Citations

3023 Background: Axi-cel (formerly KTE-C19) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy. ZUMA-1 is a multicenter, registrational trial of axi-cel in patients (pts) with refractory aggressive non-Hodgkin lymphoma. In a prespecified interim analysis, ZUMA-1 met its primary endpoint, with a 76% objective response rate and a 47% complete response rate ( Blood 2016;128:LBA-6). Post-treatment CAR T cell blood levels were associated with objective response. Here, we describe novel associations between product characteristics and CAR T cell levels in pts. Methods: CAR T cell characteristics in axi-cel produced from 62 pts were analyzed by flow cytometry and modeled against CAR T cell levels. In vivo CAR T cell levels were measured by qPCR. T cell expansion during production (fold expansion/total days in culture) was compared with CAR T cell blood levels, using a partition analysis with expansion rates of ≥1 vs < 1. Wilcoxon 2-sample test and linear regression were used. Results: Axi-cel contained CCR7+ T cells (median, 42%; range, 15–73%), with naïve (CD45RA+/CCR7+; median, 12%; range, 1–57%), central memory (CD45RA−/CCR7+; median, 29%; range, 12–49%) phenotypes, and more differentiated CCR7− effector memory and effector T cells. On infusion, CAR T cells expanded rapidly, reaching peak levels within 2 weeks (median, 43 cells/μL; range, 1–1513), and were also measurable in all pts at 1 month (median, 2 cells/μL; range, 0.03–89). The CCR7+/CCR7− T cell ratio in axi-cel associated positively with peak ( P =0.001) and cumulative ( P =0.003) CAR T cell levels through 1 month. Axi-cel lots that expanded more rapidly during production (≥1.0-fold/d; n = 18/62) associated with higher cumulative levels of CAR T cells ( P =0.03). Other product characteristics, eg, CD4/CD8 ratio or number of infused T cells, were not significantly associated with CAR T cell blood levels. Conclusions: An association was observed between CAR T cell expansion in vivo and both the T cell growth rate during production and product cell phenotype pretreatment. A key attribute of axi-cel product was the presence of CCR7+ naïve/central memory T cells, without upfront T cell subset selection. Clinical trial information: NCT02348216.

Abstract Introduction: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 CAR T cell therapy approved by the US Food and Drug Administration for patients with relapsed or refractory large B cell lymphoma with ≥2 prior systemic therapies. Results from the primary analysis of ZUMA-1 demonstrated an objective response rate of 82%, with 54% complete responses (Neelapu & Locke et al. N Engl J Med. 2017). Grade ≥3 cytokine release syndrome and neurologic events occurred at 13% and 28%, respectively, and were generally reversible. Building on previous reports of CAR treatment-related tumor microenvironment (TME) changes (Galon et al. ASCO 2017. #3025), here, we examine associations between the pretreatment TME and clinical outcomes. Methods: Patients received axi-cel (target dose, 2.0 × 106 cells/kg) in phases 1 and 2 of ZUMA-1 (NCT02348216). Baseline tumor biopsy samples were analyzed by digital gene expression (NanoStringTM). Prespecified bioinformatics algorithm and cutoffs were applied to immune-mediated tumor regression genes (Immunosign®; Galon et al. Immunity. 2013), which included T cell-specific (effector T cell, Th1) genes, interferon pathway-related genes, chemokines, cytokines, and immune checkpoints. Expression analysis and scoring examined potential associations between TME features and response. A broader, hypothesis-generating analysis was performed using all PanCancer Immune Profiling Panel genes (770 genes) by NanoStringTM. Fisher's exact test and Wilcoxon signed rank test with multiple test correction by false discovery rate (Benjamini-Hochberg) were used. Results: Tumor samples from all immediate pre-treatment biopsy samples that passed quality control (6 nonresponders; 21 responders) were analyzed. Pretreatment TME Immunosign21 scores were elevated in responders vs nonresponders. Responses were seen in 18/20 patients (90%) with high and 3/7 patients (43%) with low Immunosign21 scores. Immune-related genes from the Immunosign21 or Pan Cancer profile that showed higher expression at baseline in responders included CTLA4, CD3γ, CD3ϵ, CD27, and ICOSL. Genes with lower expression in responders at baseline included MHC class II genes and cancer-testis antigens. Additional correlative analyses between TME characteristics and CAR T cell activity will be presented. Conclusions: Increased baseline expression of TME genes related to T cell activity, along with decreased expression of MHC class II and cancer testis antigens (CTAs), may be associated with a response to axi-cel. These findings should be validated in ongoing and subsequent studies. Citation Format: John M. Rossi, Jerome Galon, Sarah Turcan, Corinne Danan, Frederick L. Locke, Sattva S. Neelapu, David B. Miklos, Caron A. Jacobson, Lazaros J. Lekakis, Yi Lin, Armin Ghobadi, William Y. Go, Adrian Bot. Characteristics of the pretreatment tumor microenvironment may influence clinical response in patients with refractory large B cell lymphoma treated with axicabtagene ciloleucel (axi-cel) in the pivotal ZUMA-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-016.

Objectives: Dizziness, vertigo, and unsteadiness are common complaints of patients who present to primary care providers. These patients often are referred to otology for assessment and management. Unfortunately, there are a small number of specialists to manage these patients. However, there are several dizziness disorders that can be successfully managed by primary care providers if the disorder is properly identified. To assist in the identification of several of the most common dizziness disorders, we developed the dizziness symptom profile (DSP). The DSP is a self-report questionnaire designed to generate one or more differential diagnoses that can be combined with the patient’s case history and physical examination. Design: This report describes three investigations. Investigations 1 and 2 (i.e., exploratory and confirmatory investigations, N = 514) describe the development of the DSP. Investigation 3 (N = 195) is a validation study that describes the level of agreement between the DSP completed by the patient, and, the differential diagnosis of the otologist. Results: The final version of the DSP consists of 31 items. Preliminary findings suggest that the DSP is in agreement with the differential diagnoses of ear specialists for Meniere’s disease (100% agreement), vestibular migraine (95% agreement), and benign paroxysmal positional vertigo (82% agreement). Conclusions: Early results suggest that DSP may be useful in the creation of differential diagnoses for dizzy patients that can be evaluated and managed locally. This has the potential to reduce the burden on primary care providers and reduce delays in the diagnosis of common dizziness and vertigo disorders.

ObjectiveThe purpose of this study was to describe the variability and test–retest reliability of a commercially available subjective visual vertical (SVV) system known as Virtual SVV (Interacoustics). In addition, the study aimed to compare the reliability of the Virtual system with a previously established bucket test of SVV.Study DesignFifteen participants with normal hearing, normal middle ear function, and normal utricular function were included in the study. Each participant underwent static SVV testing using both the Virtual system and the bucket test. Subjects completed 2 testing sessions to determine test–retest reliability. For each test, data were collected with the head at 0°, tilted 45° to the right, and tilted 45° to the left.SettingThis study was conducted in a balance function laboratory embedded in a large, tertiary care otology clinic.ResultsThe mean SVV values obtained with the Virtual system were within 1°–2° from 0 with the head positioned at 0°, which is in agreement with many other studies of SVV with the head at 0° (Akin & Murnane, 2009; Halmagyi & Curthoys, 1999; Zwergal, Rettinger, Frenzel, Dieterich, & Strupp, 2009). Using the intraclass correlation coefficient, test–retest reliability of the Virtual system was excellent in the 45° left position and fair to good in the 45° right and 0° position. Test–retest reliability of the bucket test was poor in all head positions.ConclusionsThe Virtual system is a more reliable measure of static SVV than the bucket test. Therefore, the Virtual system could be utilized as a screening device for utricular dysfunction in busy clinical settings.

Background: Two-stage subpectoral implant-based breast reconstruction is the most common method for breast reconstruction. Recent advances in surgical techniques and technology have made prepectoral implant-based breast reconstruction feasible. There are limited data on outcomes after prepectoral implant-based breast reconstruction and postmastectomy radiation therapy. Methods: A retrospective review of consecutive patients undergoing immediate two-stage prepectoral implant-based breast reconstruction with postmastectomy radiation therapy was performed. Outcomes of irradiated breasts were compared with nonirradiated breasts in bilateral cases. Results: Ninety-three cases of prepectoral implant-based breast reconstruction in 54 women who underwent immediate two-stage reconstruction (39 bilateral and 15 unilateral) and unilateral postmastectomy radiation therapy were identified. Mean follow-up was 19 months from mastectomy and tissue expander reconstruction and 9 months from implant placement. Crude complication rates in irradiated versus nonirradiated sides were as follows: surgical-site infection, 18.5 percent versus 7.7 percent; seroma, 5.6 percent versus 5.1 percent; mastectomy skin flap necrosis, 1.9 percent versus 2.6 percent; wound dehiscence, 1.9 percent versus 7.7 percent; capsular contracture, 1.9 percent versus 0 percent; hematoma, 1.9 percent versus 2.6 percent; and extrusion, 1.9 percent versus 0 percent. On univariate analysis, there were no risk factors associated with any complication, including radiation therapy, surgical-site infection, unplanned readmissions, and unplanned return to the operating room. To date, reconstruction has been completed in 96 percent of patients, with successful implant-based breast reconstruction in 81 breasts (45 irradiated breasts and 36 nonirradiated breasts). Conclusions: Early data of prepectoral implant-based breast reconstruction in patients with postmastectomy radiation therapy show promising results. Postmastectomy radiation therapy should not be an absolute contraindication to prepectoral implant-based breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Objective To compare response rate and nonresponse bias across two mixed‐mode survey designs and two single‐mode designs. Data Sources This experiment was embedded in a clinician survey of knowledge and attitudes regarding HPV vaccination ( n = 275). Study Design Clinicians were randomly assigned one of two mixed‐mode (mail/web or web/mail) or single‐mode designs (mail‐only/web‐only). Differences in response rate and nonresponse bias were assessed. Principal Findings Using a multiple‐contact protocol increased response, and sending a web survey first provided the more rapid response. Overall, the mixed‐mode survey designs generated final response rates approximately 10 percentage points higher than their single‐mode counterparts, although only the final response differences between the mail‐only and web/mail conditions attained statistical significance (32.1 percent vs. 48 percent, respectively; p = .005). Observed differences did not result in nonresponse bias. Conclusions Results support mixing modes of survey administration and web‐based data collection in a multiple contact survey data collection protocol.

OBJECTIVE Intensive treatment (INT) of type 1 diabetes reduces the incidence of cardiovascular disease (CVD) events compared with conventional treatment (CONV), but it also results in more weight gain. Our objective was to examine whether excessive weight gain from INT of type 1 diabetes is independently associated with subsequent CVD events. RESEARCH DESIGN AND METHODS Quartiles (Q) of weight gain in 1,213 participants aged 18 years and older at enrollment in the Diabetes Control and Complications Trial (DCCT) were determined within randomized treatment groups (INT vs. CONV) using change in BMI from baseline to the closeout DCCT visits. Effects of this weight gain on CVD risk factors and outcomes during an additional 20 years of observational follow-up were then determined. RESULTS The Q4 INT group experienced greater proportional weight gain (median change in BMI, 6.08 kg/m2), increases in CVD risk factors, and need for medications for hypertension and lipids compared with the Q1–3 INT and comparable CONV groups. Over a mean of 26 years of follow-up, the numbers of major and total CVD events were not statistically different in Q4 compared with Q1–3 of either the INT or CONV group. By year 14, however, the incident CVD event curve became significantly higher in the Q4 INT group than in the Q1–3 INT groups (P = 0.024) and was similar to that for the CONV group. CONCLUSIONS For the first 13 years after DCCT, INT for type 1 diabetes reduced macrovascular events compared with CONV, even when excessive weight gain occurred. After this, total CVD events significantly increased in the Q4 INT group, becoming equivalent to those in the CONV group. Longer follow-up is needed to determine whether this trend continues and results in more major CVD events.