22 research outputs found
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
Cellular and genomic disease signature of peripheral blood mononuclear cells in patients with malignant pleural mesothelioma
Background: Recent data on the incidence malignant pleural mesothelioma
(MPM) and the continued large-scale use of asbestos throughout the
developing world portends an epidemic of asbestos-related disease. MPM is
an aggressive and fatal cancer with few treatment options. Recent advances
in large scale genomic and high throughput cellular analyses now provide
the tools to more easily attain markers of disease status and potential
responsiveness to immunotherapeutics.
Materials and Methods: Here we present pre-treatment cellular and genomic
biomarker data on a cohort of chemotherapy-naïve MPM patients, and
demographically matched healthy donors (HD). MPM patients were enrolled in
a Phase 1b study utilizing CRS-207, a live, attenuated Listeria monocytogenes
strain engineered to express the tumor-associated antigen, mesothelin. Four
different multi-color flow cytometry panels were used to provide resolution on
major immune cell populations of T cells, γδ T cells, B Cells, dendritic cells,
monocytes, and natural killer cells. Together, these panels provided deeper
resolution on 39 distinct subpopulations of major immune cell subsets. RNA
from these cells was used to perform multiplex gene expression analysis on
770 genes using the Nanostring nCounter PanCancer Pathway Panel.
Results: FACS analysis yielded numerous subpopulations with statistically
significant differences between MPM patients and healthy controls. Differences
in immune populations were analyzed by median and significant findings
included populations of CD4+ T cells, CD8+ T cells, B cells, classical
monocytes, and monocytic myeloid derived suppressor cells*. Class
comparison and hierarchical clustering of gene expression data revealed
genomic markers that were significantly expressed in MPM compared to
healthy controls. Immune subset deconvolution of gene expression data
provided similar findings as FACS analysis and corroborated this disease
signature across experimental platforms.
Conclusions: Understanding a patient’s biological disease signature can
aide in diagnosis, as well as in making informed choices about therapies
amidst the complex and broadening immunotherapeutic landscape. Until
recently, existing biomarker data in MPM has been limited to a small number
of serological markers and limited immune analysis. Here, we present the
first comprehensive report of a MPM disease signature from the cellular and
genomic perspectives. Correlation of patient baseline disease signatures
with treatment outcome may yield biomarkers predictive of treatment
efficacy. Predictive signatures are being investigated in the on-going Phase
1b study of CRS-207 and chemotherapy, as well as in the Phase 2 study of
CRS-207 with pembrolizumab in MPM patients who failed prior treatment.
*Inclusion of additional subjects confirmed the significance of all immune cell subsets
except for MDSCs
Peripheral Blood Leukocyte Production of BDNF following Mitogen Stimulation in Early Onset and Regressive Autism
Differential monocyte responses to TLR ligands in children with autism spectrum disorders
Morphoelectric and transcriptomic divergence of the layer 1 interneuron repertoire in human versus mouse neocortex
Neocortical layer 1 (L1) is a site of convergence between pyramidal-neuron dendrites and feedback axons where local inhibitory signaling can profoundly shape cortical processing. Evolutionary expansion of human neocortex is marked by distinctive pyramidal neurons with extensive L1 branching, but whether L1 interneurons are similarly diverse is underexplored. Using Patch-seq recordings from human neurosurgical tissue, we identified four transcriptomic subclasses with mouse L1 homologs, along with distinct subtypes and types unmatched in mouse L1. Subclass and subtype comparisons showed stronger transcriptomic differences in human L1 and were correlated with strong morphoelectric variability along dimensions distinct from mouse L1 variability. Accompanied by greater layer thickness and other cytoarchitecture changes, these findings suggest that L1 has diverged in evolution, reflecting the demands of regulating the expanded human neocortical circuit
CRS-207 immunotherapy expressing mesothelin, combined with chemotherapy as treatment for malignant pleural mesothelioma (MPM).
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Results from a Phase IIb, Randomized, Multicenter Study of GVAX Pancreas and CRS-207 Compared with Chemotherapy in Adults with Previously Treated Metastatic Pancreatic Adenocarcinoma (ECLIPSE Study).
PURPOSE: Limited options exist for patients with advanced pancreatic cancer progressing after 1 or more lines of therapy. A phase II study in patients with previously treated metastatic pancreatic cancer showed that combining GVAX pancreas (granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated
PATIENTS AND METHODS: Patients with previously treated metastatic pancreatic adenocarcinoma were randomized 1:1:1 to receive Cy/GVAX + CRS-207 (arm A), CRS-207 (arm B), or physician\u27s choice of single-agent chemotherapy (arm C). The primary cohort included patients who had failed ≥2 prior lines of therapy, including gemcitabine. The primary objective compared OS between arms A and C in the primary cohort. The second-line cohort included patients who had received 1 prior line of therapy. Additional objectives included OS between all treatment arms, safety, and tumor responses.
RESULTS: The study did not meet its primary efficacy endpoint. At the final study analysis, median OS [95% confidence interval (CI)] in the primary cohort (
CONCLUSIONS: The combination of Cy/GVAX + CRS-207 did not improve survival over chemotherapy. (ClinicalTrials.gov ID: NCT02004262