BACKGROUND. T cells expressing antigen-specific chimeric antigen receptors (CARs) improve outcomes for CD19-expressing B cell malignancies. We evaluated a human application of T cells that were genetically modified using the Sleeping Beauty (SB) transposon/transposase system to express a CD19-specific CAR. METHODS. T cells were genetically modified using DNA plasmids from the SB platform to stably express a second-generation CD19-specific CAR and selectively propagated ex vivo with activating and propagating cells (AaPCs) and cytokines. Twenty-six patients with advanced non-Hodgkin lymphoma and acute lymphoblastic leukemia safely underwent hematopoietic stem cell transplantation (HSCT) and infusion of CAR T cells as adjuvant therapy in the autologous (n = 7) or allogeneic settings (n = 19). RESULTS. SB-mediated genetic transposition and stimulation resulted in 2,200- to 2,500-fold ex vivo expansion of genetically modified T cells, with 84% CAR expression, and without integration hotspots. Following autologous HSCT, the 30-month progression-free and overall survivals were 83% and 100%, respectively. After allogeneic HSCT, the respective 12-month rates were 53% and 63%. No acute or late toxicities and no exacerbation of graft-versus-host disease were observed. Despite a low antigen burden and unsupportive recipient cytokine environment, CAR T cells persisted for an average of 201 days for autologous recipients and 51 days for allogeneic recipients. CONCLUSIONS. CD19-specific CAR T cells generated with SB and AaPC platforms were safe, and may provide additional cancer control as planned infusions after HSCT. These results support further clinical development of this nonviral gene therapy approach. TRIAL REGISTRATION. Autologous, NCT00968760; allogeneic, NCT01497184; long-term follow-up, NCT01492036. FUNDING. National Cancer Institute, private foundations, and institutional funds. Please see Acknowledgments for details.

Currently, surveillance strategies have inadequate performance for cirrhosis and early detection of hepatocellular carcinoma (HCC). The glycosylation of serum haptoglobin has shown to have significant differences between cirrhosis and HCC, thus can be used for diagnosis. We performed a comprehensive liquid chromatography—parallel reaction monitoring—mass spectrometry (LC-PRM-MS) approach, where a targeted parallel reaction monitoring (PRM) strategy was coupled to a powerful LC system, to study the site-specific isomerism of haptoglobin (Hp) extracted from cirrhosis and HCC patients. We found that our strategy was able to identify a large number of isomeric N-glycopeptides, mainly located in the Hp glycosylation site Asn207. Four N-glycopeptides were found to have significant changes in abundance between cirrhosis and HCC samples (p < 0.05). Strategic combinations of the significant N-glycopeptides, either with alpha-fetoprotein (AFP) or themselves, better estimate the areas under the curve (AUC) of their respective receiver operating characteristic (ROC) curves with respect to AFP. The combination of AFP with the isomeric sialylated fucosylated N-glycopeptides Asn207 + 5-6-1-2 and Asn207 + 5-6-1-3, resulted with an AUC value of 0.98, while the AUC value for AFP alone was 0.85. When comparing cirrhosis vs. early HCC, the isomeric N-glycopeptide Asn207 + 5-6-0-1 better estimated AUC with respect to AFP (AUC_AFP = 0.81, and AUC_Asn207 + 5-6-0-1 = 0.88, respectively).

The biomarkers alpha-fetoprotein (AFP) and protein induced by vitamin K absence/antagonist-II (PIVKA-II) may be useful for detecting early-stage hepatocellular carcinoma (HCC). We evaluated the performance of AFP and PIVKA-II levels, alone and in combination with clinical factors, for the early detection of HCC. In a case–control study, serum AFP and PIVKA-II were measured using the ARCHITECT immunoassay analyzer system in a cohort of 119 patients with HCC, 215 patients with non-malignant liver disease, and 34 healthy subjects. Five predictive models for detecting HCC were developed based on age, gender, AFP, and/or PIVKA-II levels; the best model was validated in an independent cohort of 416 patients with HCC and 412 control subjects with cirrhosis. In both cohorts, AFP and PIVKA-II concentrations were higher in patients with HCC compared to healthy controls and patients with non-malignant liver disease. The model that combined AFP and PIVKA-II, age, and gender had the highest AUC of 0.95 (0.95, 95% CI 0.93–0.98), with a sensitivity of 93% and a specificity of 84% in the development cohort, and an AUC of 0.87 (95% CI 0.85–0.90), sensitivity of 74%, and specificity of 85% in the validation cohort. When limiting the validation cohort to only early-stage HCC, the AUC was 0.85 (95% CI 0.81–0.88), sensitivity was 70%, and specificity was 86%. Compared to each biomarker alone, the combination of AFP and PIVKA-II with age and gender improved the accuracy of detecting HCC and differentiating HCC from non-malignant liver disease.

PURPOSE: In this study, we aimed to evaluate the association between the Extension for Community Healthcare Outcomes-Palliative Care (ECHO-PC; ECHO Model–Based comprehensive educational and telementoring intervention) for health care professionals (HCPs) and change in patient-reported quality-of-life (QOL; Functional Assessment of Cancer Therapy-General [FACT-G]) among patients with advanced cancer. We also examined the association between ECHO-PC and changes in symptom distress (Edmonton Symptom Assessment Scale [ESAS]), patient experience and satisfaction, and caregiver distress scores. METHODS: ECHO-PC Clinic sessions were conducted twice a month for 1 year by an interdisciplinary team of PC clinicians at the MD Anderson Cancer Center, with participation of experts in PC in sub-Saharan Africa, using standardized curriculum on the basis of PC needs in the region. Study participants included palliative HCPs from ECHO participating programs in Kenya, Nigeria, Ghana, and South Africa. HCPs, their patients, and caregivers were assessed at baseline, 3, 6, 9, and 12 months of the study for QOL (FACT-G), ESAS-Symptom Distress Score (prorated) (SDS), patient experience, satisfaction (FAMCARE-P-16-patient), and caregiver distress (FAMCARE-caregiver). RESULTS: Two hundred seventy patients completed the assessments. Fifty-eight percent was female, the mean age was 56 years, and most common cancer type was breast cancer (24.3%). Multivariate generalized linear mixed model analysis found that ECHO-PC intervention was associated with significant improvement in QOL and symptom distress (FACT-G total score, P = .0433; FACT-G physical well-being, P < .013; FACT-G emotional well-being, P = .0232, and ESAS-SDS, P < .0001). No significant changes were found in patient experience, satisfaction, and caregiver distress scores. CONCLUSION: Our preliminary study found that the ECHO-PC intervention was significantly associated with improvement in patient outcomes including QOL and symptom distress scores. Further studies are needed.