Dendritic cells (DCs) occupy a privileged position at the interface between innate and adaptive immunity, orchestrating a large panel of responses to both physiological and pathological cues. In particular, whereas the presentation of antigens by immature DCs generally results in the development of immunological tolerance, mature DCs are capable of priming robust, and hence therapeutically relevant, adaptive immune responses. In line with this notion, functional defects in the DC compartment have been shown to etiologically contribute to pathological conditions including (but perhaps not limited to) infectious diseases, allergic and autoimmune disorders, graft rejection and cancer. Thus, the possibility of harnessing the elevated immunological potential of DCs for anticancer therapy has attracted considerable interest from both researchers and clinicians over the last decade. Alongside, several methods have been developed not only to isolate DCs from cancer patients, expand them, load them with tumor-associated antigens and hence generate highly immunogenic clinical grade infusion products, but also to directly target DCs in vivo. This intense experimental effort has culminated in 2010 with the approval by the US FDA of a DC-based preparation (sipuleucel-T, Provenge®) for the treatment of asymptomatic or minimally symptomatic metastatic castration-refractory prostate cancer. As an update to the latest Trial Watch dealing with this exciting field of research (October 2012), here we summarize recent advances in DC-based anticancer regimens, covering both high-impact studies that have been published during the last 13 mo and clinical trials that have been launched in the same period to assess the antineoplastic potential of this variant of cellular immunotherapy.

https://www.tandfonline.com/doi/pdf/10.4161/onci.25771

Trial watch: Dendritic cell-based interventions for cancer therapy.

NK cells are emerging as new effectors for immunotherapy of cancer. In particular, the genetic engraftment of chimeric Ag receptors (CARs) in NK cells is a promising strategy to redirect NK cells to otherwise NK cell-resistant tumor cells. On the basis of DNAX-activation protein 12 (DAP12), a signaling adaptor molecule involved in signal transduction of activating NK cell receptors, we generated a new type of CAR targeting the prostate stem cell Ag (PSCA). We demonstrate in this article that this CAR, designated anti-PSCA-DAP12, consisting of DAP12 fused to the anti-PSCA single-chain Ab fragment scFv(AM1) confers improved cytotoxicity to the NK cell line YTS against PSCA-positive tumor cells when compared with a CAR containing the CD3ζ signaling chain. Further analyses revealed phosphorylation of the DAP12-associated ZAP-70 kinase and IFN-γ release of CAR-engineered cells after contact with PSCA-positive target cells. YTS cells modified with DAP12 alone or with a CAR bearing a phosphorylation-defective ITAM were not activated. Notably, infused YTS cells armed with anti-PSCA-DAP12 caused delayed tumor xenograft growth and resulted in complete tumor eradication in a significant fraction of treated mice. The feasibility of the DAP12-based CAR was further tested in human primary NK cells and confers specific cytotoxicity against KIR/HLA-matched PSCA-positive tumor cells, which was further enhanced by KIR-HLA mismatches. We conclude that NK cells engineered with DAP12-based CARs are a promising tool for adoptive tumor immunotherapy.

/pdf/dap12-based-activating-chimeric-antigen-receptor-for-nk-cell-1ygqi8foe2.pdf

DAP12-Based Activating Chimeric Antigen Receptor for NK Cell Tumor Immunotherapy

Purpose: Identification of novel biomarkers and immunotherapy targets for prostate cancer (PCa) is crucial to better diagnosis and therapy. We sought to identify novel PCa tumor-associated antigens (TAA) that are expressed in PCa, absent in nonprostate human tissue, and immunogenic for immune responses restricted by human HLA. Experimental Design and Results: Using microarray analysis of normal and cancerous human prostate tissues, we identified 1,063 genes overexpressed in PCa. After validating 195 transcripts in publicly available array data sets, we interrogated expression of these TAAs in normal human tissues to identify genes that are not expressed at detectable levels in normal, nonprostate adult human tissue. We identified 23 PCa TAA candidates. Real-time PCR confirmed that 15 of these genes were overexpressed in PCa ( P single-minded homologue 2 ( SIM2 ), was selected for further evaluation as a potential target for immunotherapy. ELISA assay revealed that a fraction of PCa patients exhibited immune responsiveness to SIM2 as evidenced by the presence of autoantibodies to SIM2 in their sera. We next showed binding of putative HLA-A2.1–restricted SIM2 epitopes to human A2.1, and immunization of transgenic HLA-A2.1 mice showed induction of SIM2-specific CTL responses in vivo . Conclusions: Our findings that SIM2 is selectively expressed in PCa, that human HLA-A2.1–restricted SIM2 epitopes induce specific T cells in vivo , and that anti-SIM2 antibodies are detectable in PCa patients9 sera implicate SIM2 as a PCa-associated antigen that is a suitable potential target for PCa immunotherapy. (Clin Cancer Res 2009;15(18):5794–802)

https://clincancerres.aacrjournals.org/content/clincanres/15/18/5794.full.pdf

Identification of the Transcription Factor Single-Minded Homologue 2 as a Potential Biomarker and Immunotherapy Target in Prostate Cancer

Synthetic peptide vaccines aiming at the induction of a protective CD8+ T-cell response against infectious or malignant diseases are widely used in the clinic but, despite their success in animal models, they do not yet live up to their promise in humans. This review assesses the development of synthetic peptide vaccines, weighs it against the immunological concepts that have emerged, and identifies the key issues that play a role in the failure or success of a synthetic peptide vaccine. The current state-of-the-art peptide vaccine is a complete synthetic inflammatory product that is ingested by professional antigen-presenting cells and stimulates both CD4+ and CD8+ T cells.

Design and development of synthetic peptide vaccines: past, present and future.

Among currently available vaccine strategies for cancer, nucleotide-based vaccination is an appealing treatment modality. Curevacs' mRNA containing vaccines (RNActive®) combine the beneficial properties of sufficient antigen-expression, autologous immune-stimulation and a high flexibility with respect to production and application. CV9103 and CV9104 are novel RNActive®-derived anticancer vaccines for the treatment of patients with prostate cancer. After successful phase I/II studies with documentation of good tolerability and favorable immune-activation of CV9103, the vaccine CV9104 is currently undergoing clinical testing in specific clinical settings such as castration resistant prostate cancer and as a neoadjuvant agent in men with high risk prostate cancer prior to surgery. This review discusses the available preclinical and clinical data on the anticancer vaccination treatment with RNActive®-derived anticancer-vaccines CV9103 and CV9104.

https://www.tandfonline.com/doi/pdf/10.4161/hv.29553

mRNA vaccine CV9103 and CV9104 for the treatment of prostate cancer

Background: Dendritic cell (DC)-based immunotherapy is a promising approach to augment tumor antigen-specific T cell responses in cancer patients. However, tumor escape with down-regulation or complete loss of target antigens may limit the susceptibility of tumor cells to the immune attack. Concomitant generation of T cell responses against several immunodominant antigens may circumvent this potential drawback. In this trial, we determined the immunostimulatory capacity of autologous DC pulsed with multiple T cell epitopes derived from four different prostate-specific antigens in patients with advanced hormone-refractory prostate cancer. Patients and methods: Autologous DC of HLA-A*0201+ patients with hormone-refractory prostate cancer were loaded with antigenic peptides derived from prostate stem cell antigen (PSCA14–22), prostatic acid phosphatase (PAP299–307), prostate-specific membrane antigen (PSMA4–12), and prostate-specific antigen (PSA154–163). DC were intradermally applied six times at biweekly intervals followed—in the case of an enhanced immune response—by monthly booster injections. Immune monitoring during the time of ongoing vaccinations (12–59 weeks) included ex vivo ELISPOT measurements, MHC tetramer analysis and in vitro cytotoxicity assays. Results: Of the initial six patients, three qualified for long-term multi-epitope DC vaccination. This regime was tolerated well by all three patients. The vaccination elicited significant cytotoxic T cell responses against all prostate-specific antigens tested. In addition, memory T cell responses against the control peptides derived from influenza matrix protein and tetanus toxoid were efficiently boosted. Clinically, the long-term DC vaccination was associated with an increase in PSA doubling time. Conclusions: DC-based multi-epitope immunotherapy with repeated boosting in men with hormone-refractory prostate carcinoma is feasible and generates efficient cellular antitumor responses.

/pdf/dendritic-cell-based-multi-epitope-immunotherapy-of-hormone-4nhtbryf82.pdf

Dendritic cell-based multi-epitope immunotherapy of hormone-refractory prostate carcinoma

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Dendritic cell-based multi-epitope immunotherapy of hormone-refractory prostate carcinoma