regimen could replace chemotherapy-only standard of care in this population. Funding Parker Institute for Cancer Immunotherapy, Cancer Research Institute, and Bristol Myers Squibb.

PURPOSE. While abundant myeloid cell populations in the pancreatic ductal adenocarcinoma (PDAC) microenvironment have been postulated to suppress anti-tumor immunity, the composition of these populations, their spatial locations, and how they relate to patient outcomes are poorly understood. EXPERIMENTAL DESIGN. To generate spatially-resolved tumor and immune cell data at single cell resolution, we developed two quantitative multiplex immunofluorescence assays to interrogate myeloid cells (CD15, CD14, ARG1, CD33, HLA-DR) and macrophages [CD68, CD163, CD86, interferon regulatory factor 5 (IRF5), MRC1 (CD206)] in the PDAC tumor microenvironment. Spatial point pattern analyses were conducted to assess the degree of co-localization between tumor cells and immune cells. Multivariable-adjusted Cox proportional hazards regression was used to assess associations with patient outcomes. RESULTS. In a multi-institutional cohort of 305 primary PDAC resection specimens, myeloid cells were abundant, enriched within stromal regions, highly heterogeneous across tumors, and differed by somatic genotype. High densities of CD15(+)ARG1(+) immunosuppressive granulocytic cells and M2-polarized macrophages were associated with worse patient survival. Moreover, beyond cell density, closer proximity of M2-polarized macrophages to tumor cells was strongly associated with disease-free survival, revealing the clinical significance and biologic importance of immune cell localization within tumor areas. CONCLUSIONS. A diverse set of myeloid cells are present within the PDAC tumor microenvironment and are distributed heterogeneously across patient tumors. Not only the densities but also the spatial locations of myeloid immune cells are associated with patient outcomes, highlighting the potential role of spatially-resolved myeloid cell subtypes as quantitative biomarkers for PDAC prognosis and therapy. TRANSLATIONAL RELEVANCE. Using multiplex immunofluorescence combined with digital image analysis and supervised machine learning, we comprehensively evaluated the composition, spatial characteristics and prognostic significance of myeloid cells in the PDAC microenvironment in a multi-institutional cohort of >300 patients with resected pancreatic ductal adenocarcinoma (PDAC). Myeloid cells were highly abundant in the human PDAC microenvironment with large inter-tumor heterogeneity. Not only the densities but also the spatial locations of myeloid immune cells were associated with patient outcomes, revealing PDAC microenvironmental complexity with important implications for design and interpretation of immunotherapy clinical trials.

BackgroundPatients with cancer who are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more likely to develop severe illness and die compared with those without cancer. The impact of immune checkpoint inhibition (ICI) on the severity of COVID-19 illness is unknown. The aim of this study was to investigate whether ICI confers an additional risk for severe COVID-19 in patients with cancer.MethodsWe analyzed data from 110 patients with laboratory-confirmed SARS-CoV-2 while on treatment with ICI without chemotherapy in 19 hospitals in North America, Europe and Australia. The primary objective was to describe the clinical course and to identify factors associated with hospital and intensive care (ICU) admission and mortality.FindingsThirty-five (32%) patients were admitted to hospital and 18 (16%) died. All patients who died had advanced cancer, and only four were admitted to ICU. COVID-19 was the primary cause of death in 8 (7%) patients. Factors independently associated with an increased risk for hospital admission were ECOG ≥2 (OR 39.25, 95% CI 4.17 to 369.2, p=0.0013), treatment with combination ICI (OR 5.68, 95% CI 1.58 to 20.36, p=0.0273) and presence of COVID-19 symptoms (OR 5.30, 95% CI 1.57 to 17.89, p=0.0073). Seventy-six (73%) patients interrupted ICI due to SARS-CoV-2 infection, 43 (57%) of whom had resumed at data cut-off.InterpretationCOVID-19–related mortality in the ICI-treated population does not appear to be higher than previously published mortality rates for patients with cancer. Inpatient mortality of patients with cancer treated with ICI was high in comparison with previously reported rates for hospitalized patients with cancer and was due to COVID-19 in almost half of the cases. We identified factors associated with adverse outcomes in ICI-treated patients with COVID-19.

Introduction To evaluate the impact of Sars-Cov-2 infection on mortality and immune checkpoint inhibitor (ICI) toxicity in patients with cancer receiving ICIs compared to those not receiving ICIs. Methods We conducted a retrospective matched cohort study of 25 patients receiving ICIs within 1 year of coronavirus disease 2019 (COVID-19) diagnosis between March 20, 2020, and June 3, 2020, at the Dana-Farber Cancer Institute/Mass General Brigham. Cases were matched 1:1 with controls based on age, sex, and anticancer therapy within the prior 6 months. Results Seven of 25 (28%) patients receiving ICIs died from COVID-19 as compared with nine of 25 (36%) controls. Through multivariable analysis adjusting for age, sex, and anticancer therapy, ICI use was not associated with increased risk for COVID-19 death (OR [odds ratio] 0.36, 95% CI 0.07–1.87). Determinants of mortality included age (OR 1.14, 95% CI 1.03–1.27) and chronic obstructive pulmonary disease (OR 12.26, 95% CI 1.76–85.14). Statin use was protective against mortality (OR 0.08, 95% CI 0.01–0.63). Two patients experienced persistent immune-related adverse events (irAEs) (hypophysitis); one had new-onset irAE (hypothyroidism) during their COVID-19 course. Patients with ICIs had significantly higher platelet (p = 0.017) and D-dimer (p = 0.037) levels. Elevated troponin levels (p = 0.01) were associated with COVID-19 death in patients using ICI. Conclusion There is insufficient evidence to conclude COVID-19–related outcomes are associated with ICIs, and we did not observe an increased risk of COVID-19–related death associated with ICIs. The potential protective effect of statin therapy and role of laboratory biomarkers warrant further investigation.

Purpose: Prospective human data are lacking regarding safety, efficacy, and immunologic impacts of different radiation doses administered with combined PD-L1/CTLA-4 blockade. Patients and Methods: We performed a multicenter phase II study randomly assigning patients with metastatic microsatellite stable colorectal cancer to repeated low-dose fractionated radiation (LDFRT) or hypofractionated radiation (HFRT) with PD-L1/CTLA-4 inhibition. The primary endpoint was response outside the radiation field. Correlative samples were analyzed using multiplex immunofluorescence (IF), IHC, RNA/T-cell receptor (TCR) sequencing, cytometry by time-of-flight (CyTOF), and Olink. Results: Eighteen patients were evaluable for response. Median lines of prior therapy were four (range, 1–7). Sixteen patients demonstrated toxicity potentially related to treatment (84%), and 8 patients had grade 3–4 toxicity (42%). Best response was stable disease in 1 patient with out-of-field tumor shrinkage. Median overall survival was 3.8 months (90% confidence interval, 2.3–5.7 months). Correlative IF and RNA sequencing (RNA-seq) revealed increased infiltration of CD8+ and CD8+/PD-1+/Ki-67+ T cells in the radiation field after HFRT. LDFRT increased foci of micronuclei/primary nuclear rupture in two subjects. CyTOF and RNA-seq demonstrated significant declines in multiple circulating immune populations, particularly in patients receiving HFRT. TCR sequencing revealed treatment-associated changes in T-cell repertoire in the tumor and peripheral blood. Conclusions: We demonstrate the feasibility and safety of adding LDFRT and HFRT to PD-L1/CTLA-4 blockade. Although the best response of stable disease does not support the use of concurrent PD-L1/CTLA-4 inhibition with HFRT or LDFRT in this population, biomarkers provide support that both LDFRT and HFRT impact the local immune microenvironment and systemic immunogenicity that can help guide future studies.

Background There are conflicting data regarding the vulnerability of cancer patients receiving immune checkpoint inhibitors (ICIs) to COVID-19 infection.1–3 In addition, immune-related adverse events (irAEs) driven in part by cytokine dysregulation could parallel the cytokine storm implicated in COVID-19. We sought to evaluate the impact of COVID-19 infection on irAEs and mortality in cancer patients receiving ICIs. Methods We performed a retrospective matched cohort study of 25 patients receiving ICIs within one year of a confirmed COVID-19 diagnosis between March 20, 2020 and June 3, 2020 at the Dana-Farber Cancer Institute/Mass General Brigham network. Cases were matched 1:1 with controls without ICI use based on age, sex, and use of non-ICI anti-cancer therapy within 6 months prior to COVID-19 diagnosis. The primary outcome was death due to COVID-19, and potential covariates (patient comorbidities, concomitant medications, ICI therapy, other anti-cancer therapy) were explored using multivariable logistic regression models. Results We reviewed the records of 611 patients with prior ICI use who were evaluated at our institutions. The final study population included 25 patients who tested positive for COVID-19. The median age was 72 years (range 45–83) and 11 patients (44%) were female (table 1). Seven of 25 (28%) patients on ICIs died from COVID-19 compared to 9 of 25 (36%) controls (figure 1). In multivariable analysis, determinants of mortality included age (OR 1.14, 95% CI 1.03–1.27) and chronic obstructive pulmonary disease (OR 12.26, 95% CI 1.76–85.14), while concomitant statin use was protective against mortality (OR 0.08, 95% CI 0.01–0.63). After adjusting for age, sex, and anti-cancer therapy, ICI use was not associated with increased risk for COVID-19 death (OR 0.36, 95% CI 0.07–1.87, figure 2). Two patients experienced persistent irAEs (hypophysitis) and one patient had new onset irAE (hypothyroidism) during their COVID-19 course. Patients with ICI use presented with significantly higher platelet (p = 0.017) and D-dimer (p = 0.037) levels compared to controls (figure 3A). Elevated troponin levels (p = 0.01) were associated with COVID-19 death in patients using ICI but not in controls (figure 3B). Conclusions In our study, ICI use was not associated with increased risk of COVID-19 related death. We observed low rates of new or persistent irAEs within our small sample. The potential protective effect of statin therapy and predictive role of laboratory biomarkers warrants further investigation. Our findings are promising for the continuation of immunotherapy in cancer patients with COVID-19. Acknowledgements K.T. and A.N.B. contributed equally. N.R.L. and O.E.R. contributed equally.The authors would like to acknowledge the DFCI Oncology Data Retrieval System (OncDRS) for the aggregation, management, and delivery of the clinical and operational research data used in this project. The content is solely the responsibility of the authors. Ethics Approval This project was approved by the Partners Healthcare Institutional Review Board (#2020P000851). References Robilotti EV, Babady NE, Mead PA, et al. Determinants of COVID-19 disease severity in patients with cancer. Nature Medicine 2020. In press. Luo J, Rizvi H, Egger JV, Preeshagul IR, Wolchok JD, Hellmann MD. Impact of PD-1 blockade on severity of COVID-19 in patients with lung cancers. Cancer Discov 2020. In press. Lee LYW, Cazier JB, Starkey T, Turnbull CD, Kerr R, Middleton G. COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study. Lancet 2020;395(10241):1919–1926.

AIMS A varied spectrum of histopathological changes has been associated with immune checkpoint inhibitor (ICI) colitis. This study was performed to evaluate the prevalence of different histopathological patterns of injury in patients with ICI colitis and their association with specific immune check-point inhibitors. METHODS AND RESULTS Biopsies from patients with clinically and histologically confirmed ICI colitis were reviewed blindly to determine the predominant pattern of injury and to quantitate discrete histological parameters using the Geboes score. Paneth cell metaplasia, intraepithelial lymphocytes, abnormal subepithelial collagen and degree of crypt epithelial apoptosis was also recorded. A total of 86 patients with ICI colitis (ipilimumab, n = 14; ipilimumab + nivolumab, n = 29; nivolumab, n = 20 and pembrolizumab, n = 23) were included. The patterns of injury identified included diffuse active colitis (n = 22), chronic active colitis (n = 22), lymphocytic colitis (LC, n = 16), collagenous colitis (CC, n = 14), graft-versus-host disease-like colitis (n = 7) and mixed colitis (n = 5). Patients on ipilimumab were more likely to have a diffuse active colitis pattern without features of chronicity (P

Purpose: Despite the expansion of immune checkpoint inhibitor (ICI) indications, the relationship between ICI dose and toxicity or response is not well established. To understand this correlation, we performed a meta-analysis of ICI trials that used dose escalation. Experimental Design: We searched PubMed and abstracts presented at (inter)national meetings for trials using FDA-approved ICIs. The reported rates of grade 3–5 adverse events (G3–5 AE), immune-related adverse events (irAE), and response were correlated with doses within each ICI using marginal exact generalized linear models. Results: A total of 74 trials (7,469 patients) published between January 2010 and January 2017 were included. For ipilimumab, the incidence of G3–5 AEs was 34% with a significant 27% reduced risk in lower doses (P = 0.002). However, no relationship was observed between dose and irAEs or response. For nivolumab, the incidence of G3–5 AEs was 20.1% which was lower in non–small cell lung cancer (NSCLC) compared with renal cell carcinoma (RCC) or melanoma (P ≤ 0.05) with no dose-toxicity relationship. In melanoma and NSCLC, a dose–response association was observed, which was not observed in RCC. For pembrolizumab, the incidence of G3–5 AEs was 13.3%, which was lower in melanoma compared with NSCLC (P = 0.03) with no dose-toxicity relationship. In melanoma, lower dose levels correlated with decreased odds of response (P = 0.01), a relationship that was not observed in NSCLC. Conclusions: Our analysis shows a lack of consistent dose-toxicity or dose–response correlation with ICIs. Therefore, dose escalation is not an appropriate design to conduct ICI studies. Here we present an innovative trial design for immune-modulating agents.

Background In the current study, the authors assessed the risks and outcomes of immune checkpoint inhibitor (ICI) rechallenge in patients with resolved grade 3 to 4 ICI hepatitis because current guidelines recommend permanent ICI discontinuation in these patients. Methods The authors performed a retrospective cohort study from 2010 through 2019 of patients with melanoma who were treated with ≥1 ICIs and who recovered from grade 3 to 4 ICI hepatitis. The primary outcome was hepatitis recurrence and the secondary outcome was the development of any immune-related adverse event (irAE) requiring the discontinuation of ICI rechallenge. Best overall response and time to all-cause death were compared between the patients who did and those who did not undergo ICI rechallenge. Grading was performed using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Results Of the 102 patients with melanoma who developed high-grade ICI hepatitis, 31 underwent ICI rechallenge. Although 15 of 31 patients (48%) developed an irAE of any grade, only 6 patients (19%) required ICI discontinuation due to irAE severity (4 of 29 patients [14%] rechallenged with anti-PD-1 or anti-PD-L1 and 2 of 2 patients [100%] rechallenged with ipilimumab). Recurrent hepatitis accounted for 4 of these 6 cases. Rechallenged patients who did not require ICI discontinuation were found to be significantly less likely to receive ipilimumab rather than anti-PD-1 or anti-PD-L1 monotherapy (0% vs 33%; relative risk (RR), 0.1 [95% CI, 0.1-0.3; P = .032]) and significantly less likely to be rechallenged with their original ICI (8% vs 50%; RR, 0.2 [95% CI, 0.1-0.7; P = .038]). There was no difference noted with regard to best overall response or time to death between rechallenged and non-rechallenged patients. Conclusions ICI therapy can be resumed in patients with melanoma who have recovered from grade 3 to 4 ICI hepatitis with a modest risk of serious irAEs. It remains unclear whether ICI retreatment improves clinical outcomes.

Limited data exist on safety and efficacy of immune checkpoint inhibitors (ICIs) among organ transplant recipients. The objective of this study was to report a case series of two patients with renal transplant who received treatment with an ICI and to conduct a pooled analysis of published cases to describe the safety and efficacy of ICIs in organ transplant patients. A systematic search in the Google Scholar and PubMed databases was carried out to include all the published cases of organ transplant patients who received treatment with ICIs including programmed cell death protein 1 (PD-1), programmed death-ligand 1, or cytotoxic lymphocyte antigen-4 inhibitors since their inscription to January 31, 2019. In the present series of two cases with renal allografts who received pembrolizumab, one patient with squamous cell carcinoma of the skin experienced complete response (CR), whereas another patient with melanoma had a mixed response. Both patients experienced allograft rejection, but graft was salvaged. The pooled analysis of 64 patients published in literature showed that overall allograft rejection rate is 41% in organ transplant recipients following ICI therapy. The graft rejection rate was 44% (17/39) for renal, 39% (7/19) for liver, and 20% (1/5) for cardiac allografts. The highest risk was seen among patients who were treated with PD-1 inhibitors, 20/42 (48%)—13/24 (54%) on nivolumab and 7/18 (39%) on pembrolizumab. The risk was lowest with ipilimumab, 23% (3/13). The overall response rate (CR + partial response [PR]) was 20% with ipilimumab, 26% with nivolumab, and 53% with pembrolizumab, whereas disease control rate (CR + PR + stable disease) was 35% with ipilimumab, 37% with nivolumab, and 53% with pembrolizumab. None of the variables including age, gender, type of cancer, type of allograft, type of immunosuppression, time since transplantation to initiation of ICI, and prior history of rejection were significantly associated with the transplant rejection on univariate analysis. The efficacy of ICI among patients with organ transplant appears promising, warranting testing in prospective clinical trials. The risk of rejection and allograft loss is considerable; therefore, the risk and alternative form of therapies should be thoroughly discussed with the transplant patients prior to initiating ICI therapy. Implications for Practice Transplant recipients are at higher risk of developing cancers. Although immune checkpoint inhibitors have been shown to improve the outcome in more than one cancer type, transplant recipients were excluded from these trials. Most of the data on the safety and efficacy of immune checkpoint inhibitors in transplant patients are based upon case series and case reports. The pooled data from these reports suggest that anti-programmed death-ligand 1 inhibitors have reasonable safety and efficacy among organ transplant patients, which warrants testing in clinical trials.

Background Immune checkpoint inhibitors targeting PD-1/PD-L1 pathway demonstrated promising activities in variety of malignancies, however little is known regarding their efficacy in adults aged ≥65 years. Methods We conducted a systematic review and a study-level meta-analysis to explore efficacy of ICIs based on age, younger vs older than 65 years. We included in this analysis randomized controlled phase II or III studies in patients with metastatic solid tumors that compared efficacy of PD-1 or PD-L1 inhibitors to a non-PD-1/PD-L1 inhibitor. Aggregated estimates of overall survival (OS) and progression-free survival (PFS) are based on random/mixed effects (RE) models to allow for heterogeneity between the studies. Results Initial search identified 53 articles, 17 were randomized controlled trials that compared nivolumab, pembrolizumab or atezolizumab to chemotherapy or targeted therapy. Only 9 trials reported hazard ratiios (HR) for OS based on age and were included in this meta-analysis. Out of those studies seven reported HR for PFS but only 4 studies included subgroup-analysis based on age for PFS. The overall estimated random-effects HR for death was 0.64 with 95% CI of 0.54–0.76 in patients ≥65 years vs. 0.68 with 95% CI of 0.61–0.75 in patients

Importance Total neoadjuvant therapy (TNT) is often used to downstage locally advanced rectal cancer (LARC) and decrease locoregional relapse; however, more than one-third of patients develop recurrent metastatic disease. As such, novel combinations are needed. Objective To assess whether the addition of pembrolizumab during and after neoadjuvant chemoradiotherapy can lead to an improvement in the neoadjuvant rectal (NAR) score compared with treatment with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) and chemoradiotherapy alone. Design, setting, and participants In this open-label, phase 2, randomized clinical trial (NRG-GI002), patients in academic and private practice settings were enrolled. Patients with stage II/III LARC with distal location (cT3-4 ≤ 5 cm from anal verge, any N), with bulky disease (any cT4 or tumor within 3 mm of mesorectal fascia), at high risk for metastatic disease (cN2), and/or who were not candidates for sphincter-sparing surgery (SSS) were stratified based on clinical tumor and nodal stages. Trial accrual opened on August 1, 2018, and ended on May 31, 2019. This intent-to-treat analysis is based on data as of August 2020. Interventions Patients were randomized (1:1) to neoadjuvant FOLFOX for 4 months and then underwent chemoradiotherapy (capecitabine with 50.4 Gy) with or without intravenous pembrolizumab administered at a dosage of 200 mg every 3 weeks for up to 6 doses before surgery. Main outcomes and measures The primary end point was the NAR score. Secondary end points included pathologic complete response (pCR) rate, SSS, disease-free survival, and overall survival. This report focuses on end points available after definitive surgery (NAR score, pCR, SSS, clinical complete response rate, margin involvement, and safety). Results A total of 185 patients (126 [68.1%] male; mean [SD] age, 55.7 [11.1] years) were randomized to the control arm (CA) (n = 95) or the pembrolizumab arm (PA) (n = 90). Of these patients, 137 were evaluable for NAR score (68 CA patients and 69 PA patients). The mean (SD) NAR score was 11.53 (12.43) for the PA patients (95% CI, 8.54-14.51) vs 14.08 (13.82) for the CA patients (95% CI, 10.74-17.43) (P = .26). The pCR rate was 31.9% in the PA vs 29.4% in the CA (P = .75). The clinical complete response rate was 13.9% in the PA vs 13.6% in the CA (P = .95). The percentage of patients who underwent SSS was 59.4% in the PA vs 71.0% in the CA (P = .15). Grade 3 to 4 adverse events were slightly increased in the PA (48.2%) vs the CA (37.3%) during chemoradiotherapy. Two deaths occurred during FOLFOX: sepsis (CA) and pneumonia (PA). No differences in radiotherapy fractions, FOLFOX, or capecitabine doses were found. Conclusions and relevance Pembrolizumab added to chemoradiotherapy as part of total neoadjuvant therapy was suggested to be safe; however, the NAR score difference does not support further study. Trial registration ClinicalTrials.gov Identifier: NCT02921256.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the second most common cause of cancer death worldwide. Current treatment options for patients with intermediate and advanced HCC are limited, and there is an unmet need for novel therapeutic approaches. HCC is an attractive target for immunomodulation therapy, since it arises in an inflammatory milieu due to hepatitis B and C infections and cirrhosis. However, a major barrier to the development and success of immunotherapy in patients with HCC is the liver's inherent immunosuppressive function. Recent advances in the field of cancer immunology allowed further characterization of immune cell subsets and function, and created new opportunities for therapeutic modulation of the immune system. In this review, we present the different immune cell subsets involved in potential immune modulation of HCC, discuss their function and clinical relevance, review the variety of immune therapeutic agents currently under investigation in clinical trials, and outline future research directions.

Purpose: Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including that of hepatocellular carcinoma (HCC), and is associated with poor prognosis. Endoglin is essential for angiogenesis, and its expression is induced by hypoxia and VEGF pathway inhibition. TRC105 is a chimeric IgG1 CD105 mAb that inhibits angiogenesis and causes antibody-dependent cellular cytotoxicity and apoptosis of proliferating endothelium. Experimental Design: Patients with HCC (Child–Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, and 15 mg/kg every 2 weeks given with sorafenib 400 mg twice daily. Correlative biomarkers included DCE-MRI and plasma levels of angiogenic factors, including soluble endoglin. Pharmacokinetics were assessed in serum. Results: Twenty-six patients were enrolled, of whom 25 received treatment, 15 with cirrhosis. Hep B/C: 3/15; M:F 19:6; mean age of 60 (range, 18–76); 1 DLT (grade 3 AST) occurred at 10 mg/kg. The most frequent toxicity was low-grade epistaxis, a known toxicity of TRC105. One patient experienced an infusion reaction and was replaced. One patient with coronary stenosis developed a fatal myocardial infarction, and one patient developed G3 cerebral tumor hemorrhage. MTD was not established and DL4 (15 mg/kg) was expanded. The overall response rate in 24 evaluable patients at all 4 dose levels was 21% [95% confidence interval (CI), 7.1–42.2], and 25% (95% CI, 8.7–49.1) in patients with measureable disease. Four patients had confirmed stable disease, one of whom was treated for 22 months. Median progression-free survival (PFS) for 24 patients evaluable for PFS was 3.8 months (95% CI, 3.2–5.6 months); median overall survival was 15.5 months (95% CI, 8.5–26.3 months). Conclusions: TRC105 combined with sorafenib was well tolerated at the recommended single agent doses of both drugs. Encouraging evidence of activity to date (PR rate 25%) was observed, and the study is now continuing to recruit in the phase II stage as a multicenter study to confirm activity of the combination. Clin Cancer Res; 23(16); 4633–41. ©2017 AACR.

Background & Aims Tremelimumab is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of activated T lymphocytes. Ablative therapies induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment in patients with advanced hepatocellular carcinoma (HCC). This study aimed to demonstrate whether tremelimumab could be combined safely and feasibly with ablation. Methods Thirty-two patients with HCC were enrolled: male:female: 28:4; median age: 62 (range 36–76). Patients were given tremelimumab at two dose levels (3.5 and 10mg/kg i.v.) every 4weeks for 6 doses, followed by 3-monthly infusions until off-treatment criteria were met. On day 36, patients underwent subtotal radiofrequency ablation or chemoablation. Staging was performed by contrast-enhanced CT or MRI scan every 8weeks. Results No dose-limiting toxicities were encountered. The most common toxicity was pruritus. Of the 19 evaluable patients, five (26.3%; 95% CI: 9.1–51.2%) achieved a confirmed partial response. Twelve of 14 patients with quantifiable HCV experienced a marked reduction in viral load. Six-week tumor biopsies showed a clear increase in CD8 + T cells in patients showing a clinical benefit only. Six and 12-month probabilities of tumor progression free survival for this refractory HCC population were 57.1% and 33.1% respectively, with median time to tumor progression of 7.4months (95% CI 4.7 to 19.4months). Median overall survival was 12.3months (95% CI 9.3 to 15.4months). Conclusions Tremelimumab in combination with tumor ablation is a potential new treatment for patients with advanced HCC, and leads to the accumulation of intratumoral CD8 + T cells. Positive clinical activity was seen, with a possible surrogate reduction in HCV viral load. Lay summary Studies have shown that the killing of tumors by direct methods (known as ablation) can result in the immune system being activated or switched on. The immune system could potentially also recognize and kill the cancer that is left behind. There are new drugs available known as immune checkpoint inhibitors which could enhance this effect. Here, we test one of these drugs (tremelimumab) together with ablation. Clinical trial number ClinicalTrials.gov: NCT01853618.

BACKGROUND: Colorectal cancer (CRC) represents a major public health problem as the second leading cause of cancer-related mortality in the United States. Of an estimated 140,000 newly diagnosed CRC cases in 2018, roughly one-third of these patients will have a primary tumor located in the distal large bowel or rectum. The current standard of care approach includes curative-intent surgery, often following preoperative (neoadjuvant) radiotherapy (RT) to increase rates of tumor downstaging, clinical and pathologic response, as well as improving surgical resection quality. However, despite advancements in surgical techniques, as well as sharpened precision of dosimetry offered by contemporary RT delivery platforms, the oncology community continues to face challenges related to disease relapse. METHODS: Ongoing investigations are aimed at testing novel radiosensitizing agents and treatments that might exploit the systemic antitumor effects of RT utilizing immunotherapies. If successful, these treatments may usher in a new curative paradigm for rectal cancers such that surgical interventions may be avoided. Importantly, this disease offers an opportunity to correlate matched paired biopsies, radiographic response and molecular mechanisms of treatment sensitivity and resistance with clinical outcomes. RESULTS: Herein, the authors highlight the available evidence from preclinical models and early-phase studies, with an emphasis on promising developmental therapeutics undergoing prospective validation in larger-scale clinical trials. CONCLUSIONS: This review by the NCI’s Radiation Research Program Colorectal Cancer Working Group provides an updated comprehensive examination of the continuously evolving State of the Science regarding radiosensitizer drug development in the curative treatment of CRC.

Background: ICI are widely used in the treatment of various cancer types. It has been hypothesized that ICI could confer an increased risk of severe acute lung injury or other complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: We analyzed data from 113 patients with laboratory-confirmed COVID-19 while on treatment with ICI without chemotherapy in 19 hospitals in North America, Europe, and Australia. Data collected included details on symptoms, comorbidities, medications, treatments and investigations for COVID-19, and outcomes (hospital admission, ICU admission, and mortality). Results: The median age was 63 years (range 27–86); 40 (35%) patients were female. Most common malignancies were melanoma (n=64, 57%), non-small cell lung cancer (n=19, 17%), and renal cell carcinoma (n=11, 10%); 30 (27%) patients were treated for early (neoadjuvant/adjuvant) and 83 (73%) for advanced cancer. Most patients received anti-PD-1 (n=85, 75%), combination anti-PD-1 and anti-CTLA-4 (n=15, 13%), or anti-PD-L1 (n=8, 7%) ICI. Comorbidities included cardiovascular disease (n=31, 27%), diabetes (n=17, 15%), and pulmonary disease (n=14, 12%). Symptoms were present in 68 (60%) patients; 46 (68%) had fever, 40 (59%) cough, and 23 (34%) dyspnea. Overall, ICI was interrupted in 58 (51%) patients. At data cutoff, 33 (29%) patients were admitted to hospital, 6 (5%) to ICU, and 9 (8%) patients died. COVID-19 was the primary cause of death in 7 patients, 3 of whom were admitted to ICU. Cancer types in patients who died were melanoma (2), non-small cell lung cancer (2), renal cell carcinoma (2), and others (3); all (9) patients had advanced cancer. Administered treatments were oxygen therapy (8), mechanical ventilation (2), vasopression (2), antibiotics (7), antiviral drugs (4), glucocorticoids (2), and anti-IL-6 (2). Of all hospitalized patients, 20 (61%) had been discharged and 4 (12%) were still in hospital at data cutoff. Conclusion: The mortality rate of COVID-19 in patients on ICI is higher than rates reported for the general population without comorbidities but may not be higher than rates reported for the cancer population. Despite these preliminary findings, COVID-19 patients on ICI may not have symptoms and a proportion may continue ICI. Correlative analyses are ongoing and will be presented. Citation Format: Aljosja Rogiers, Carlo Tondini, Joe M. Grimes, Megan H. Trager, Sharon Nahm, Leyre Zubiri, Neha Papneja, Arielle Elkrief, Jessica Borgers, April Rose, Johanna Mangana, Michael Erdmann, Ines Pires da Silva, Christian Posch, Axel Hauschild, Lisa Zimmer, Paola Queirolo, Caroline Robert, Karijn Suijkerbuijk, Paolo A. Ascierto, Paul Lorigan, Richard Carvajal, Osama E Rahma, Mario Mandala, Georgina V. Long. Clinical characteristics and outcomes of coronavirus 2019 disease (COVID-19) in cancer patients treated with immune checkpoint inhibitors (ICI) [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr S02-01.

Background: OX40 is a costimulatory receptor transiently expressed on the surface of activated T cells and some innate immune cells (e.g. NK cells). OX40 agonists have been shown to increase antitumor immunity and improve tumor-free survival in preclinical models, demonstrating increased efficacy when given in combination with a PD-1 inhibitor. GSK998 is a humanized IgG1 agonistic OX40 monoclonal antibody. Methods: ENGAGE-1 (NCT02528357) is a Phase 1 dose escalation study evaluating safety, PK, PD, and clinical activity of GSK998 (0.003-10 mg/kg IV Q3W) alone (Part 1) and in combination with pembrolizumab 200 mg IV Q3W (Part 2) in pts with previously treated advanced solid tumors: non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck, renal cell carcinoma, melanoma (MEL), bladder cancer, soft tissue sarcoma (STS), triple-negative breast cancer, and MSI-high colorectal carcinoma. Dose escalation used a continuous reassessment method and 4-week DLT period. Results: A total of 138 pts were enrolled (45 Part 1, 96 Part 2; 3 crossed over from Part 1). Two DLTs occurred in Part 2 only (G3 non-malignant pleural effusion 0.03 mg/kg; G1 myocarditis 10 mg/kg); MTD was not established. Most common (≥10%) treatment-related AEs (mostly G1-2) were diarrhea, fatigue (Part 1) and fatigue, nausea (Part 2). GSK998 demonstrated target engagement in the periphery as evidenced by PK and receptor occupancy (RO); a dose of 0.3 mg/kg was the threshold for linear PK & peripheral RO saturation over the 3-wk dose interval and was selected for further clinical evaluation in MEL, STS, and NSCLC in Part 2 expansion. Clinical responses and SD ≥24 weeks were observed in both PD-1/L1 naïve and experienced pts: Part 1 (1 PR, 1 SD; both 0.3 mg/kg) and Part 2 (2 CR, 7 PR, 9 SD; 0.01-3 mg/kg); Part 2 clinical responses were not correlated with baseline tumor PD-L1 expression levels; including one MEL pt with PD-L1 TPS=0 who progressed on prior CTLA-4/PD-1 treatment and had a CR (>18mo). Overall, peripheral and tumor expression of OX40 was low ( Citation Format: Sophie Postel-Vinay, Vincent K. Lam, Willeke Ros, Todd M. Bauer, Aaron R. Hansen, Daniel C. Cho, F. Stephen Hodi, Jan H.M. Schellens, Jennifer K. Litton, Sandrine Aspeslagh, Karen A. Autio, Frans L. Opdam, Meredith McKean, Neeta Somaiah, Stephane Champiat, Mehmet Altan, Anna Spreafico, Osama Rahma, Elaine M. Paul, Christoph M. Ahlers, Helen Zhou, Herbert Struemper, Shelby A. Gorman, Maura Watmuff, Kaitlin M. Yablonski, Niranjan Yanamandra, Michael J. Chisamore, Emmett V. Schmidt, Axel Hoos, Aurélien Marabelle, Jeffrey S. Weber, John V. Heymach. A first-in-human phase I study of the OX40 agonist GSK3174998 (GSK998) +/- pembrolizumab in patients (Pts) with selected advanced solid tumors (ENGAGE-1) [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 CT150.

Summary Checkpoint blockade with antibodies specific for the PD-1 and CTLA-4 inhibitory receptors can induce durable responses in a wide range of human cancers. However, the immunological mechanisms responsible for severe inflammatory side effects remain poorly understood. Here we report a comprehensive single-cell analysis of immune cell populations in colitis, a common and severe side effect of checkpoint blockade. We observed a striking accumulation of CD8 T cells with highly cytotoxic and proliferative states and no evidence of regulatory T cell depletion. T cell receptor (TCR) sequence analysis demonstrated that a substantial fraction of colitis-associated CD8 T cells originated from tissue-resident populations, explaining the frequently early onset of colitis symptoms following treatment initiation. Our analysis also identified cytokines, chemokines, and surface receptors that could serve as therapeutic targets for colitis and potentially other inflammatory side effects of checkpoint blockade.

TPS3158 Background: Immune checkpoint inhibitors (ICI) such as anti-PD-1/PD-L1 antibodies have become a pivotal approach to cancer therapy. Nivolumab is an anti-PD1 antibody approved for an increasing number of solid tumors and hematological malignancies. However, patients (pts) with history of autoimmune disorders are excluded from the majority of clinical trials testing ICI. Consequently, the risks of flares and worsening of pre-existing autoimmune disorders in pts with tumor types who otherwise stand to benefit from ICI therapy are largely unknown, posing a challenge for oncologists. We are conducting a phase Ib study to test the hypothesis that nivolumab can be safely administered to pts with varying severity of Dermatomyositis, Systemic Sclerosis, Rheumatoid Arthritis, Systemic Lupus Erythematosus, Inflammatory Bowel Disease, Multiple Sclerosis, Sjögren's Syndrome and Other Autoimmune Disorders (AIM-Nivo). Methods: AIM-Nivo is an open-label, multi-center ongoing phase Ib study with nivolumab 480mg IV every 28 days in pts with autoimmune diseases and advanced malignancies (NCT03816345). The study has autoimmune disease-specific cohorts overseen by a multidisciplinary group of experts. The primary objective is to assess the overall safety and toxicity profile of nivolumab in pts with autoimmune disorders and advanced malignancies. Secondary objectives are to evaluate the antitumor efficacy, the impact of nivolumab on the autoimmune disease severity indices, and to explore potential biomarkers of response, resistance or toxicity. Key overall inclusion criteria include age ≥18 years, histologically confirmed advanced malignancies in which ICI are approved or have shown clinical activity. Key overall exclusion criteria include prior therapy with anti-PD-1/PD-L1 antibodies. Specific eligibility criteria are defined for each disease-specific cohort. For each autoimmune disorder, severity level of the disease as defined by disease-specific severity indices will be assessed, and up to a total of 12 pts will be included in each disease cohort at each severity level. Primary endpoints are dose-limiting toxicities, adverse events (AEs) and serious AEs. Continuous monitoring of toxicity will be conducted. Key secondary endpoints are best objective response, progression free and overall survival and cohort specific tumor tissue, blood and non-tumor tissue-based biomarkers. The AIM-Nivo trial opened in May 2019 and is enrolling pts through the National Cancer Institute Experimental Therapeutics Clinical Trials Network (ETCTN). Clinical trial information: NCT03816345 .

89 Background: There is a lack of predictive markers informing on the risk of colitis in patients treated with immune checkpoint inhibitors (ICIs). The aim of this study was to identify potential factors associated with development of ICI colitis. Methods: We performed a retrospective analysis of melanoma patients at Dana-Farber Cancer Institute who received PD-1, CTLA-4, or combination blockade between May 2011 to October 2017. Clinical and laboratory characteristics associated with pathologically confirmed ICI colitis were evaluated using multivariate logistic regression analyses. External validation was performed on an independent cohort from Massachusetts General Hospital. Results: The discovery cohort included 213 patients of whom 37 developed ICI colitis (17%). The odds of colitis were higher in patients treated with ipilimumab either as monotherapy or in combination with nivolumab compared to those treated with pembrolizumab. Vitamin D use was recorded in 66/213 patients (31%) before starting ICIs. In multivariable regression analysis, vitamin D use conferred significantly reduced odds of developing ICI colitis (OR 0.35, 95% CI 0.1–0.9). These results were confirmed in the validation cohort of 169 patients of whom 49 developed ICI colitis (29%). Pretreatment neutrophil/lymphocyte ratio (NLR) ≥5 predicted reduced odds of colitis (OR 0.34, 95% CI 0.1–0.9) only in the discovery cohort. Conclusions: This is the first study to report that among patients treated with ICIs, vitamin D intake is associated with reduced risk for ICI colitis. This finding is consistent with prior reports of prophylactic use of vitamin D in ulcerative colitis and GVHD. This observation should be validated prospectively in future studies. [Table: see text]

14 Background: ICOS is a costimulatory molecule upregulated on activated T cells. Vopra is an investigational ICOS agonist antibody that results in activation and proliferation of primed CD4 T effector cells. Vopra was assessed in heavily pretreated patients with advanced solid tumors as monotherapy (mono) or in combination with nivolumab (nivo) in the Phase 1/2 ICONIC trial (NCT02904226). Emergence of a distinct ICOS high (hi) population of peripheral CD4 T effector cells, not seen with PD-1 inhibitors alone, was associated with improved ORR, PFS and OS with vopra mono and combo therapy (AACR 2019). Baseline tumor and blood biomarkers were assessed for ability to predict ICOS hi CD4 T cell emergence and clinical outcomes. Methods: Fresh pre-treatment tumor biopsies were assessed by RS, a gene signature describing immune cell infiltration, and other biomarkers, including PD-L1 TPS by IHC. Pts were classified as RS1 and RS2 based on medium and high cutoffs. Associations between potential predictive biomarkers, ICOS hi CD4 T cell emergence and clinical outcomes were evaluated. Results: Baseline RS is significantly higher in patients with emergence of ICOS hi CD4 T cells. High RS was associated with increased emergence of ICOS hi CD4 T cells, accompanied by improved RECIST response, PFS, and OS. In contrast, no association was noted with PD-L1 IHC. Clinical trial information: NCT02904226. Conclusions: In this retrospective subset analysis, the RS score, but not PD-L1, in baseline tumor biopsies was predictive of emergence of an ICOS hi CD4 T cell population and improved RECIST response, PFS, and OS in patients treated with vopra alone and in combination with nivo. Clinical evaluation of vopra and investigational PD-1 inhibitor JTX-4014 in cancer patients with RS selection is planned. [Table: see text]

TPS784 Background: Patients(pts) with metastatic pancreatic cancer (PC) have a median survival of less than one year even with use of multiagent chemotherapy programs. Pancreatic tumors are composed of multiple cell types and a dense extracellular matrix that may support cancer cell proliferation and impede chemotherapy delivery. Cancer-associated fibroblasts (CAF’s) in the tumor microenvironment secrete pro-inflammatory factors and components of the extracellular matrix. In PC laboratory models, engagement of the vitamin D receptor (VDR) by VDR agonists shifts CAFs toward a more quiescent phenotype with reduced tumor growth and improved chemotherapy penetration (Sherman. Cell, 2014). Paricalcitol is a synthetic VDR agonist used in patients with secondary hyperparathyroidism due to chronic kidney disease. A prior pilot study evaluated IV paricalcitol with gemcitabine (G) and nab-paclitaxel (A) before surgical resection in patients with resectable PC (NCT02030860). Methods: Pts with previously-untreated metastatic PC will be enrolled in a two-stage study consisting of a safety run-in and a randomized phase 2 study (NCT03520790). In the run-in stage, 36 pts will be randomized 1:1:1 to G (1000 mg/m2) and A (125 mg/m2) given 3 weeks on and 1 week off plus: (a) paricalcitol 25mcg IV thrice weekly, (b) paricalcitol 16mcg oral daily, or (c) placebo oral daily. Grade 3/4 hypercalcemia or genitourinary stones will be considered dose limiting toxicities.Pts will undergo paired pre- and on-treatment tumor biopsies to examine pharmacodynamic (PD) markers by bulk and single cell RNA sequencing and multiplex immunofluoresence.Assuming safety and supportive PD assessments, the phase 2 study will randomize an additional 76 pts to two treatment arms with GA plus: (a) paricalcitol or (b) placebo.Paricalcitol formulation (IV or oral) will be determined based on data from the run-in stage.The primary endpoint of the phase 2 study is overall survival, with a total of 100 pts needed to identify a hazard ratio of 0.6 with 80% power and one-sided alpha of 0.10.Secondary endpoints include safety, response rate, and progression free survival.Trial funding provided by SU2C, CRUK,Lustgarten Foundation, and AACR. Clinical trial information: NCT03520790.

Gastrointestinal toxicities are among the leading causes of immune-related adverse effects of checkpoint blockade. These adverse events can be severe enough to require interruption or withdrawal of immune checkpoint blockade therapy. Patients with immune-related adverse effects require early recognition with an evaluation to rule out alternative etiologies and effective management to minimize complications. This article reviews the gastrointestinal and hepatic toxicities of the antibodies that target immune checkpoints CTLA-4 and PD-1/PD-L1 and provides an approach to their diagnosis and management.

The advent of immune checkpoint inhibitors (ICIs) has changed the landscape of cancer treatment. Older adults represent the majority of cancer patients; however, direct data evaluating ICIs in this patient population is lacking. Aging is associated with changes in the immune system known as "immunosenescence" that could impact the efficacy and safety profile of ICIs. In this paper, we review aging-associated changes in the immune system as they may relate to cancer and immunotherapy, with mention of the effect of chronic viral infections and frailty. Furthermore, we summarize the current clinical evidence of ICI effectiveness and toxicity among older adults with cancer.

Background: Checkpoint inhibitors such as anti-PD-1 are ineffective as single agents for patients (pts) with PDAC. Preclinical data suggest that chemotherapy with agonistic CD40 antibodies can be combined with anti-PD-1 to trigger effective T cell immunity. We conducted a multi-center, open label clinical trial to evaluate the combination of APX005M with nivo and standard chemotherapy (gem and NP). Herein, we report safety and efficacy from the ongoing study. Methods: Pts with previously untreated PDAC were enrolled in 4 cohorts: Gem/NP/APX005M 0.1 mg/kg (B1), Gem/NP/APX005M 0.3 mg/kg (B2), Gem/NP/Nivo/APX005M 0.1 mg/kg (C1) and Gem/NP/Nivo/APX005M 0.3 mg/kg (C2). Primary objectives were to evaluate safety and determine the recommended Phase II dose (RP2D) of APX005M. Secondary objectives included tumor response and immune pharmacodynamics. Analyses were performed on dose-limiting toxicity (DLT)-evaluable subjects, defined as receiving 1 dose of APX005M and ≥ 2 doses of gem/NP during Cycle 1 and remaining on study through Cycle 2 Day 1. Results: N=30 pts dosed; 24 DLT-evaluable (6 per cohort). Median follow up is 32.2 weeks. N=13 (54%) pts experienced an AE leading to discontinuation, and 10 (42%) pts experienced a treatment-related serious AE. Two DLTs were observed, 1 each in cohorts B2 and C1 (grade 3 and 4 febrile neutropenia, respectively). AE rates were similar across cohorts. Four (17%) subjects died (2 each in Cohorts B1 and C1) due to disease progression (n=2) and AE (n=2, sepsis and septic shock in the setting of neutropenia). Within the DLT-evaluable population, best overall responses included 14 (58%) PR (11 confirmed, 3 unconfirmed), 8 (33%) SD, 1 (4%) PD and 1 (4%) NE. Post-baseline tumor assessments were available for 2 of the 6 DLT-inevaluable pts (best overall responses of SD and confirmed PR). Multiplexed IHC analysis of baseline tumors revealed a low CD8 T cell and high macrophage infiltrate. Analysis of circulating mutant KRAS DNA showed marked and rapid decrease with therapy in some pts. Immune profiling of PBMCs at baseline and on-treatment by CyTOF revealed remodeling of the myeloid compartment in response to treatment, with rapid activation of dendritic cells in most pts. Conclusions: Gem/NP/APX005M ± nivo demonstrated manageable safety profiles and promising antitumor activity in untreated metastatic PDAC pts. APX005M 0.3 mg/kg was selected as the dose for a randomized Phase II study in which the primary endpoint is 1-year overall survival. Clinical trial information: NCT02482168. Citation Format: Mark H. O'Hara, Eileen M. O'Reilly, Mick Rosemarie, Gauri Varadhachary, Zev A. Wainberg, Andrew Ko, George A. Fisher, Osama Rahma, Jaclyn P. Lyman, Christopher R. Cabanski, Erica L. Carpenter, Travis Hollmann, Pier Federico Gherardini, Lacey Kitch, Cheryl Selinsky, Theresa LaVallee, Ovid C. Trifan, Ute Dugan, Vanessa M. Hubbard-Lucey, Robert H. Vonderheide. A Phase Ib study of CD40 agonistic monoclonal antibody APX005M together with gemcitabine (Gem) and nab-paclitaxel (NP) with or without nivolumab (Nivo) in untreated metastatic ductal pancreatic adenocarcinoma (PDAC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT004.

Background: ICOS is a costimulatory molecule upregulated on activated T cells. JTX-2011 is an ICOS agonist antibody intended to stimulate primed CD4 T effector cells. JTX-2011 was assessed in pts with advanced solid tumors as monotherapy (mono) and combination (combo) with nivolumab (nivo) in the Phase I/II ICONIC trial (NCT02904226). Peripheral T cell phenotyping in ICONIC demonstrated emergence of an ICOS high (hi) subset of CD4 T cells associated with tumor reductions in mono and combo pts. In ex vivo studies, soluble JTX-2011 stimulated a polyfunctional cytokine response only in ICOS hi cells. Methods: Ad hoc flow cytometry phenotyping on PBMCs from a subset of pts with evaluable samples (n=50) was initiated retrospectively in early 2018 in ongoing pts, then prospectively on newly enrolled pts. Clinical characteristics and outcomes were analyzed, including unadjusted p-values for post-hoc statistical analyses. Phenotyping was also done on samples from pts treated with PD-1/L1 inhibitor (PD-1/L1i) mono collected outside of ICONIC. Results: Emergence of ICOS hi CD4 T effector cells (all FoxP3-, subset Tbet+ Ki67+) was observed in all pts with ≥30% target lesion tumor reduction by investigator assessment on mono and combo therapy (n=7). Emergence was seen in pts with stable target lesions (n=11/23) including loss of these cells with disease progression. ICOS hi cells were not seen in ICONIC pts with target lesion increase ≥20% (n=14), or in pts treated with PD-1/L1i mono, including responders. Emergence of ICOS hi CD4 T cells correlated with improved PFS and OS (Table). ICONIC Pt characteristicsICOS hi (N=18)ICOS low (N=32)≥3 prior therapies, n (%)13 (72.2)18 (56.3)Prior immunotherapy, n (%)6 (33.3)15 (46.9)Tumor type, n (%)Gastric n=9 (50), NSCLC n=3 (16.7), TNBC n=2 (11.1), Other n=4 (22.2)Gastric n=8 (25), NSCLC n=6 (18.8), TNBC n=4 (12.5), Other n=14 (43.8),Mono vs Combo, n (%)Mono n=2 (11.1), Combo n=16 (88.9)Mono n=11 (34.4), Combo n=21 (65.6)G3-4 treatment-related adverse events, n (%)1 (5.6)2 (6.3)Time on JTX-2011, median mths (range), p=0.00065.6 (1.45-18.4)1.41 (0.03-6.28)PFS, investigator and central imaging review, median mths, (investigator, p Conclusion: Emergence of a distinct ICOS hi population of peripheral CD4 T cells is associated with improved PFS and OS with JTX-2011 mono and combo therapy. Two JTX-2011 development paths are planned: (1) combo with agents that induce ICOS hi CD4 T cells; (2) use of potential putative biomarkers predictive of emergence of this T cell population and JTX-2011 response. Citation Format: Timothy Anthony Yap, Justin F. Gainor, Margaret K. Callahan, Gerald S. Falchook, Russell Kent Pachynski, Patricia LoRusso, Shivaani Kummar, Geoffrey Thomas Gibney, Howard A. Burris, Scott S. Tykodi, Osama E. Rahma, Tanguy Seiwert, Kyriakos P. Papadopoulos, Ellen Hooper, Christopher J. Harvey, Amanda Hanson, Sean Lacey, Rachel McComb, Courtney Hart, Haley Laken, Ty McClure, Elizabeth Trehu. Improved progression-free and overall survival (PFS/OS) in patients (pts) with emergence of JTX-2011 associated biomarker (ICOS high CD4 T cells) on the ICONIC trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT189.

e14172 Background: Management of Immune checkpoint inhibitors (ICIs) associated irAEs requires accurate diagnosis and severity measurement. However, outside of clinical trials, there is no clear definition of irAEs to guide treatment. Methods: We established a dedicated immune toxicity inpatient service (ITox) for patients admitted with irAEs using institution-developed guidelines adapted from NCCN and ASCO. We developed definitions for ICI associated hepatitis, colitis and pneumonitis and created algorithms for defining an irAEs as definite, likely, possible, or unlikely. Algorithm fields were completed twice, by two independent reviewers including medical oncology specialists and toxicity specialists (a pulmonologist or gastroenterologist) to evaluate the accuracy of the algorithm in defining irAEs. Results: From June to November 2018, 65 patients were admitted to iTox with suspected irAEs. Various cancers patients treated with ICI were included; with lung and head and neck cancers the most common (36.9%). Pembrolizumab was the most common ICI (47.7%). ICI in combination with non-checkpoint inhibitor treatment was used in 23 (37.7%) and concurrent radiation therapy in 5 patients (7.7%). Forty (71.4%) patients discontinued ICI due to toxicity. Fifty-one patients were evaluable with irAEs: colitis (19); pneumonitis (24) and hepatitis (8). Multiple irAEs were reported in 17 patients. When applied to clinical cases, our algorithms generated a toxicity definition in 63% of cases, with which reviewers agreed most of the time (84-100%) (Kappa 0.7-1.0). Concordance between the two reviewers was 75-87% (Kappa 0.55-0.82) (Table). Conclusions: Our algorithms generated irAEs definitions with fair inter-rater reliability. These findings have real-world implications; accurate diagnosis of irAEs is essential for proper management. Defining irAEs outside the clinical trial context remains an important challenge. [Table: see text]

e14160 Background: Ang-2 is produced by endothelial cells, predominantly in tissues undergoing vascular remodeling and in hypoxic microenvironments. Ang-2 partially suppresses T cell activation by increasing PD-L1 expression and decreasing monocyte activation. Our group demonstrated that high pre-treatment serum Ang-2 is associated with reduced overall survival (OS) in patients treated with PD-1 blockade. Methods: We initiated a phase 1b trial to evaluate the safety, efficacy, and immunological effect of the combination of pembrolizumab and trebananib, an Ang-1/2 neutralizing peptibody, in solid tumors. Treatment consisted of an induction phase of pembrolizumab 200 mg every 3 weeks and trebananib weekly (with an initial run-in dose escalation of 15-30 mg/kg) for 12 weeks followed by pembrolizumab alone for 2 years. Here we present the preliminary data in the fully enrolled CRC expansion cohort. Results: The study enrolled a total of 18 microsatellite stable (MSS) heavily pretreated CRC patients. There were no DLTs and 30mg/kg was deemed to be the MTD. This summary is based on 15 CRC patients treated with 30 mg/kg trebananib (3 in dose escalation, 12 in dose expansion) plus pembrolizumab. Nine patients (60%) were female and the median age was 51 years (43-63). The most common treatment-related adverse events (AEs) were abdominal distension, diarrhea, limb edema, transaminitis, and proteinuria (each reported in 40% of the patients). One grade 3 transaminitis and one grade 4 pneumonitis related to pembrolizumab were reported. As of the date of data retrieval, 11 patients were off treatment and four were continuing with a median follow-up of 6.1 months. The response rate was 7% (1 partial response for 14 months) and the disease control rate was 33% (4 stable disease with CEA trending down). Median time to progression and OS were 2.8 (90% CI: 1.5 to 4.9 months) and 11.4 months (90% CI: 2.6 months to ∞), respectively. Conclusions: The combination of pembrolizumab and trebananib is well tolerated and demonstrated promising activity in heavily pretreated MSS CRC. Paired biopsies and blood were collected for planned correlative immune analyses which will be presented at the meeting. Clinical trial information: NCT03239145.

2582 Background: Colitis is a frequent toxicity of ICI therapy but there is paucity of data on risk factors. Specific serological markers and genetic polymorphisms have been associated with inflammatory bowel disease (IBD) (ulcerative colitis, Crohn’s disease). However, the prevalence of these markers in pts with ICI colitis is unknown. We performed a pilot study to determine the prevalence of IBD-associated genetic and serologic biomarkers in pts with ICI colitis. Methods: Cancer pts with histologically confirmed ICI enteritis/colitis and no history of IBD underwent commercial IBD panel testing. The panel included 4 genetic markers ( ATG16L1, NXK2–3, ECM1, STAT3), 8 serological markers (anti-A4-Fla2, anti-A4-FlaX, anti-CBir1, anti-OmpC, ASCAIgA, ASCA-IgG, pANCA, ANCA), and 5 inflammatory markers (vascular endothelial growth factor [VEGF], intracellular adhesion molecule 1[ICAM-1], vascular cell adhesion molecule 1 [VCAM-1], C-reactive protein, serum amyloid A [SAA]). Clinical testing on serum samples was performed by Prometheus Laboratories (San Diego, CA). Results: Of 15 cancer pts with biopsy confirmed ICI colitis, 10 (67%) were homozygous for 1 or more of 4 genetic markers. The remaining 5 pts were all heterozygous for two or more of the genetic markers. One or more serologic markers associated with IBD were elevated in 7/15 (47%) pts. Serum reactivity was noted for ASCA-IgA (1/15, 7%), ASCA-IgG (1/15, 7%), anti-OmpC (3/15, 20%), anti-CBR IgG (2/15, 13%), anti-A4-FlaX (1/15, 7%), and ANCA (2/15, 13%). One or more inflammatory markers were elevated in 13/15 (88%) pts. Elevations in VEGF, VCAM-1, ICAM-1, and SAA were noted in 2 (13%), 8 (53%), 8 (53%), and 11 (73%) pts, respectively. Only 6 (40%) pts had elevations in CRP levels despite the presence of active inflammation on biopsy. The IBD panel was reported as being consistent with Crohn’s disease in 2 pts, ulcerative colitis in 1 pt and inconclusive for type but consistent with IBD in 1 pt. Conclusions: In this pilot study, all patients with ICI colitis, were either homozygous or heterozygous for two or more high risk IBD alleles. If validated, such testing may prospectively identify pts at risk for developing ICI colitis.

49 Background: Pre-clinical and clinical evidence support immune effects of targeted radiation (RT) resulting in synergy with immune checkpoint therapy. However, prospective data are lacking in regards to safety, efficacy and immunologic impacts of different doses of RT given in conjunction with PD-L1 and CTLA-4 blockade. Methods: ETCTN 10021 is a multicenter randomized phase 2 study evaluating repeated low-dose fractionated RT (LDFRT) or hypofractionated RT (HFRT) in combination with PD-L1 and CTLA-4 inhibition in metastatic microsatellite-stable colorectal cancer (CRC) refractory to first-line chemotherapy, or non-small cell lung cancer progressive on prior PD-1 inhibition. The primary endpoint is objective response excluding irradiated lesions. Pre- and on-treatment biopsies were analyzed using multiplex immunofluorescence (IF) evaluating multiple immune markers. We report the prespecified analysis of the CRC cohort. Results: Twenty CRC patients were randomized, 19 of whom were treated with immunotherapy and RT, and 18 of whom were evaluable for response. Median lines of prior therapy were 4 (range 1-7). There were 16 patients with toxicity potentially related to treatment (84%), and 8 patients with possibly associated grade 3-5 toxicity (42%). Best response was stable disease in one patient with an abscopal out-of-field response who developed new lesions after HFRT and 4 cycles with decreasing overall disease burden. Correlative IF performed on 5 sample pairs revealed that HFRT, but not LDFRT, increased infiltration of CD8+, and CD8+/PD1+/Ki67+ T-cells in the RT field. Conclusions: We demonstrate the feasibility of a multicenter randomized study adding different RT regimens to PD-L1/CTLA-4 blockade. Toxicity was, in general, consistent with PD-L1/CTLA-4 inhibition with no significant RT-related toxicities noted. Although the best response of stable disease doesn’t support the use of PD-L1/CTLA-4 inhibition with HFRT or LDFRT in this population using these RT regimens and schedule, integrated biomarkers provide support that HFRT impacts the local immune microenvironment. Clinical trial information: NCT02888743.

381 Background: Atezo (anti–PD-L1) was the first immune checkpoint inhibitor approved for mUC. Here, we describe pt characteristics, time on tx (TOT) and distribution of tx cycles for pts receiving atezo in clinical practice, to complement data from clinical trial setting. Methods: Pts diagnosed with mUC who initiated atezo monotherapy in the first-line (1L) or second-line and beyond (2L+; prior platinum tx) settings on or before Jun 30, 2017, were identified from the US-based Flatiron Health electronic health record–derived database. Tx data were analyzed through Mar 31, 2018. TOT was defined as time from first to last atezo administration, plus 1 cycle length. Median TOT was calculated by tx line using the Kaplan-Meier method. Tx cycles were calculated by the number of atezo doses received during TOT. Corresponding results from global atezo clinical trials are presented. Results: Real-world data (RWD) from 312 pts (n = 102, 1L; n = 210, 2L+) met the study selection criteria (Table). Median TOT was 3 and 3.5 months in the 1L and 2L+ settings, respectively, with 95% CIs overlapping with the trial TOT data. A median of 4 cycles (IQR, 2-7, 1L; 2-9, 2L+) was administered in both settings. Conclusions: This is the first study of RW atezo use in mUC. The TOT with atezo observed in a US RW setting and the clinical setting (IMvigor210/IMvigor211) was similar. [Table: see text]

TPS467 Background: CIT has significant survival benefits across multiple tumor types, but durable response is experienced by only subsets of patients (pts). To extend clinical benefit to more pts, efficacious CIT combinations (combos) targeting multiple cancer immune escape mechanisms need to be identified. The MORPHEUS platform includes multiple ph Ib/II trials designed to identify early signals of safety and efficacy of CIT combos. Using a randomized trial design, multiple treatment (tx) arms are compared with a single control arm in each pt cohort. We present three GI-specific MORPHEUS trials, each assessing CIT combos that could concurrently enhance multiple aspects of the cancer immune response. Methods: The MORPHEUS trials described here are global, open-label, randomized, Ph Ib/II trials enrolling pts with pancreatic ductal adenocarcinoma (PDAC), gastric or gastroesophageal junction cancers or colorectal cancer (CRC). New arms with novel CIT combos (table) are opened as new txs become available, and arms with minimal efficacy or unacceptable toxicity are closed. Studies include multiple cohorts for pts receiving different lines of tx (1L and 2L PDAC and gastric; 3L CRC). Pts with loss of clinical benefit or unacceptable toxicity may be eligible to enroll in a different CIT combo arm. Primary endpoints include safety and investigator-assessed ORR (RECIST v1.1); secondary endpoints: PFS, OS, DCR and DOR. Clinical trial information: NCT03193190, NCT03281369, NCT03555149. [Table: see text]

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

The eukaryotic translation initiation factor 4E (eIF4E) is a potent oncogene that is found to be dysregulated in 30% of human cancer, including colorectal carcinogenesis (CRC). ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of the eIF4E protein. In preclinical studies we found that EIF4e ASOs reduced expression of EIF4e mRNA and inhibited proliferation of colorectal carcinoma cells. An additive antiproliferative effect was observed in combination with irinotecan. We then performed a clinical trial evaluating this combination in patients with refractory cancer. No dose-limiting toxicities were seen but based on pharmacokinetic data and tolerability the dose of irinotecan was reduced to 160 mg/m(2) biweekly. Efficacy was evaluated in 15 patients with irinotecan-refractory colorectal cancer. The median time of disease control was 22.1 weeks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13 of 19 patients. Matched pre- and posttreatment tumor biopsies showed decreased eIF4E mRNA levels in five of nine patients. In tumor tissue, the intracellular and stromal presence of ISIS 183750 was detected by IHC in all biopsied patients. Although there were no objective responses stable disease was seen in seven of 15 (47%) patients who were progressing before study entry, six of whom were stable at the time of the week 16 CT scan. We were also able to confirm through mandatory pre- and posttherapy tumor biopsies penetration of the ASO into the site of metastasis.

Immune checkpoint inhibitors have been identified as breakthrough treatment in melanoma given its dramatic response to PD-1/PD-L1 blockade. This is likely to extend to many other cancers as hundreds of clinical trials are being conducted or proposed using this exciting modality of therapy in a variety of malignancies. While immune checkpoint inhibitors have been extensively studied in melanoma and more recently in lung cancer, little is known regarding immune checkpoint blockade in other cancers. This review will focus on the tumor immune microenvironment, the expression of PD-1/PD-L1 and the effect of immune modulation using PD-1 or PD-L1 inhibitors in patients with head and neck, prostate, urothelial, renal, breast, gastrointestinal and lung cancers.

The incidence of pancreatic cancer has been increasing while its 5-year survival rate has not changed in decades. In the era of personalized medicine, immunotherapy has emerged as a promising treatment modality in a variety of malignancies, including pancreatic cancer. This review will discuss the unique pancreatic tumor microenvironment, including the cells and receptors that transform the pancreas from its normal architecture into a complex mix of suppressor immune cells and dense extracellular matrix that allows for the unrestricted growth of cancer cells. Next, we will highlight the recently completed immunotherapy clinical trials in pancreatic cancer. Finally, we will explore the on-going immunotherapy clinical trials and future directions of this engaging and changing field.