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

Őrszemnyirokcsomó-biopszia terhességi emlőrákban [Sentinel lymph node biopsy in pregnancy-associated breast cancer]

The incidence of pregnancy-associated breast cancer is rising. Sentinel lymph node biopsy is the method of choice in clinically node negative cases as the indicated minimally invasive regional staging procedure. Some reports have linked radioisotope and blue dye required for lymphatic mapping to teratogenic effects, the idea of which has become a generalized statement and, until recently, contraindication for these agents was considered during pregnancy. Today, there are many published reports of successful interventions with low-dose 99mTc-labeled human albumin nanocolloid, based on dosimetric modeling demonstrating a negligible radiation exposure of the fetus. These results contributed to the seemingly safe and successful use of sentinel lymph node biopsy during pregnancy, though generally it can not replace axillary lymphadenectomy in the absence of high-quality evidence. The possibility of sentinel lymph node biopsy should be offered to pregnancy-associated early breast cancer patients with clinically negative axilla, and patients should be involved in the decision making following extensive counselling. This paper presents the successful use of sentinel lymph node biopsy with low-dose tracer during two pregnancies (in the first and third trimesters) and, for the first time in Hungarian language, it offers a comprehensive literature review on this topic. Orv. Hetil., 154(50), 1991-1997