14 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
In vivo effects of tepoxalin, an inhibitor of cyclooxygenase and lipoxygenase, on prostanoid and leukotriene production in dogs with chronic osteoarthritis
Effects of zoledronate on markers of bone metabolism and subchondral bone mineral density in dogs with experimentally induced cruciate-deficient osteoarthritis
Exaggerated expression of skeletal muscle-derived interleukin-6, but not TNFα, in mice lacking interleukin-10
Antibodies to C1q in systemic lupus erythematosus: Characteristics and relation to FcγRIIA alleles
Cosmology Intertwined : A Review of the Particle Physics, Astrophysics, and Cosmology Associated with the Cosmological Tensions and Anomalies
Contribution to Snowmass 2021. 224 pages, 27 figures. Accepted for publication in JHEApPeer reviewe
Cosmology Intertwined: A Review of the Particle Physics, Astrophysics, and Cosmology Associated with the Cosmological Tensions and Anomalies
In this paper we will list a few important goals that need to be addressed in
the next decade, also taking into account the current discordances between the
different cosmological probes, such as the disagreement in the value of the
Hubble constant , the -- tension, and other less
statistically significant anomalies. While these discordances can still be in
part the result of systematic errors, their persistence after several years of
accurate analysis strongly hints at cracks in the standard cosmological
scenario and the necessity for new physics or generalisations beyond the
standard model. In this paper, we focus on the tension between
the {\it Planck} CMB estimate of the Hubble constant and the SH0ES
collaboration measurements. After showing the evaluations made from
different teams using different methods and geometric calibrations, we list a
few interesting new physics models that could alleviate this tension and
discuss how the next decade's experiments will be crucial. Moreover, we focus
on the tension of the {\it Planck} CMB data with weak lensing measurements and
redshift surveys, about the value of the matter energy density , and
the amplitude or rate of the growth of structure (). We
list a few interesting models proposed for alleviating this tension, and we
discuss the importance of trying to fit a full array of data with a single
model and not just one parameter at a time. Additionally, we present a wide
range of other less discussed anomalies at a statistical significance level
lower than the -- tensions which may also constitute hints towards
new physics, and we discuss possible generic theoretical approaches that can
collectively explain the non-standard nature of these signals.[Abridged]Comment: Contribution to Snowmass 2021. 224 pages, 27 figures. Accepted for
publication in JHEA
Cosmology intertwined: A review of the particle physics, astrophysics, and cosmology associated with the cosmological tensions and anomalies
The standard Λ Cold Dark Matter (ΛCDM) cosmological model provides a good description of a wide range of astrophysical and cosmological data. However, there are a few big open questions that make the standard model look like an approximation to a more realistic scenario yet to be found. In this paper, we list a few important goals that need to be addressed in the next decade, taking into account the current discordances between the different cosmological probes, such as the disagreement in the value of the Hubble constant H0, the σ8–S8 tension, and other less statistically significant anomalies. While these discordances can still be in part the result of systematic errors, their persistence after several years of accurate analysis strongly hints at cracks in the standard cosmological scenario and the necessity for new physics or generalisations beyond the standard model. In this paper, we focus on the 5.0σ tension between the Planck CMB estimate of the Hubble constant H0 and the SH0ES collaboration measurements. After showing the H0 evaluations made from different teams using different methods and geometric calibrations, we list a few interesting new physics models that could alleviate this tension and discuss how the next decade's experiments will be crucial. Moreover, we focus on the tension of the Planck CMB data with weak lensing measurements and redshift surveys, about the value of the matter energy density Ωm, and the amplitude or rate of the growth of structure (σ8,fσ8). We list a few interesting models proposed for alleviating this tension, and we discuss the importance of trying to fit a full array of data with a single model and not just one parameter at a time. Additionally, we present a wide range of other less discussed anomalies at a statistical significance level lower than the H0–S8 tensions which may also constitute hints towards new physics, and we discuss possible generic theoretical approaches that can collectively explain the non-standard nature of these signals. Finally, we give an overview of upgraded experiments and next-generation space missions and facilities on Earth that will be of crucial importance to address all these open questions