Final results regarding the addition of dendritic cell vaccines to neoadjuvant chemotherapy in early HER2-negative breast cancer patients: clinical and translational analysis

Background: Primary breast cancer (BC) has shown a higher immune infiltration than the metastatic disease, justifying the optimal scenario for immunotherapy. Recently, neoadjuvant chemotherapy (NAC) combined with immune checkpoint inhibitors has demonstrated a gain in pathological complete responses (tpCR) in patients with BC. The aim of our study is to evaluate the safety, feasibility, and efficacy of the addition of dendritic cell vaccines (DCV) to NAC in HER2-negative BC patients. Methods: Thirty-nine patients with early BC received DCV together with NAC conforming the vaccinated group (VG) and compared with 44 patients as the control group (CG). All patients received anthracyclines and taxanes-based NAC (ddECx4→Dx4) followed by surgery ± radiotherapy ± hormonotherapy. Results: The tpCR rate was 28.9% in the VG and 9.09% in the CG (p=0.03). Pathological CR in the triple negative (TN) BC were 50.0% versus 30.7% (p=0.25), 16.6% versus 0% in luminal B (p=0.15), and none among luminal A patients in VG versus CG, respectively. Impact of DCV was significantly higher in the programmed cell death ligand 1 (PD-L1) negative population (p<0.001). PD-L1 expression was increased in patients with residual disease in the VG as compared with the CG (p<0.01). No grade ⩾3 vaccine-related adverse events occurred. With a median follow-up of 8years, no changes were seen in event-free survival or overall survival. Phenotypic changes post DCV in peripheral blood were observed in myeloid-derived suppressor cells (MDSC), NK, and T cells. Increase in blood cell proliferation and interferon (IFN)-γ production was detected in 69% and 74% in the VG, respectively. Humoral response was also found. Clonality changes in TCR-β repertoire were detected in 67% of the patients with a drop in diversity index after treatment. Conclusion: The combination of DCV plus NAC is safe and increases tpCR, with a significant benefit among PD-L1-negative tumors. DCV modify tumor milieu and perform cellular and humoral responses in peripheral blood with no impact in outcome. Trial registration: ClinicalTrials.gov number: NCT01431196. EudraCT 2009-017402-36

CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome

Identification of new markers associated with long-term efficacy in patients treated with CAR T cells is a current medical need, particularly in diseases such as multiple myeloma. In this study, we address the impact of CAR density on the functionality of BCMA CAR T cells. Functional and transcriptional studies demonstrate that CAR T cells with high expression of the CAR construct show an increased tonic signaling with up-regulation of exhaustion markers and increased in vitro cytotoxicity but a decrease in in vivo BM infiltration. Characterization of gene regulatory networks using scRNA-seq identified regulons associated to activation and exhaustion up-regulated in CARHigh T cells, providing mechanistic insights behind differential functionality of these cells. Last, we demonstrate that patients treated with CAR T cell products enriched in CARHigh T cells show a significantly worse clinical response in several hematological malignancies. In summary, our work demonstrates that CAR density plays an important role in CAR T activity with notable impact on clinical response

Modification of Breast Cancer Milieu with Chemotherapy plus Dendritic Cell Vaccine: An Approach to Select Best Therapeutic Strategies

Background: The addition of dendritic cell vaccines (DCV) to NAC could induce immune responses in those patients with residual disease (RD) by transforming the tumor microenvironment. Methods: Core diagnostic biopsies and surgical specimens from 80 patients (38 in the vaccinated group plus NAC (VG) and 42 in the control group (CG, treated only with NAC) were selected. We quantify TILs (CD8, CD4 and CD45RO) using immunohistochemistry and the automated cellular imaging system (ACIS III) in paired samples. Results: A CD8 rise in TNBC samples was observed after NAC plus DCV, changing from 4.48% in the biopsy to 6.70% in the surgical specimen, not reaching statistically significant differences (p = 0.11). This enrichment was seen in up to 67% of TNBC patients in the experimental arm as compared with the CG (20%). An association between CD8 TILs before NAC (4% cut-off point) and pathological complete response in the VG was found in the univariate and multivariate analysis (OR = 1.41, IC95% 1.05&ndash;1.90; p = 0.02, and OR = 2.0, IC95% 1.05&ndash;3.9; p = 0.03, respectively). Conclusion: Our findings suggest that patients with TNBC could benefit from the stimulation of the antitumor immune system by using DCV together with NAC

Additional file 1: Figures S1-S4. of Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft-versus-host disease development

Figure S1. Effect of BKM120 and BEZ235 on the percentage of central memory, effector memory, and effector/TEMRA T cells. Percentage of central memory, effector memory and effector/TEMRA cells among CD4+ and CD8+ cells unstimulated or stimulated in the presence of different concentrations of BKM120 or BEZ235. Mean ± SEM of five different experiments. # p < 0.05 with respect to stimulated untreated samples (0 μM). Figure S2. Effect of BKM120 and BEZ235 on the phenotype of different CD4+ T cell maturation subsets. Percentage of cells expressing CD25, IFN-γ, and granzyme B among different CD4+ T cell maturation subsets, in samples unstimulated or stimulated in the presence of different concentrations of BKM120 or BEZ235. Mean + SD of five different experiments. # p < 0.05 with respect to stimulated untreated samples (0 μM). Figure S3. Effect of BKM120 and BEZ235 on the phenotype of different CD8+ T cell maturation subsets. Percentage of cells expressing CD25, IFN-γ, and granzyme B among different CD8+ T cell maturation subsets, in samples unstimulated or stimulated in the presence of different concentrations of BKM120 or BEZ235. Mean + SD of five different experiments. # p < 0.05 with respect to stimulated untreated samples (0 μM). Figure S4. Effect of BKM120 and BEZ235 on granzyme B expression by effector/TEMRA T cells. Median fluorescence intensity (MFI) of granzyme B among effector/TEMRA CD4+ and CD8+ T cells unstimulated or stimulated in the presence of different concentrations of BKM120 or BEZ235. Mean + SD of four different experiments. # p < 0.05 with respect to stimulated untreated samples (0 μM). (PDF 334 kb

Tolerogenic dendritic cell-based treatment for multiple sclerosis (MS): a harmonised study protocol for two phase I clinical trials comparing intradermal and intranodal cell administration

INTRODUCTION: Based on the advances in the treatment of multiple sclerosis (MS), currently available disease-modifying treatments (DMT) have positively influenced the disease course of MS. However, the efficacy of DMT is highly variable and increasing treatment efficacy comes with a more severe risk profile. Hence, the unmet need for safer and more selective treatments remains. Specifically restoring immune tolerance towards myelin antigens may provide an attractive alternative. In this respect, antigen-specific tolerisation with autologous tolerogenic dendritic cells (tolDC) is a promising approach. METHODS AND ANALYSIS: Here, we will evaluate the clinical use of tolDC in a well-defined population of MS patients in two phase I clinical trials. In doing so, we aim to compare two ways of tolDC administration, namely intradermal and intranodal. The cells will be injected at consecutive intervals in three cohorts receiving incremental doses of tolDC, according to a best-of-five design. The primary objective is to assess the safety and feasibility of tolDC administration. For safety, the number of adverse events including MRI and clinical outcomes will be assessed. For feasibility, successful production of tolDC will be determined. Secondary endpoints include clinical and MRI outcome measures. The patients' immune profile will be assessed to find presumptive evidence for a tolerogenic effect in vivo. ETHICS AND DISSEMINATION: Ethics approval was obtained for the two phase I clinical trials. The results of the trials will be disseminated in a peer-reviewed journal, at scientific conferences and to patient associations. TRIAL REGISTRATION NUMBERS: NCT02618902 and NCT02903537; EudraCT numbers: 2015-002975-16 and 2015-003541-26