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

Designing and Implementing a Variable Energy Neutron System to Search for Conventional Explosives.

Research was conducted to design an active neutron interrogation system to search for conventional explosives. The work began with a review of the current methods for explosives detection, with a particular focus on active neutron interrogation. The next step was to design a layered shield for an isotopic neutron generator that limited the influence of unattenuated neutrons at undesirable angles. The final shielding design was then adapted for neutron and gamma ray detector collimation in an active neutron interrogation system, and a modular shielding arrangement was proposed. Focus then shifted to improving the flexibility of the active neutron interrogation system via introduction of a method to reliably vary the energy from nearly monoenergetic sealed-tube deuterium-deuterium or deuterium-tritium neutron generators. This was accomplished through single neutron elastic scatter off a target of known composition, resulting in neutrons with predictable energies that can be adjusted through manipulation of the interrogation target location relative to the scatter target and neutron generator. This neutron elastic scatter system was optimized through the adoption of a neutron time-of-flight (TOF) method, where the hydrogen nuclei in the start detector (scatter target) also served as the scattering medium, signaling neutron scatter and allowing for discrimination of neutrons that did not interact in the scatter target. Laboratory measurements and simulations were performed to characterize the new variable energy neutron elastic scatter (VENES) system and evaluate its effectiveness in performing fast neutron resonance radiography. Preliminary investigations on the application of VENES to fast neutron analysis and neutron backscatter were also conducted to direct future work. There was a particular interest in combining all three active neutron interrogation methods with the VENES system and proposed shield designs, allowing for investigations across multiple different neutron energies in the MeV range. The VENES system permits for reliable alteration of neutron energy in active interrogation systems, using relatively cheap, portable, and easily operated components that are either currently, or soon-to-be, commercially available. The improvements on current active neutron interrogation sources should result in its eventual adoption to a variety of applications.PHDNuclear Engineering and Radiological SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/113596/1/zacwhets_1.pd