Genomic Drivers of Large B-Cell Lymphoma Resistance to CD19 CAR-T Therapy

Introduction: Anti-CD-19 chimeric antigen receptor-reprogrammed autologous T cells are breakthrough immunotherapies for heavily pretreated patients with aggressive B-cell lymphomas; however, across CAR-19 products, ~60% of patients do not achieve remission or relapse and unfortunately typically progress and rapidly die. Factors associated with impaired response to CAR-19 include inflammatory markers such as interferon signaling and clinical factors such as the need for bridging therapy and high pre-CAR-19 tumor burden, but cell-intrinsic driver of CAR-19 resistance remain largely undefined. Methods: To characterize the genomic mechanisms involved in diffuse large B cell lymphoma (DLBCL) resistance to CAR-19, we interrogated whole genome sequencing (WGS) from 28 relapsed/refractory (r/r) aggressive lymphoma patients treated with axicabtagene ciloleucel (axi-cel). The median coverage was 44.8X. To increase statistical power of analyses, we included also 50 newly diagnosed DLBCL patients from the Pan-Cancer Analysis of Whole Genomes (PCAWG). Results: As reported in other series, neither double hit cytogenetics nor MYC-BCL2 double expression associated with CAR-19 resistance, despite their negative predictive power for newly diagnosed DLBCL patients. Chapuy and LymphGen classification algorithms also demonstrated no prognostic significance. Among known mutated driver genes, only TP53 was significantly enriched in our cohort in comparison to the PCAWG cohort (p=0.002), but it did not predict poor CAR-19 outcome. Among other genes known to be involved in DLBCL pathogenesis, only mutations in NFKBIA or MYC, associated with worse PFS (p=0.04, p=0.025 respectively). Next, we identified 12 single base substitution (SBS) mutational signatures detected in our cohort of r/r lymphomas, four of which are caused by exposure to distinct chemotherapies (Landau et al., 2020, Nat Comm). The melphalan-related signature (SBS-MM1) was identified in 4 out 5 patients who received high dose melphalan followed by autologous stem cell transplant, and 75% of patients exposed to platinum had evidence of one of the three known platinum signatures. Across different SBS signatures, only presence of APOBEC (SBS2 and SBS13) associated with worse PFS with 4/5 patients progressing (p=0.03). We compared newly diagnosed and r/r DLBCL by GISTIC2.0 copy number variation (CNV) analysis, revealing three gene deletions significantly enriched in our r/r cohort: TP53, RHOA and RB1. Interestingly, the deletions involving RHOA and RB1 both independently predicted poor outcome (p=0.0007 and p=0.05 respectively) with 5/5 and 6/8 patients progressing respectively. The third, involving TP53 (46.4% of patients), had no prognostic impact but reflected the high-risk nature of the heavily pretreated tumors. WGS allows detailed identification of structural variants and complex events. Indeed, we found evidence of chromothripsis, a catastrophic event in which one or more chromosomes are shattered and aberrantly reassembles generating multiple aneuploidies, in 39.3% of r/r DLBCL. This strongly associated with poor CAR-19 outcome, with 9/11 affected cases experiencing early progression (p=0.041). Finally, reduced expression (n=3) or genomic alteration (n=3) of CD19 did not associate with poor outcome. We found one case, with durable response, containing a sub-clonal mutation in CD19 (L174V) at baseline, previously reported as associated with CAR-19 resistance. In line with recent evidence, these findings indicate that antigen-mediated tumor killing is not the only mechanism of tumor eradication, and CD19-independent resistance mechanisms predominate. Conclusions: Leveraging the high resolution of WGS, we observed that markers of genomic complexity (chromothripsis and APOBEC) and specific genomic alterations (RHOA and RB1 deletion) associate with resistance to CAR-19 immunotherapy for aggressive B-cell lymphomas. Fifteen out of sixteen patients (93.8%) who relapsed on CAR-19 contained at least one of the described genomic alterations. Recent data demonstrate that an immunosuppressed TME leads to CAR-19 failure in patients, and animal studies show activation of host T cells by CAR-T cells. Combining these findings with these genomics findings, successful CAR-19 therapy must overcome the immune-exhausted tumor microenvironment to mobilize the host immune system and eliminate the tumor. Figure 1 Figure 1. Disclosures Jain: Takeda: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria. Faramand: Novartis: Research Funding; Kite/Gilead: Research Funding. Landgren: Amgen: Research Funding; Janssen: Research Funding; Amgen: Honoraria; Celgene: Research Funding; Janssen: Other: IDMC; Janssen: Honoraria; Takeda: Other: IDMC; GSK: Honoraria. Locke: Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; Gerson Lehrman Group: Consultancy; Calibr: Consultancy, Other: Scientific Advisory Role; Janssen: Consultancy, Other: Scientific Advisory Role; Umoja: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Takeda: Consultancy, Other; Emerging Therapy Solutions: Consultancy; EcoR1: Consultancy; Cowen: Consultancy; Wugen: Consultancy, Other; Legend Biotech: Consultancy, Other; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy. Maura: Medscape: Consultancy, Honoraria; OncLive: Honoraria. Davila: Precigen: Research Funding.

Primary Progression on Frontline Therapy for Diffuse Large B-Cell Lymphoma Is Associated with a Poor Outcome Despite Subsequent CD19 Targeted CAR T-Cell Therapy

Introduction: Between 50-80% of patients with diffuse large B-cell lymphoma (DLBCL) are cured by frontline (1L) R-CHOP immunochemotherapy. Ultra-high risk (UHR) features for poor overall survival (OS) include: progression through the frontline therapy (primary progression, PP), presence of a MYC translocation (MYC-R+), and a high or high-intermediate National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) (Costa, Am. J. Hematol., 2017). We aim to explore the role of these UHR factors in the outcomes of DLBCL patients receiving standard of care (SOC) anti-CD19 CAR T-cell therapy. Methods: This is a retrospective single-center study of relapsed/refractory (R/R) DLBCL patients treated with either axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) as SOC at Moffitt Cancer Center according to the FDA label as of March 2021, or who were treated on the expanded access programs (EAP) for axi-cel (NCT03153462) and tisa-cel (NCT03601442) for the provision of CAR T when products fell outside of manufacturing specifications (OOS). We excluded patients who had received prior therapy for indolent B-cell lymphomas (iNHL). We defined patients with primary treatment failure (PTF) as: PP, residual disease after 1L therapy (RD), or early relapse within 6 months of 1L therapy (ER). For patients with PTF, we calculated the number of UHR features (0 to 3): MYC status, NCCN-IPI, and PP. Kaplan-Meier survival curves were used to compare progression free survival (PFS) and overall survival (OS) starting from the date of CAR T-cell infusion, with statistical significance determined using the log-rank test at the P<0.05 threshold. Results: A total of 187 R/R DLBCL patients received SOC or EAP CAR T-cell therapy, of which 116 had DLBCL with no prior therapy for iNHL and were included in this analysis. PTF occurred in 75 patients (65%), of which 30 (40%) patients had primary progression as the failure pattern, 23 (30.7%) patients had MYC-R detected by FISH, and 37 (49.3%) patients had intermediate-high/high NCCN-IPI scores at the time of PTF. The median follow up was 10.05 months. Of the 75 patients with PTF, 69 received axi-cel and 6 received tisa-cel. Main 1L therapies were R-CHOP in 59 (78.6%) cases and DA-EPOCH-R in 14 (18.7%). The median lines of therapy prior to CAR T-cell therapy was 3 (range 2-6 lines). The number of UHR features was associated with a shorter OS after CAR T-cell therapy. The OS for patients with 2-3 and 0-1 UHR were 5.3 months (95% CI, 3.7 to 15.13 months) and not reached, respectively (P=0.005; Figure 1A). In terms of PTF patterns, PP was associated with worse PFS and OS after CAR T-cell therapy compared to other patterns (RD/ER) (PP, mPFS 3.1 months vs RD/ER, mPFS not reached; p<0.001; PP, median OS 5.63 months vs RD/ER, mOS not reached, P<0.001; Figure 1B). Patients with PTF and MYC-R+ had no difference in PFS (P=0.51) but a shorter OS after CAR T-cell therapy compared to those without an identified MYC translocation (P=0.05). Patients with intermediate-high or high NCCN-IPI at time of PTF had similar PFS (P=0.75) and OS (P=0.34) to patients with intermediate-low or low NCCN-IPI. Conclusion: Patients with DLBCL who experience PP to frontline immunochemotherapy had shorter PFS and OS after subsequent CAR T-cell therapy compared to other PTF patterns. R/R DLBCL patients with PP represent a poor prognosis subgroup, even with CAR T-cell therapy. It will be important to determine if patients with primary progression have increased benefit from CAR T-cell therapy if it is provided at first relapse rather than after 2 or more prior lines of therapy. Our study suggests that mechanisms of tumor resistance to CAR T-cell therapy may be present in some patients from the time of upfront therapy. Figure 1 Figure 1. Disclosures Chavez: AstraZeneca: Research Funding; Merk: Research Funding; ADC Therapeutics: Consultancy, Research Funding; BMS: Speakers Bureau; MorphoSys, Bayer, Karyopharm, Kite, a Gilead Company, Novartis, Janssen, AbbVie, TeneoBio, and Pfizer: Consultancy; MorphoSys, AstraZeneca, BeiGene, Genentech, Kite, a Gilead Company, and Epizyme: Speakers Bureau. Shah: Pfizer: Consultancy, Other: Expenses; Incyte: Research Funding; Acrotech/Spectrum: Honoraria; BeiGene: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Precision Biosciences: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Other: Expenses; Servier Genetics: Other; Jazz Pharmaceuticals: Research Funding; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Adaptive Biotechnologies: Consultancy. Nishihori: Karyopharm: Research Funding; Novartis: Research Funding. Lazaryan: Kadmon: Consultancy; Avrobio: Membership on an entity's Board of Directors or advisory committees; Humanigen: Membership on an entity's Board of Directors or advisory committees. Davila: Precigen: Research Funding. Locke: Wugen: Consultancy, Other; Umoja: Consultancy, Other; Cowen: Consultancy; EcoR1: Consultancy; Takeda: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Legend Biotech: Consultancy, Other; Janssen: Consultancy, Other: Scientific Advisory Role; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; Emerging Therapy Solutions: Consultancy; Gerson Lehrman Group: Consultancy; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy. Gaballa: Adaptive Biotechnologies: Research Funding; Epizyme: Consultancy, Research Funding; TG therapeutics: Consultancy, Speakers Bureau; Beigene: Consultancy; ADC Therapeutics: Consultancy. Jain: Kite/Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

A Phase 1/2 Dose-Escalation and Dose-Expansion Study of the Safety and Efficacy of Anti-CD7 Allogeneic CAR-T Cells (WU-CART-007) in Patients with Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia (T-ALL)/ Lymphoblastic Lymphoma (LBL)

Background T-ALL/LBL represent a class of devastating hematologic cancers with high rates of relapse and mortality in both children and adults. Despite intensive multi-agent chemotherapy regimens, fewer than 50% of adults and 85% of children with T-ALL survive beyond five years. For those who relapse after initial therapy, salvage regimens induce remissions in only ~20-30% of cases, and survival is dismal. T-ALL/LBL is a genetically diverse group, but with universal overexpression of CD7, making this a suitable target for immunotherapy. Despite the success of CAR-T cells in B-cell malignancies, CAR-T cell development in T-cell malignancies has proven challenging due to fratricide and high risk of contamination of the genetically modified CAR-T product with the patient's malignant T cells. WU-CART-007 is a CD7-directed, genetically modified, allogeneic, 'off the shelf', fratricide-resistant chimeric antigen receptor (CAR) T-cell product for the treatment of CD7+ve hematologic malignancies. Methods This multicenter, open-label, dose-escalation, Phase 1/2 study (NCT#04984356) of WU-CART-007 in patients ≥ 12 years old, with relapsed or refractory T-ALL/LBL is designed to characterize the safety, tolerability, dose-limiting toxicities (DLTs), and maximum tolerated dose (MTD)/maximum administered dose (MAD; if no MTD defined) (Phase 1), and to investigate the preliminary anti-tumor activity, as measured by objective response rate (ORR) and duration of response (DOR) (Phase 2). Phase 1 is comprised of a dose escalation segment and will proceed according to a standard 3+3 design testing up to 4 dose levels from 1 to 9 x 10 8 cells. Adolescent patients, ages 12-17, will be eligible for enrollment in Phase 1 Dose Escalation beginning at Dose level 3 and 4, and during Phase 2 Cohort Expansion. Upon reaching the MTD and/or RP2D, the Phase 2 portion comprised of the cohort expansion segment will be launched. A Simon's optimal two-stage design will be implemented to enroll patients (an interim analysis for futility in the first stage and the final analysis in the second stage) for Phase 2 dose expansion cohort to confirm safety and explore preliminary efficacy. All patients will receive a single infusion of WU-CART-007 cells on day 1 following a lymphodepleting conditioning therapy consisting of fludarabine and cyclophosphamide on days -5 to -3. Patients will be hospitalized for a minimum of 7 days following WU-CART-007 administration. Response will be assessed on Cycle 1 Day 28 (± 1 days), and at Months 3, 6, 12, and 24, by bone marrow aspirate and biopsy and PET/CT if indicated. Response will be defined as per modified NCCN Guidelines Version 2.2020. Disclosures Ghobadi: Atara: Consultancy; Amgen: Consultancy, Research Funding; Wugen: Consultancy; Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Locke: Janssen: Consultancy, Other: Scientific Advisory Role; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; Legend Biotech: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Takeda: Consultancy, Other; Wugen: Consultancy, Other; Cowen: Consultancy; Umoja: Consultancy, Other; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; EcoR1: Consultancy; Emerging Therapy Solutions: Consultancy; Gerson Lehrman Group: Consultancy; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy. Maude: Wugen: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Davidson-Moncada: Wugen: Current Employment. Cooper: Wugen: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Patents & Royalties; NeoImmune Tech: Patents & Royalties; RiverVest: Consultancy.

Concurrent Monitoring of Peripheral Blood Circulating Tumor DNA and Circulating Tumor Cells in Relapsed/Refractory Follicular Lymphoma Patients Post Axicabtagene Ciloleucel, a Single Center Experience

Background: Monitoring of peripheral blood (PB) circulating tumor DNA (ctDNA) in DLBCL post axi-cel can risk stratify and predict outcomes in DLBCL (Frank et al, JCO 2021). The utility of monitoring minimal residual disease (MRD) in follicular lymphoma (FL) post-CART therapy is currently unknown and the correlation between ctDNA and circulating tumor cells (CTC) as a MRD tool in this context is not yet determined. We present data from a retrospective pilot study to detect MRD by ctDNA (from banked serum) and CTC (from banked PB mononuclear cells, PBMCs) post axi-cel therapy in patients (pts) with R/R FL pts enrolled on the Zuma-5 trial at Moffitt Cancer Center. Methods: Lymphoma clonotype(s) were identified in extracted tumor DNA from banked archival FFPE tissue by NGS (clonoSEQ®;Adaptive Biotechnologies) to identify rearranged IgH (VDJ), IgH (DJ), IgK and IgL receptor gene sequences. MRD was monitored with PCR and NGS (clonoSEQ) in banked serum (ctDNA) and PBMCs (CTC) samples (pre-lymphodepletion, weekly during the first month, and subsequently every 3 months (mo) up to 2 years when available). We compared MRD measured by ctDNA versus CTC and correlated both with clinical responses by PET imaging per Lugano criteria (performed at day 30, then every 3 months post axi-cel infusion). Results Fifteen pts received axi-cel for R/R FL between June 2018 and July 2019. One pt failed to have a clone suitable for MRD tracking and was excluded from the current analysis. After a median follow up of 31.7 mo, the median PFS and OS were not reached and the estimated PFS and OS at 2.5 years were 57% and 85%, respectively. Six pts developed disease progression, all but one in the first year with that patient progressing at 18 mo. PET response at day 30 was CR in 8 pts (57%) and PR in 6 pts (43%). Six pts developed PD at a median of 7 mo post axi-cel infusion (range 3-19 mo) and 5 of them received a second infusion of axi-cel (3 had durable remissions afterwards). Prior to CART infusion, MRD was detected in 55% (cfDNA) and 64% (CTC) of available baseline samples. MRD was cleared rapidly within the first 2 weeks post axi-cel infusion, and MRD positive rates were as follows: day 7: ctDNA=54%, CTC 29%; day 14: ctDNA 17%, CTC 7%. Thus, ctDNA was more frequently positive than CTC when done at the same time points. All available samples at day 14, day 21, and day 28 were MRD negative when assessed by ctDNA or CTC. There was no difference in the incidence of disease relapse, response by PET at day 30, or PFS between MRD negative and MRD positive pts at days 7 or 14 when assessed by ctDNA or CTC. There was no correlation between the MRD clone copy numbers prior to lymphodepletion and responses assessed by PET, PFS, severity of cytokine release, or severity of neurotoxicity. Ten pts had available samples beyond day 28 post axi-cel infusion (median 192 days, range 90-418 days), of which 5/10 later developed PD including 2 pts (see figure 1) with banked samples close to the time of relapse. In both of these 2 pts, MRD was detectable at the time of progression on PET (n=1) or 3 mo prior to progression on PET (detected by ctDNA but not CTC). Both of those pts were retreated with axi-cel upon evidence of PD on PET. Otherwise pts who remained in CR continued to have negative MRD by ctDNA and CTC (n=5). There was only one patient who developed PD without detectable MRD at baseline or the time of relapse. Conclusion To our knowledge, this is the first study to assess MRD measured by ctDNA and CTC at concomitant time points in pts with FL post CART therapy. Our pilot study suggests that ctDNA is more sensitive than CTC to detect MRD in PB. Unlike reported experiences in DLBCL post-CART, in our small cohort, detectable MRD at day 7 did not predict future relapse or correlate with PFS. However, MRD by ctDNA was detected in pts prior to clinical or radiologic progression of disease. A prospective ctDNA MRD monitoring study in FL is warranted and an MRD driven early retreatment CART trial should be considered. Figure 1 Figure 1. Disclosures Gaballa: Adaptive Biotechnologies: Research Funding; Epizyme: Consultancy, Research Funding; TG therapeutics: Consultancy, Speakers Bureau; Beigene: Consultancy; ADC Therapeutics: Consultancy. Chavez: Merk: Research Funding; MorphoSys: Speakers Bureau; Novartis: Consultancy; Gilead: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Karyopharm: Consultancy; Epysime: Speakers Bureau; BMS: Speakers Bureau; BeiGene: Speakers Bureau; AstraZeneca: Research Funding. Jain: Takeda: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria. Shah: Pfizer: Consultancy, Other: Expenses; Amgen: Consultancy; Acrotech/Spectrum: Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Precision Biosciences: Consultancy; BeiGene: Consultancy, Honoraria; Novartis: Consultancy, Other: Expenses; Incyte: Research Funding; Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Jazz Pharmaceuticals: Research Funding; Servier Genetics: Other. Davila: Precigen: Research Funding. Locke: Amgen: Consultancy, Other: Scientific Advisory Role; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Umoja: Consultancy, Other; Takeda: Consultancy, Other; Wugen: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Legend Biotech: Consultancy, Other; Janssen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; Cowen: Consultancy; EcoR1: Consultancy; Emerging Therapy Solutions: Consultancy; Gerson Lehrman Group: Consultancy; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy.

Change in Patients' Perceived Cognition Among Chimeric Antigen Receptor T-Cell Therapy Recipients at Day 360

Introduction: Chimeric antigen receptor (CAR) T-cell therapy can lead to durable responses in patients with relapsed/refractory hematologic malignancies. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurs in up to 64% of patients. There is concern that ICANS places patients at risk for longer-term cognitive impairment. This study examined changes in patients' perceived cognition from prior to CAR T-cell therapy to days 90 and 360 in patients diagnosed with non-Hodgkins lymphoma, as well as CAR T-cell therapy-specific risk factors (e.g., ICANS, cytokine release syndrome [CRS]) and non-specific risk factors (e.g., age, education) associated with changes in cognition. Methods: Patients' perceived cognition was assessed at baseline and at days 90 and 360 with the Everyday Cognition Questionnaire (ECog), that provides scores for global cognition (which includes subscales for memory, language, visuospatial abilities, planning, organization, divided attention), and satisfaction with cognition. Quality of life was scored using the Patient-Reported Outcomes Measurement Information System-29. Frailty was examined with the hand grip strength test. Cognitive reserve was examined with the Weschler Test of Adult Reading. Clinical variables were extracted from medical records. Demographic variables were self-reported by participants. Percentages of patients reporting clinically significant worsening, clinically significant improvement, and unchanged cognition over time were calculated. Piecewise mixed models were used to examine average change in perceived cognition from baseline to day 90 and from day 90 to day 360, as well as to explore potential risk factors of average change in global cognition. Risk factors included demographic (i.e., age, education) and clinical factors (i.e., grade>2 CRS, grade>2 ICANS, disease response at days 90 and 360, baseline grip strength, baseline cognitive reserve) as well as baseline quality of life variables (i.e., fatigue, physical function, pain, depression, anxiety). Results: A total of 118 participants provided data (mean age 61, 59% male, 86% diagnosed with large B-cell lymphomas, 87% received axicabtagene ciloleucel). At day 90, relative to baseline, 17% of participants reported worsened global cognition, 10% improved global cognition, and 73% no change in global cognition (Figure 1). At day 360, relative to baseline, 28% reported worsened global cognition, 11% improved global cognition, and 61% no change in global cognition (Figure 1). Piecewise mixed models indicated that from baseline to day 90, there were no changes on average in global cognition or in any cognitive domain (ps>.05). In contrast, from day 90 to 360, participants reported, on average, worsened global cognition (p=.01), language (p=.04), visuospatial abilities (p=.04), divided attention (p=.03) and satisfaction with cognition (p=.01). At baseline, greater fatigue, anxiety and depression were associated with worse concurrent perceived cognition (p<.01). From baseline to day 90, physical functioning was associated with worsening cognition such that participants with better baseline physical functioning reported better perceived cognition at day 90 relative to participants with worse baseline physical functioning (p=.05). No other risk factors (e.g., CRS, ICANS) were associated with changes in global cognition from baseline to day 90 or from day 90 to day 360 (ps>.05). Post-hoc analyses indicated no differences in cognition by disease status at day 360 (ps>.05). Conclusions: Results suggest that perceived cognition worsens on average beyond day 90, with patients reporting worse baseline physical functioning being at risk of worse perceived cognition by day 90. Results should be incorporated when preparing patients about what to expect when receiving CAR T-cell therapy. Further research is needed regarding objective neurocognitive performance after CAR T-cell therapy. Figure 1 Figure 1. Disclosures Barata: Grifols: Current holder of individual stocks in a privately-held company; Almirall: Current holder of individual stocks in a privately-held company. Gonzalez: SureMed Compliance Equity: Consultancy; Elly Health, Inc.: Consultancy. Kirtane: Oncternal Therapeutics: Current holder of individual stocks in a privately-held company; Seattle Genetics: Current holder of individual stocks in a privately-held company; Myovant Sciences: Current holder of individual stocks in a privately-held company; Veru: Current holder of individual stocks in a privately-held company. Jain: Kite/Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Mokhtari: Kite: Consultancy. Chavez: ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Speakers Bureau; AstraZeneca: Research Funding; Merck: Research Funding; Novartis: Consultancy; Epizyme: Speakers Bureau; BeiGene: Speakers Bureau; Kite/Gilead: Consultancy; Adaptive: Research Funding; Karyopharm Therapeutics: Consultancy; MorphoSys: Speakers Bureau; Abbvie: Consultancy. Lazaryan: Kadmon: Consultancy; Avrobio: Membership on an entity's Board of Directors or advisory committees; Humanigen: Membership on an entity's Board of Directors or advisory committees. Shah: Novartis: Consultancy, Other: Expenses; Pfizer: Consultancy, Other: Expenses; Amgen: Consultancy; Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; BeiGene: Consultancy, Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Servier Genetics: Other; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Adaptive Biotechnologies: Consultancy. Locke: Gerson Lehrman Group: Consultancy; Emerging Therapy Solutions: Consultancy; EcoR1: Consultancy; Cowen: Consultancy; Umoja: Consultancy, Other; Wugen: Consultancy, Other; Takeda: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Legend Biotech: Consultancy, Other; Janssen: Consultancy, Other: Scientific Advisory Role; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy. Jim: Kite pharma: Research Funding; Merck: Consultancy; Janssen Scientific Affairs: Consultancy; RedHill Biopharma: Consultancy.

Do Overlapped Audit Committee Directors Affect Tax Avoidance?

This research is motivated by the Omani government’s desire to reduce tax avoidance and bolster tax revenue collected from financial institutions. The purpose of this paper is to examine the impact of overlapped audit committee (AC) chairs and other directors on tax avoidance practice and whether they play a monitoring or advisory role in tax avoidance practice. As a measure of overlapped AC chairs, we used a dummy variable to indicate whether an AC chair sits on other committees within a company or not. We used the proportion of AC members who serve on the AC and other committees within a company as our proxy for overlapped AC directors. We used a company’s cash effective tax rate as a proxy for tax avoidance. We regressed tax avoidance on overlapped AC membership and other control variables, using a sample of 204 firm-year observations from financial institutions listed on the Muscat Stock Exchange between 2014 and 2019. Our regression results show that a higher proportion of overlapped AC members and the presence of an overlapped AC chair were both associated with lower effective tax rates, which equated to more tax avoidance. This suggests that these directors play an advisory role in the Omani context. We found, however, that these directors play a monitoring role when firms take a loss. From these findings, we draw important implications for regulators who need to rethink the potential consequences of having overlapped AC chairs and AC directors. Our study focuses on Omani financial institutions, which are highly regulated and monitored by the central bank, and our findings may not be directly applicable to non-financial institutions that are less regulated, so caution is needed when interpreting the findings. Further research could employ a repeated measured research design, such as ours, and explore the same research question in non-financial institutions.

EP.TU.520ISC0Re Begins: An independent research group for junior doctors

Research is often a difficult component of training for many surgical trainees and junior medical officers (JMOs) wanting to apply for surgical training in Australia. In 2014, we established an independent research group called Institute of Surgical Collaboration for Research (ISCoRe) to develop a research culture amongst surgical trainees and junior medical officers (JMOs). The group was chaired by an unaccredited surgical registrar with a strong interest in surgical research and a general surgeon with a wealth of experience in presentations and publications in an advisory role. Being a small independent research group allows us to work very closely with JMOs and surgical trainees to identify their career interests, coming up with research topics and ideas and guiding the research group members through the process of data collection, analysis, writing up abstracts and submitting abstracts to conferences. We have had a good initial success with the research output from the group, with multiple research abstracts accepted and presented in various international conferences in our first two years of the formation of the group. However, being an independent group does have its disadvantages. The biggest challenges we face involve manpower and financial support. We are hopeful that by training up JMOs who have been with us for one or two years, they will in turn be able to help us guide new group members.

Following the science? Views from scientists on government advisory boards during the COVID-19 pandemic: a qualitative interview study in five European countries

IntroductionIn order to tackle the pandemic, governments have established various types of advisory boards to provide evidence and recommendations to policy makers. Scientists working on these boards have faced many challenges, including working under significant time constraints to produce ‘evidence’ as quickly as possible. However, their voices are still largely missing in the discussion. This study explores the views and experiences of scientists working on government advisory boards during the COVID-19 pandemic, with the aim to learn lessons for future pandemic management and preparedness.MethodsWe conducted online video or telephone semi-structured interviews between December 2020 and April 2021 with 21 scientists with an official government advisory role during the COVID-19 pandemic in Belgium, the Netherlands, UK, Sweden and Germany. The interviews were audio-recorded and transcribed and analysed using a combination of inductive and deductive thematic analysis techniques.ResultsScientists viewed the initial focus on biomedically oriented work during the pandemic as somewhat one-dimensional, but also highlighted difficulties of working in an interdisciplinary way. They found it difficult at times to ensure that the evidence is understood and taken on board by governments. They found themselves taking on new roles, the boundaries of which were not clearly defined. Consequently, they were often perceived and treated as a public figure.ConclusionScientists working on advisory boards in European countries faced similar challenges, highlighting key lessons to be learnt. Future pandemic preparedness efforts should focus on building interdisciplinary collaboration through development of scientists’ skills and appropriate infrastructure; ensuring transparency in how boards operate; defining and protecting the boundaries of the scientific advisor role; and supporting scientists to inform the public in the fight against disinformation, while dealing with potential hostile reactions.

Somalia’s peacekeeping transition faces dilemmas

Significance The report and the reactions to it have raised serious questions about the future of peacekeeping in Somalia. Impacts Peacekeepers playing a larger role in service delivery may disincentivise Somali authorities from taking responsibility for these tasks. New troop contributors could refresh AMISOM’s flagging fortunes, but would face a steep learning curve in a tough operating environment. External actors could play a vital advisory role in support of Somali efforts to overhaul the domestic security architecture.

Leasing as an Alternative Form of Financing within Family Businesses: The Important Advisory Role of the Accountant

Although leasing can be an interesting financing option from an economic point of view, family businesses are found to be less prone to lease. In this study, we examine the view of the external accountant on leasing as an alternative form of financing within family businesses. After all, as the most trusted advisor, the accountant likely has a significant influence on the financial decisions that are taken within private family businesses. By means of an exploratory qualitative study, we examine what factors influence the advice for a particular financing option and the accountant’s recommendation to lease or not to lease within family businesses. By combining the extant literature with the results of this exploratory qualitative research, we formulate propositions that form fruitful avenues for future research.