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1578 Background: Acute care visits (emergency department [ED] visits or inpatient admissions) for patients with cancer are growing disproportionately. Traditional oncology care models have not effectively identified and managed at-risk patients to prevent acute care. A next step is to harness advances in technology and mobile applications to enable patients to report symptoms any time, enabling “digital hovering” - intensive monitoring and management of high-risk patients. Our objective was to evaluate a digital platform that identifies and remotely monitors high-risk patients initiating intravenous antineoplastic therapy with the goal of preventing unnecessary acute care visits. Methods: This was a single-institution matched cohort quality improvement study conducted at an NCI-designated cancer center between January 1, 2019 and March 31, 2020. Eligible patients were those initiating intravenous antineoplastic therapy who were identified as high-risk for seeking acute care. Patients were identified as high-risk for an acute care visit by their oncologist with decision support from a web-based machine learning model. Enrolled patients’ symptoms were monitored using a digital platform. The platform is integrated into the EMR and includes: 1) a secure patient portal enabling communication and daily delivery of electronic patient-reported outcomes symptom assessments; 2) clinical alerts for concerning symptoms; and 3) a symptom trending application. A dedicated team of registered nurses and nurse practitioners managed reported symptoms. These clinicians acted as an extension of the primary oncology team, assisting with patient management exclusively through the platform. The primary outcomes evaluated were incidence of ED visits and inpatient admissions within six months of intravenous antineoplastic initiation. Results: Eighty-one high-risk patients from the intervention arm were matched by stage and disease with contemporaneous high-risk control patients. Matched cohorts had similar baseline characteristics, including age, sex, race, and treatment. ED visits and hospitalizations within six months of treatment initiation were analyzed using cumulative incidence analyses with a competing risk of death. The cumulative incidence of an ED visit for the intervention cohort was 0.27 (95% CI: 0.17, 0.37) at six months compared to 0.47 (95% CI: 0.36, 0.58) in the control group (p = 0.01). The cumulative incidence of an inpatient admission was 0.23 (95% CI: 0.14, 0.33) in the intervention group versus 0.41 (95% CI: 0.30, 0.51) in the control group (p = 0.02). Conclusions: The narrow employment of technology solutions to complex care delivery challenges in oncology can improve outcomes and innovate care. This program was a first step in using a digital platform and a remote team to improve symptom care in the home for high-risk patients.

Background:Oncologists often order genomic testing to inform treatment for worsening cancer. The resulting correlation between genomic testing timing and prognosis, or “informative entry,” can bias observational clinico-genomic research. The efficacy of existing approaches to this problem in clinico-genomic cohorts is poorly understood.Methods:We simulated clinico-genomic cohorts followed from an index date to death. Subgroups in each cohort who underwent genomic testing before death were “observed.” We varied data generation parameters under four scenarios: (i) independent testing and survival times; (ii) correlated testing and survival times for all patients; (iii) correlated testing and survival times for a subset of patients; and (iv) testing and mortality exclusively following progression events. We examined the behavior of conditional Kendall tau (Tc) statistics, Cox entry time coefficients, and biases in overall survival (OS) estimation and biomarker inference across scenarios.Results:Scenario #1 yielded null Tc and Cox entry time coefficients and unbiased OS inference. Scenario #2 yielded positive Tc, negative Cox entry time coefficients, underestimated OS, and biomarker associations biased toward the null. Scenario #3 yielded negative Tc, positive Cox entry time coefficients, and underestimated OS, but biomarker estimates were less biased. Scenario #4 yielded null Tc and Cox entry time coefficients, underestimated OS, and biased biomarker estimates. Transformation and copula modeling did not provide unbiased results.Conclusions:Approaches to informative clinico-genomic cohort entry, including Tc and Cox entry time statistics, are sensitive to heterogeneity in genotyping and survival time distributions.Impact:Novel methods are needed for unbiased inference using observational clinico-genomic data.

Not available.

PURPOSE: Timely surgical cavity stereotactic radiosurgery (SRS) is an important adjuvant to brain metastasis resection, with earlier treatment associated with less frequent recurrence. The logistical complexity of treatment organization, however, has resulted in suboptimal start times postsurgically. We implemented a process improvement approach to reduce the time from surgery to adjuvant irradiation of resected brain metastases. METHODS: A multidisciplinary working group used process mapping to identify opportunities to reduce visits and shorten treatment times. The care delivery process was modified to streamline perioperative SRS preparation with (1) early patient identification, (2) preoperative intrateam communication, and (3) consolidation of required steps. Plan-Do-Study-Act cycles were used for process improvement. The surgery-to-SRS initiation time interval was the primary outcome. Secondary outcomes included the number of associated patient encounters. RESULTS: After implementation, the median (interquartile range) interval from surgery to SRS was reduced 48% from 27 (21-34) to 14 days (13-17; P < .001). The rate of surgical cavity SRS within 30 days increased from 64% (n = 63 of 98) to 97% (n = 60 of 62; P < .001). The median (interquartile range) number of CNS-associated encounters between resection and SRS decreased from 5 (4-6) to 4 (3-5; P < .001). The proportion of patients who had > 1 magnetic resonance imaging/computed tomography between surgery and SRS decreased from 45% (44 of 98) to 13% (8 of 62; P < .001). The time from surgery to systemic therapy resumption/initiation among patients treated within 90 days postoperatively decreased from 35 (24-48) to 32 days (23-40; P = .074). There were no wound complications in either group. CONCLUSION: Adjuvant SRS latency and treatment-associated encounters were significantly reduced after care-coordination implementation. This approach reduces patient and health care system burden and can be applied to other scenarios where early postoperative SRS administration is critical.

Background Little is known about patient outcomes with advanced melanoma following inpatient initiation or continuation of immune checkpoint blockade (ICB). Methods and Results We conducted a single institution retrospective case series of advanced melanoma patients who initiated ICB as an inpatient (initial inpatient cohort, n = 9), or continued ICB as an inpatient after previously starting as an outpatient (outpatient then inpatient cohort, n = 5). One patient had a partial response to ICB initiated as an inpatient, but ultimately died of melanoma after 13.5 months. Median overall survival for initial inpatient cohort was 1.0 month (95% CI: 0.2-11.2), and 1.4 months (95% CI: 0.4-58.0) for the outpatient then inpatient cohort. Three patients were alive >6 months after inpatient ICB administration. Conclusion Despite overall poor outcomes, some patients may benefit from inpatient ICB. This study provides additional information for clinicians to appropriately counsel patients on expectations following inpatient ICB.

Immune checkpoint inhibitors (ICIs), now mainstays in the treatment of cancer treatment, show great potential but only benefit a subset of patients. A more complete understanding of the immunological mechanisms and pharmacodynamics of ICI in cancer patients will help identify the patients most likely to benefit and will generate knowledge for the development of next-generation ICI regimens. We set out to interrogate the early temporal evolution of T cell populations from longitudinal single-cell flow cytometry data. We developed an innovative statistical and computational approach using a Latent Dirichlet Allocation (LDA) model that extends the concept of topic modeling used in text mining. This powerful unsupervised learning tool allows us to discover compositional topics within immune cell populations that have distinct functional and differentiation states and are biologically and clinically relevant. To illustrate the model’s utility, we analyzed ∼17 million T cells obtained from 138 pre- and on-treatment peripheral blood samples from a cohort of melanoma patients treated with ICIs. We identified three latent dynamic topics: a T-cell exhaustion topic that recapitulates a LAG3+ predominant patient subgroup with poor clinical outcome; a naive topic that shows association with immune-related toxicity; and an immune activation topic that emerges upon ICI treatment. We identified that a patient subgroup with a high baseline of the naïve topic has a higher toxicity grade. While the current application is demonstrated using flow cytometry data, our approach has broader utility and creates a new direction for translating single-cell data into biological and clinical insights.

A375 Lipidomics

Mutations assessed at VICC.

ZMEL in vitro lipidomics

Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies have become a mainstay in advanced melanoma treatment. We sought to evaluate whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune therapy in melanoma. We identified 229 patients with melanoma treated with immune therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1 (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune therapy for patients with or without NRAS mutations. Of the 229 patients with melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild type. The NRAS-mutant cohort had superior or a trend to superior outcomes compared with the other cohorts in terms of response to first-line immune therapy (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P = 0.07), clinical benefit (response + stable disease lasting ≥24 weeks; 50% vs. 31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P = 0.09). Benefit from anti–PD-1/PD-L1 was particularly marked in the NRAS cohort (clinical benefit rate 73% vs. 35%). In an independent group of patient samples, NRAS-mutant melanoma had higher PD-L1 expression (although not statistically significant) compared with other genotypes (8/12 vs. 9/20 samples with ≥1% expression; 6/12 vs. 6/20 samples with ≥5% expression), suggesting a potential mechanism for the clinical results. This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes. If confirmed by prospective studies, this may be explained in part by high rates of PD-L1 expression. Cancer Immunol Res; 3(3); 288–95. ©2015 AACR.

ZMEL in vivo lipidomics

PDF file - 88K, Supplemental Figure 3. PBMCs from metastatic melanoma patients treated with ipilimumab depleted of CD14-expressing cells were stimulated to proliferate with OKT-3 and IL-2. CFSE dilution of CD3+ T cells in the culture is measured in the absence of CD14+ cells or with CD14+ cells added back.

PDF file - 101K, Supplemental Figure 4. Different summary statistics can be applied to measure HLA-DR expression on lineage negative, CD14+CD11b+ cells and assess relationship to overall survival (using maximum logrank statistics as described in Methods). CV was used as a self-normalizing measurement that was preferred to eliminate non-biological variation in clinical measurements (e.g. day-to-day variation, differences in sample handling and FACS acquisition).

Supplementary Methods. Supplementary Table S1: Baseline characteristics of PCNSL Patients. Supplementary Table S2: Baseline characteristics of SCNSL patients. Supplementary Table S3: Corticosteroid use. Supplementary Table S4: Genes with Recurrent Mutations in PCNSL (non-aSHM). Supplementary Table S5: Genes that are targeted by aSHM in PCNSL. Supplementary Table S6: Comparison of mutation prevalence in current PCNSL genomic landscape analysis (red) with prior studies in PCNSL and DLBCL. Supplementary Table S7: Gene set enrichment analysis of CD79B-mutant PCNSLs compared to CD79B-wildtype PCNSLs. Supplementary Figure S1: Ibrutinib concentrations in Cerebrospinal Fluid (CSF). Supplementary Figure S2: Comparison of mutation frequencies in PCNSL and DLBCL outside the CNS. Supplementary Figure S3: Cell-of-origin (COO) Markers in PCNSL. Supplementary Figure S4: CD79B-mutant PCNSL xenograft models. Supplementary Figure S5: Comparison of PCNSL cells with non-CNS DLBCL cell lines. Supplementary Figure S6: Inhibition of individual PI3K isoforms does not induce cell death in CD79B-mutant PCNSL cells. Supplementary Figure S7: In-vitro effects of ibrutinib on CD79B-mutant PCNSL cells.

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Supplementary Figure S1: RNA-seq analysis of human A375 melanoma cells in co-culture with adipocytes compared to monoculture controls Supplementary Figure S2: Lipid transfer and melanoma cell uptake of long chain fatty acids Supplementary Figure S3: Adipocytes do not increase glycolysis in melanoma cells Supplementary Figure S4: Endogenous FATP expression in control tissues and patient-derived xenografts Supplementary Figure S5: Absence of lipid-laden tumor cells in in vivo setting devoid of adipocytes Supplementary Figure S6: Lipidomics reveals specific lipid species transferred from adipocytes to melanoma cells Supplementary Figure S7: FATP1 expression and survival Supplementary Figure S8: Validation of FATP1 knockdown Supplementary Figure S9: Lipofermata targets FATP1 Supplementary Figure S10: Compounds that are structurally similar to Lipofermata do not cause decreases in lipid uptake or increased cell death Supplementary Figure S11: Measurement of apoptosis in Lipofermata-treated cells

A375 RNA-seq

PDF file - 103K, Supplemental table 1. Univariate analysis of relationship between m-MDSC and overall survival at pre-treatment baseline and week 6 after ipilimumab treatment at 10mg/kg and 3mg/kg.

Evaluation of myeloid-derived suppressor cells (MDSC), a cell type implicated in T-cell suppression, may inform immune status. However, a uniform methodology is necessary for prospective testing as a biomarker. We report the use of a computational algorithm-driven analysis of whole blood and cryopreserved samples for monocytic MDSC (m-MDSC) quantity that removes variables related to blood processing and user definitions. Applying these methods to samples from patients with melanoma identifies differing frequency distribution of m-MDSC relative to that in healthy donors. Patients with a pretreatment m-MDSC frequency outside a preliminary definition of healthy donor range (+ T-cell expansion following ipilimumab. Algorithm-driven analysis may enable not only development of a novel pretreatment biomarker for ipilimumab therapy, but also prospective validation of peripheral blood m-MDSCs as a biomarker in multiple disease settings. Cancer Immunol Res; 2(8); 812–21. ©2014 AACR.

PDF file - 58K, Supplemental Figure 2. PBMCs available in multiple aliquots were serially analyzed over 3 weeks to evaluate day-to-day reproducibility of CVHLA-DR measures. A standard error of measurement of 1.4% and 0.7%, respectively for QC sample 1 and 2 was detected.

PDF file - 142K, Supplemental Figure 1. m-MDSC gating strategy using various HLA-DR cutoffs based on expression of HLA-DR in lineage positive cells yields differing m-MDSC frequencies and is susceptible to inter-user variability.

Time from prior treatment to start of treatment within this protocol

MAF file

Kaplan-Meier curves for overall survival. (A) PD-1 monotherapy by driver class. (B) nivolumab plus ipilimumab by driver class. (C) PD-1 monotherapy by primary site of melanoma. (D) nivolumab plus ipilimumab by primary site of melanoma.

Additional description of correlative immunologic assays

Absolute numbers (absolute lymphocyte count * proportion) of designated cell populations at pre-treatment baseline (V1); after the completion of RT/prior to the 3rd dose of immunotherapy (week 6-9, V2); and at the timepoint of first radiographic assessment (Week 10-14, V3). Patients with response (green), stable disease (yellow), and progressive disease (red) outside of the irradiated volume are shown. Symbols reflect unique patients.

Purpose: Activation of the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase/AKT pathway seems to be critical for melanoma proliferation. Components of these pathways are client proteins of heat-shock protein 90 (hsp90), suggesting that inhibition of hsp90 could have significant antimelanoma effects. We conducted a phase II trial using the hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in melanoma patients. The primary end points were clinical responses and whether treatment inhibited MAPK pathway activity.Experimental Design: Melanoma patients with measurable disease were stratified on the basis of whether or not their tumor harbored a V600E BRAF mutation. The hsp90 inhibitor 17-AAG was administered i.v. once weekly ×6 weeks at 450 mg/m2. Tumor biopsies were obtained pretreatment and 18 to 50 hours after the first dose of 17-AAG, and were snap-frozen.Results: Fifteen evaluable patients were treated; nine had BRAF mutations and six were wild-type. No objective responses were observed. Western blot analysis of tumor biopsies showed an increase in hsp70 and a decrease in cyclin D1 expression in the posttreatment biopsies but no significant effect on RAF kinases or phospho–extracellular signal-regulated kinase expression. Plasma analyzed by mutant-specific PCR for V600E BRAF showed 86% sensitivity and 67% specificity in predicting tumor DNA sequencing results.Conclusions: At this dose and schedule of 17-AAG, the effects of 17-AAG on RAF kinase expression were short-lived, and no objective antimelanoma responses were seen. Future trials in melanoma should focus on a more potent hsp90 inhibitor or a formulation that can be administered chronically for a more prolonged suppression of the MAPK pathway.

Purpose: We compared the efficacy of human Langerhans cells (LC) as tumor immunogens in vivo with monocyte-derived dendritic cells (moDC) and investigated how interleukin 15 (IL15) supports optimal DC-stimulated antitumor immunity.Experimental Design: American Joint Committee on Cancer stage III/IV melanoma patients participated in this first clinical trial comparing melanoma peptide-pulsed LC with moDC vaccines (NCT00700167, www.ClinicalTrials.gov). Correlative studies evaluated mechanisms mediating IL15 support of DC-stimulated antitumor immunity.Results: Both DC vaccines were safe and immunogenic for melanoma antigens. LC-based vaccines stimulated significantly greater tyrosinase–HLA-A*0201 tetramer reactivity than the moDC-based vaccines. The two DC subtypes were otherwise statistically comparable, in contrast to extensive prior data in vitro showing LC superiority. LCs synthesize much more IL15 than moDCs and stimulate significantly more antigen-specific lymphocytes with a cytolytic IFN-γ profile even without exogenous IL15. When supplemented by low-dose IL15, instead of IL2, moDCs stimulate 5 to 6 logs more tumor antigen–specific effector memory T cells (TEMRA) over 3 to 4 weeks in vitro. IL2 and IL15 can be synergistic in moDC stimulation of cytolytic T cells. IL15 promotes T-cell expression of the antiapoptotic bcl-2 and inhibits candidate regulatory T-cell (Treg) expansion after DC stimulation, countering two effects of IL2 that do not foster tumor immunity.Conclusions: MoDC-based vaccines will require exogenous IL15 to achieve clinical efficacy. Alternatively, LCs can couple the endogenous production of IL15 with potent T-cell stimulatory activity. Optimization of full-length tumor antigen expression for processing into multiple immunogenic peptides for presentation by both class I and II MHC therefore merits emphasis to support more effective antitumor immunity stimulated by LCs. Clin Cancer Res; 17(7); 1984–97. ©2011 AACR.

Purpose: Bevacizumab is associated with decreased vascular permeability that allows for more aggressive radiotherapy schedules. We conducted a phase II trial in newly diagnosed glioblastoma utilizing a novel hypofractionated stereotactic radiotherapy (HFSRT) schedule combined with temozolomide and bevacizumab.Experimental Design: Patients with tumor volume ≤60 cc were treated with HFSRT (6 × 6 Gy to contrast enhancement and 6 × 4 Gy to FLAIR hyperintensity with dose painting) combined with concomitant/adjuvant temozolomide and bevacizumab at standard doses. Primary endpoint was 1-year overall survival (OS): promising = 70%; nonpromising = 50%; α = 0.1; β = 0.1.Results: Forty patients were enrolled (median age: 55 years; methylated MGMT promoter: 23%; unmethylated: 70%). The 1-year OS was 93% [95% confidence interval (CI), 84–100] and median OS was 19 months. The median PFS was 10 months, with no pseudo-progression observed. The objective response rate (ORR) was 57%. Analysis of The Cancer Genome Atlas glioblastoma transcriptional subclasses (Nanostring assay) suggested patients with a proneural phenotype (26%) fared worse (ORR = 14%, vs. 77% for other subclasses; P = 0.009). Dynamic susceptibility-contrast perfusion MRI showed marked decreases in relative cerebral blood volume over time (P < 0.0001) but had no prognostic value, whereas higher baseline apparent diffusion coefficient (ADC) ratios and persistent hypermetabolism at the 6-month FDG-PET predicted poor OS (P = 0.05 and 0.0001, respectively). Quality-of-life (FACT-BR-4) and neuropsychological test scores were stable over time, although some domains displayed transient decreases following HFSRT.Conclusions: This aggressive radiotherapy schedule was safe and more convenient for patients, achieving an OS that is comparable with historical controls. Analysis of advanced neuroimaging parameters suggests ADC and FDG-PET as potentially useful biomarkers, whereas tissue correlatives uncovered the poor prognosis associated with the proneural signature in non–IDH-1–mutated glioblastoma. Clin Cancer Res; 20(19); 5023–31. ©2014 AACR.

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Supplementary Data Legends

Levels of eotaxin were higher in cohort A compared to cohort B. Patients with response in cohort A appeared to have high levels of eotaxin. Symbols reflect unique patients.

Supplementary Data 1 ELIGIBILITY CRITERIA. Supplementary Data 2 HYPOFRACTIONATED STEREOTACTIC RADIOTHERAPY PLANNING. Supplementary Data 3 MRI ACQUISITION PARAMETERS AND PROCESSING. Supplementary Data 4 Nanostring-based Tissue Correlates Methods. Supplementary Data 5 Number of patients experiencing Grades 3-5 treatment-related toxicities. Supplementary Data 6 Univariate analysis of DSC MR perfusion and diffusion MRI. Supplementary Data 7 NEUROPSYCHOLOGICAL TEST Z-SCORES, QUALITY OF LIFE, DEPRESSION AND FATIGUE SCORES OVER TIME.

Supplementary Figures S1-S3.

Supplementary Data from Phase II Trial of 17-Allylamino-17-Demethoxygeldanamycin in Patients with Metastatic Melanoma

PDF file - 2798K, Immunohistochemical (IHC) staining of high pAKT tumors

TRAE (grade {greater than or equal to}2 events or grade 1 events occurring in {greater than or equal to}2 patients)