Perfusion imaging with arterial spin labeling (ASL)-MRI predicts malignant progression in low‑grade (WHO grade II) gliomas

PURPOSE: Predicting malignant progression of grade II gliomas would allow for earlier initiation of treatment. The hypothesis for this single-centre, case-control study was that the perfusion signal on ASL-MRI predicts such malignant progression in the following 12 months. METHODS: Consecutive patients with the following criteria were included: ≥ 18 years, grade II glioma (biopsied or resected) and an ASL-MRI 6-12 months prior to malignant progression (cases) or stable disease (controls). Malignant progression was defined either radiologically (new T1w-contrast enhancement) or histologically (neurosurgical tissue sampling). Three controls were matched with each case. Some patients served as their own control by using earlier imaging. The ASL-MRIs were reviewed by two neuroradiologists and classified as positive (hyper-intense or iso-intense compared to cortical grey matter) or negative (hypo-intense). In patients with epilepsy, a neurologist reviewed clinicoradiological data to exclude peri-ictal pseudoprogression. The statistical analysis included diagnostic test properties, a Cohen's Kappa interrater reliability coefficient and stratification for previous radiotherapy. RESULTS: Eleven cases (median age = 48, IQR = 43-50 years) and 33 controls (43, 27-50 years) were included. Malignant progression appeared at 37 months (median, IQR = 17-44) after first surgery. Thirty ASL-MRIs were assessed as negative and 14 as positive. None of the MRIs showed signs of peri-ictal pseudoprogression. ASL significantly predicted subsequent malignant progression (sensitivity = 73%; specificity = 82%; OR = 12; 95%-CI = 2.4-59.1; p = 0.002). The interrater reliability coefficient was 0.65. In stratified analysis, ASL-MRI predicted malignant progression both in patients with previous radiotherapy and in those without (Mantel-Haenszel test, p = 0.003). CONCLUSION: Perfusion imaging with ASL-MRI can predict malignant progression within 12 months in patients with grade II glioma

Conventional MRI Criteria to Differentiate Progressive Disease from Treatment-Induced Effects in High-Grade (WHO Grade 3-4) Gliomas

BACKGROUND AND OBJECTIVES: Posttreatment radiologic deterioration of an irradiated high-grade (WHO grade 3-4) glioma (HGG) may be the result of true progressive disease or treatment-induced effects (TIE). Differentiation between these entities is of great importance but remains a diagnostic challenge. This study assesses the diagnostic value of conventional MRI characteristics to differentiate progressive disease from TIE in HGGs. METHODS: In this single-center, retrospective, consecutive cohort study, we included adults with a HGG who were treated with (chemo-)radiotherapy and subsequently developed a new or increasing contrast-enhancing lesion on conventional follow-up MRI. TIE and progressive disease were defined radiologically as stable/decreased for ≥6 weeks or Response Assessment in Neuro-Oncology progression and histologically as TIE without viable tumor or progressive disease. Two neuroradiologists assessed 21 preselected MRI characteristics of the progressive lesions. The statistical analysis included logistic regression to develop a full multivariable model, a diagnostic model with model reduction, and a Cohen kappa interrater reliability (IRR) coefficient. RESULTS: A total of 210 patients (median age 61 years, interquartile range 54-68, 189 male) with 284 lesions were included, of whom 141 (50%) had progressive disease. Median time to progressive disease was 2 (0.7-6.1) and to TIE 0.9 (0.7-3.5) months after radiotherapy. After multivariable modeling and model reduction, the following determinants prevailed: radiation dose (odds ratio [OR] 0.68, 95% CI 0.49-0.93), longer time to progression (TTP; OR 3.56, 95% CI 1.84-6.88), marginal enhancement (OR 2.04, 95% CI 1.09-3.83), soap bubble enhancement (OR 2.63, 95% CI 1.39-4.98), and isointense apparent diffusion coefficient (ADC) signal (OR 2.11, 95% CI 1.05-4.24). ORs >1 indicate higher odds of progressive disease. The Hosmer & Lemeshow test showed good calibration ( p = 0.947) and the area under the receiver operating characteristic curve was 0.722 (95% CI 0.66-0.78). In the glioblastoma subgroup, TTP, marginal enhancement, and ADC signal were significant. IRR analysis between neuroradiologists revealed moderate to near perfect agreement for the predictive items but poor agreement for others. DISCUSSION: Several characteristics from conventional MRI are significant predictors for the discrimination between progressive disease and TIE. However, IRR was variable. Conventional MRI characteristics from this study should be incorporated into a multimodal diagnostic model with advanced imaging techniques. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with irradiated HGGs, radiation dose, longer TTP, marginal enhancement, soap bubble enhancement, and isointense ADC signal distinguish progressive disease from TIE

Cancer immunotherapy by nc410, a lair-2 fc protein blocking human lair-collagen interaction

Collagens are a primary component of the extracellular matrix and are functional ligands for the inhibitory immune receptor leukocyte-associated immunoglobulin-like receptor (LAIR)-1. LAIR-2 is a secreted protein that can act as a decoy receptor by binding collagen with higher affinity than LAIR-1. We propose that collagens promote immune evasion by interacting with LAIR-1 expressed on immune cells, and that LAIR-2 releases LAIR-1-mediated immune suppression. Analysis of public human datasets shows that collagens, LAIR-1 and LAIR-2 have unique and overlapping associations with survival in certain tumors. We designed a dimeric LAIR-2 with a functional IgG1 Fc tail, NC410, and showed that NC410 increases human T cell expansion and effector function in vivo in a mouse xenogeneic-graft versus-host disease model. In humanized mouse tumor models, NC410 reduces tumor growth that is dependent on T cells. Immunohistochemical analysis of human tumors shows that NC410 binds to collagen-rich areas where LAIR-1+ immune cells are localized. Our findings show that NC410 might be a novel strategy for cancer immunotherapy for immune-excluded tumors

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival