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

Dynamics of Dual Prism Adaptation: Relating Novel Experimental Results to a Minimalistic Neural Model

<div><p>In everyday life, humans interact with a dynamic environment often requiring rapid adaptation of visual perception and motor control. In particular, new visuo–motor mappings must be learned while old skills have to be kept, such that after adaptation, subjects may be able to quickly change between two different modes of generating movements (‘dual–adaptation’). A fundamental question is how the adaptation schedule determines the acquisition speed of new skills. Given a fixed number of movements in two different environments, will dual–adaptation be faster if switches (‘phase changes’) between the environments occur more frequently? We investigated the dynamics of dual–adaptation under different training schedules in a virtual pointing experiment. Surprisingly, we found that acquisition speed of dual visuo–motor mappings in a pointing task is largely independent of the number of phase changes. Next, we studied the neuronal mechanisms underlying this result and other key phenomena of dual–adaptation by relating model simulations to experimental data. We propose a simple and yet biologically plausible neural model consisting of a spatial mapping from an input layer to a pointing angle which is subjected to a global gain modulation. Adaptation is performed by reinforcement learning on the model parameters. Despite its simplicity, the model provides a unifying account for a broad range of experimental data: It quantitatively reproduced the learning rates in dual–adaptation experiments for both direct effect, i.e. adaptation to prisms, and aftereffect, i.e. behavior after removal of prisms, and their independence on the number of phase changes. Several other phenomena, e.g. initial pointing errors that are far smaller than the induced optical shift, were also captured. Moreover, the underlying mechanisms, a local adaptation of a spatial mapping and a global adaptation of a gain factor, explained asymmetric spatial transfer and generalization of prism adaptation, as observed in other experiments.</p></div

Virtual reality setup.

<p><b>A</b>) A Subject sees the VR screen via a mirror, and executes pointing movements with a manipulandum. A head post constrains head movements of the subject, while wearing shutter glasses for 3D perception. <b>B</b>) VR screen showing the virtual hand, the target, and the frame.</p