Dendritic cell (DC)-based vaccination effectively induces anti-tumor immunity, although in the majority of cases this does not translate into a durable clinical response.,However, DC vaccination is characterized by a robust safety profile, making this treatment a potential candidate for effective combination cancer immunotherapy.,To explore this possibility, understanding changes occurring in the tumor microenvironment (TME) upon DC vaccination is required.,In this line, quantitative and qualitative changes in tumor-infiltrating T lymphocytes (TILs) induced by vaccination with autologous tumor lysate/homogenate loaded DCs were investigated in a series of 16 patients with metastatic melanoma.,Immunohistochemistry for CD4, CD8, Foxp3, Granzyme B (GZMB), PDL1, and HLA class I was performed in tumor biopsies collected before and after DC vaccination.,The density of each marker was quantified by automated digital pathology analysis on whole slide images.,Co-expression of markers defining functional phenotypes, i.e., Foxp3+ regulatory CD4+ T cells (Treg) and GZMB+ cytotoxic CD8+ T cells, was assessed with sequential immunohistochemistry.,A significant increase of CD8+ TILs was found in post-vaccine biopsies of patients who were not previously treated with immune-modulating cytokines or Ipilimumab.,Interestingly, along with a maintained tumoral HLA class I expression, after DC vaccination we observed a significant increase of PDL1+ tumor cells, which significantly correlated with intratumoral CD8+ T cell density.,This observation might explain the lack of a significant concurrent cytotoxic reactivation of CD8+ T cell, as measured by the numbers of GZMB+ T cells.,Altogether these findings indicate that DC vaccination exerts an important role in sustaining or de novo inducing a T cell inflamed TME.,However, the strength of the intratumoral T cell activation detected in post-DC therapy lesions is lessened by an occurring phenomenon of adaptive immune resistance, yet the concomitant PDL1 up-regulation.,Overall, this study sheds light on DC immunotherapy-induced TME changes, lending the rationale for the design of smarter immune-combination therapies.
Preclinical studies suggest that BRAF inhibitors enhance anti-tumor immunity and antigen presentation.,Combination BRAF inhibition with immunotherapy is an appealing therapeutic approach.,We sequenced vemurafenib with HD IL-2 in patients with BRAF-mutated metastatic melanoma to improve long term outcomes.,Eligible patients were HD IL-2 eligible with metastatic BRAF V600 mutated melanoma.,Cohort 1 was treatment naïve and received vemurafenib 960 mg BID for 6 weeks before HD IL-2.,Cohort 2 received vemurafenib for 7-18 weeks before enrollment.,Both cohorts received HD IL-2 at 600,000 IU/kg every 8 h days 1-5 and days 15-19.,The primary objective was to assess complete responses (CR) at 10 weeks ±3 (assessment 1) and 26 weeks ±3 (assessment 2) from the start of HD IL-2.,Fifty-three patients were enrolled, (cohort 1, n = 38; cohort 2, n = 15).,Of these, 39 underwent assessment 1 and 15 assessment 2.,The CR rate at assessment 1 was 10% (95% CI 3-24) for both cohorts combined, and 27% (95% CI 8-55) at assessment 2.,Three-year survival was 30 and 27% for cohort 1 and cohort 2, respectively.,No unexpected toxicities occurred.,A shift in the melanoma treatment landscape during this trial adversely affected accrual, leading to early trial closure.,Vemurafenib in sequence with HD IL-2 did not change the known toxicity profile for either agent.,Lower than expected response rates to vemurafenib were observed.,Overall response rates and durability of responses appear similar to that observed with HD IL-2 alone.,NCTN, NCT01683188.,Registered 11 September 2012, http://www.clinicaltrials.gov/NCT01683188