Hanna Kemeny

Novel role of hematopoietic stem cells in immunologic rejection of malignant gliomas.

Adoptive cellular therapy (ACT) after lymphodepletive conditioning can induce dramatic clinical responses, but this approach has been largely limited to melanoma due to a lack of reliable methods for expanding tumor-specific lymphocytes from the majority of other solid cancers. We have employed tumor RNA-pulsed dendritic cells (DCs) to reliably expand CD4+ and CD8+ tumor-reactive T lymphocytes for curative ACT in a highly-invasive, chemotherapy- and radiation-resistant malignant glioma model. Curative treatment of established intracranial tumors involved a synergistic interaction between myeloablative (MA) conditioning, adoptively transferred tumor-specific T cells, and tumor RNA-pulsed DC vaccines. Hematopoietic stem cells (HSCs), administered for salvage from MA conditioning, rapidly migrated to areas of intracranial tumor growth and facilitated the recruitment of tumor-specific lymphocytes through HSC-elaborated chemokines and enhanced immunologic rejection of intracranial tumors during ACT. Furthermore, HSC transplant under non-myeloablative (NMA) conditions also enhanced immunologic tumor rejection, indicating a novel role for the use of HSCs in the immunologic treatment of malignant gliomas and possibly other solid tumors.

T-Cell Exhaustion Signatures Vary with Tumor Type and Are Severe in Glioblastoma

Purpose: T-cell dysfunction is a hallmark of glioblastoma (GBM). Although anergy and tolerance have been well characterized, T-cell exhaustion remains relatively unexplored. Exhaustion, characterized in part by the upregulation of multiple immune checkpoints, is a known contributor to failures amid immune checkpoint blockade, a strategy that has lacked success thus far in GBM. This study is among the first to examine, and credential as bona fide, exhaustion among T cells infiltrating human and murine GBM. Experimental Design: Tumor-infiltrating and peripheral blood lymphocytes (TILs and PBLs) were isolated from patients with GBM. Levels of exhaustion-associated inhibitory receptors and poststimulation levels of the cytokines IFNγ, TNFα, and IL2 were assessed by flow cytometry. T-cell receptor Vβ chain expansion was also assessed in TILs and PBLs. Similar analysis was extended to TILs isolated from intracranial and subcutaneous immunocompetent murine models of glioma, breast, lung, and melanoma cancers. Results: Our data reveal that GBM elicits a particularly severe T-cell exhaustion signature among infiltrating T cells characterized by: (1) prominent upregulation of multiple immune checkpoints; (2) stereotyped T-cell transcriptional programs matching classical virus-induced exhaustion; and (3) notable T-cell hyporesponsiveness in tumor-specific T cells. Exhaustion signatures differ predictably with tumor identity, but remain stable across manipulated tumor locations. Conclusions: Distinct cancers possess similarly distinct mechanisms for exhausting T cells. The poor TIL function and severe exhaustion observed in GBM highlight the need to better understand this tumor-imposed mode of T-cell dysfunction in order to formulate effective immunotherapeutic strategies targeting GBM. Clin Cancer Res; 24(17); 4175–86. ©2018 AACR. See related commentary by Jackson and Lim, p. 4059

Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors

T cell dysfunction contributes to tumor immune escape in patients with cancer and is particularly severe amidst glioblastoma (GBM). Among other defects, T cell lymphopenia is characteristic, yet often attributed to treatment. We reveal that even treatment-naïve subjects and mice with GBM can harbor AIDS-level CD4 counts, as well as contracted, T cell–deficient lymphoid organs. Missing naïve T cells are instead found sequestered in large numbers in the bone marrow. This phenomenon characterizes not only GBM but a variety of other cancers, although only when tumors are introduced into the intracranial compartment. T cell sequestration is accompanied by tumor-imposed loss of S1P1 from the T cell surface and is reversible upon precluding S1P1 internalization. In murine models of GBM, hindering S1P1 internalization and reversing sequestration licenses T cell–activating therapies that were previously ineffective. Sequestration of T cells in bone marrow is therefore a tumor-adaptive mode of T cell dysfunction, whose reversal may constitute a promising immunotherapeutic adjunct.Patients with glioblastoma experience lymphopenia and sequestration of T cells in the bone marrow, which is recapitulated in mice with brain tumors, where the reversible nature of this effect is demonstrated by an approach that enables the efficacy of other immunotherapeutics.

Systemic activation of antigen-presenting cells via RNA-loaded nanoparticles

ABSTRACT While RNA-pulsed dendritic cell (DC) vaccines have shown promise, the advancement of cellular therapeutics is fraught with developmental challenges. To circumvent the challenges of cellular immunotherapeutics, we developed clinically translatable nanoliposomes that can be combined with tumor-derived RNA to generate personalized tumor RNA-nanoparticles (NPs) with considerable scale-up capacity. RNA-NPs bypass MHC restriction, are amenable to central distribution, and can provide near immediate immune induction. We screened commercially available nanoliposomal preparations and identified the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) as an efficient mRNA courier to antigen-presenting cells (APCs). When administered intravenously, RNA-NPs mediate systemic activation of APCs in reticuloendothelial organs such as the spleen, liver, and bone marrow. RNA-NPs increase percent expression of MHC class I/II, B7 co-stimulatory molecules, and maturation markers on APCs (all vital for T-cell activation). RNA-NPs also increase activation markers on tumor APCs and elicit potent expansion of antigen-specific T-cells superior to peptide vaccines formulated in complete Freunds adjuvant. We demonstrate that both model antigen-encoding and physiologically-relevant tumor-derived RNA-NPs expand potent antitumor T-cell immunity. RNA-NPs were shown to induce antitumor efficacy in a vaccine model and functioned as a suitable alternative to DCs in a stringent cellular immunotherapy model for a radiation/temozolomide resistant invasive murine high-grade glioma. Although cancer vaccines have suffered from weak immunogenicity, we have advanced a RNA-NP formulation that systemically activates host APCs precipitating activated T-cell frequencies necessary to engender antitumor efficacy. RNA-NPs can thus be harnessed as a more feasible and effective immunotherapy to re-program host-immunity.

Prevalence and Cost Analysis of Complex Regional Pain Syndrome (CRPS): A Role for Neuromodulation

The diagnosis and treatment of complex regional pain syndrome (CRPS) is challenging and there is a paucity of data describing its overall cost burden and quantifying its impact on the US healthcare system. The aim of this study was to assess the prevalence and healthcare utilization costs associated with CRPS.

Prevalence and Cost Analysis of Chronic Pain After Hernia Repair: A Potential Alternative Approach With Neurostimulation: PAIN AFTER HERNIA REPAIR: A POTENTIAL WITH NEUROSTIMULATION

Chronic pain (CP) affects a significant number of patients following hernia repair, ranging from 11 to 54% in the literature. The aim of this study was to assess the prevalence, overall costs, and health care utilization associated with CP after hernia repair.

Influence of racial disparities on patient-reported satisfaction and short- and long-term perception of health status after elective lumbar spine surgery

OBJECTIVE In spine surgery, racial disparities have been shown to impact various aspects of surgical care. Previous studies have associated racial disparities with inferior surgical outcomes, including increased complication and 30-day readmission rates after spine surgery. Recently, patient-reported outcomes (PROs) and satisfaction measures have been proxies for overall quality of care and hospital reimbursements. However, the influence that racial disparities have on short- and long-term PROs and patient satisfaction after spine surgery is relatively unknown. The aim of this study was to investigate the impact of racial disparities on 3- and 12-month PROs and patient satisfaction after elective lumbar spine surgery. METHODS This study was designed as a retrospective analysis of a prospectively maintained database. The medical records of adult (age ≥ 18 years) patients who had undergone elective lumbar spine surgery for spondylolisthesis (grade 1), disc herniation, or stenosis at a major academic institution were included in this study. Patient demographics, comorbidities, postoperative complications, and 30-day readmission rates were collected. Patients had prospectively collected outcome and satisfaction measures. Patient-reported outcome instruments-Oswestry Disability Index (ODI), visual analog scale for back pain (VAS-BP), and VAS for leg pain (VAS-LP)-were completed before surgery and at 3 and 12 months after surgery, as were patient satisfaction measures. RESULTS The authors identified 345 medical records for 53 (15.4%) African American (AA) patients and 292 (84.6%) white patients. Baseline patient demographics and comorbidities were similar between the two cohorts, with AA patients having a greater body mass index (33.1 ± 6.6 vs 30.2 ± 6.4 kg/m2, p = 0.005) and a higher prevalence of diabetes (35.9% vs 16.1%, p = 0.0008). Surgical indications, operative variables, and postoperative variables were similar between the cohorts. Baseline and follow-up PRO measures were worse in the AA cohort, with patients having a greater baseline ODI (p < 0.0001), VAS-BP score (p = 0.0002), and VAS-LP score (p = 0.0007). However, mean changes from baseline to 3- and 12-month PROs were similar between the cohorts for all measures except the 3-month VAS-BP score (p = 0.046). Patient-reported satisfaction measures at 3 and 12 months demonstrated a significantly lower proportion of AA patients stating that surgery met their expectations (3 months: 47.2% vs 65.5%, p = 0.01; 12 months: 35.7% vs 62.7%, p = 0.007). CONCLUSIONS The study data suggest that there is a significant difference in the perception of health, pain, and disability between AA and white patients at baseline and short- and long-term follow-ups, which may influence overall patient satisfaction. Further research is necessary to identify patient-specific factors associated with racial disparities that may be influencing outcomes to adequately measure and assess overall PROs and satisfaction after elective lumbar spine surgery.