Dendritic Cell Cancer Vaccines: From the Bench to the Bedside

The recognition that the development of cancer is associated with acquired immunodeficiency, mostly against cancer cells themselves, and understanding pathways inducing this immunosuppression, has led to a tremendous development of new immunological approaches, both vaccines and drugs, which overcome this inhibition. Both “passive” (e.g. strategies relying on the administration of specific T cells) and “active” vaccines (e.g. peptide-directed or whole-cell vaccines) have become attractive immunological approaches, inducing cell death by targeting tumor-associated antigens. Whereas peptide-targeted vaccines are usually directed against a single antigen, whole-cell vaccines (e.g. dendritic cell vaccines) are aimed to induce robust responsiveness by targeting several tumor-related antigens simultaneously. The combination of vaccines with new immuno-stimulating agents which target “immunosuppressive checkpoints” (anti-CTLA-4, PD-1, etc.) is likely to improve and maintain immune response induced by vaccination

MUC1-C drives myeloid leukaemogenesis and resistance to treatment by a survivin-mediated mechanism

Acute myeloid leukaemia (AML) is an aggressive haematological malignancy with an unmet need for improved therapies. Responses to standard cytotoxic therapy in AML are often transient because of the emergence of chemotherapy-resistant disease. The MUC1-C oncoprotein governs critical pathways of tumorigenesis, including self-renewal and survival, and is aberrantly expressed in AML blasts and leukaemia stem cells (LSCs). However, a role for MUC1-C in linking leukaemogenesis and resistance to treatment has not been described. In this study, we demonstrate that MUC1-C overexpression is associated with increased leukaemia initiating capacity in an NSG mouse model. In concert with those results, MUC1-C silencing in multiple AML cell lines significantly reduced the establishment of AML in vivo. In addition, targeting MUC1-C with silencing or pharmacologic inhibition with GO-203 led to a decrease in active β-catenin levels and, in-turn, down-regulation of survivin, a critical mediator of leukaemia cell survival. Targeting MUC1-C was also associated with increased sensitivity of AML cells to Cytarabine (Ara-C) treatment by a survivin-dependent mechanism. Notably, low MUC1 and survivin gene expression were associated with better clinical outcomes in patients with AML. These findings emphasize the importance of MUC1-C to myeloid leukaemogenesis and resistance to treatment by driving survivin expression. Our findings also highlight the potential translational relevance of combining GO-203 with Ara-C for the treatment of patients with AML

The Medical Research Council Myeloma IX trial: the impact on treatment paradigms*

Osteolytic bone disease is a hallmark of symptomatic multiple myeloma. Bisphosphonates have been the mainstay of treatment to preserve skeletal integrity and prevent skeletal-related events in patients with myeloma-related bone disease. Recently, the MRC Myeloma IX trial demonstrated for the first time improved survival and delayed disease progression with the use of an intravenous amino-bisphosphonate, zoledronic acid, vs. an oral agent, clodronate, with intensive and non-intensive anti-myeloma treatment regimens in patients with newly diagnosed multiple myeloma. These results validate a large body of preclinical, translational and other clinical data suggesting anti-myeloma effects of amino-bisphosphonates. In addition, this trial also provided the first head-to-head evidence for superiority of one bisphosphonate over another (zoledronic acid vs. clodronate) for reducing skeletal morbidity in patients with multiple myeloma, as well as a prospective comparison of toxicities. Despite the use of non-bortezomib containing anti-myeloma treatment regimens in the MRC Myeloma IX trial, these results are encouraging and provide an impetus to continue to evaluate current treatment guidelines for myeloma-associated bone disease

Leukemia vaccine overcomes limitations of checkpoint blockade by evoking clonal T cell responses in a murine acute myeloid leukemia model

We have developed a personalized vaccine whereby patient derived leukemia cells are fused to autologous dendritic cells, evoking a polyclonal T cell response against shared and neo-antigens. We postulated that the dendritic cell (DC)/AML fusion vaccine would demonstrate synergy with checkpoint blockade by expanding tumor antigen specific lymphocytes that would provide a critical substrate for checkpoint blockade mediated activation. Using an immunocompetent murine leukemia model, we examined the immunologic response and therapeutic efficacy of vaccination in conjunction with checkpoint blockade with respect to leukemia engraftment, disease burden, survival and the induction of tumor specific immunity. Mice treated with checkpoint blockade alone had rapid leukemia progression and demonstrated only a modest extension of survival. Vaccination with DC/AML fusions resulted in the expansion of tumor specific lymphocytes and disease eradication in a subset of animals, while the combination of vaccination and checkpoint blockade induced a fully protective tumor specific immune response in all treated animals. Vaccination followed by checkpoint blockade resulted in upregulation of genes regulating activation and proliferation in memory and effector T cells. Long term survivors exhibited increased T cell clonal diversity and were resistant to subsequent tumor challenge. The combined DC/AML fusion vaccine and checkpoint blockade treatment offers unique synergy inducing the durable activation of leukemia specific immunity, protection from lethal tumor challenge and the selective expansion of tumor reactive clones

Therapeutic dendritic cell cancer vaccines in hematologic malignancies

Abstract Tumor cells present antigen in the context of negative costimulation and immunosuppressive factors, resulting in the inhibition of T cell activation and immune tolerance. Dendritic cells (DCs) are a complex network of antigen presenting cells that play a critical role in maintaining the equilibrium between immune activation directed against pathogens and tolerance necessary to prevent damage mediated by autoreactive T cell clones. DCs uniquely induce primary immune responses through the constitutive and enhanced expression of positive costimulatory molecules and inflammatory cytokines necessary for T cell activation. In this context, the design of a cancer vaccine is based on the effective presentation tumor associated antigens to evoke an antigen specific activated T cell response, and importantly, immune memory. As such, DCs have played a major role in the development of cancer vaccine therapy as critical mediators of antigen presentation reversing a major component of tumor mediated immune suppression. DC based vaccines have involved the loading of individual tumor associated antigens or the use of whole tumor cells and have demonstrated potent induction of tumor specific immunity. The correlation of immune response with clinical outcome and integration of DC vaccines with other immune based therapy is currently being explored

Neoantigen‐based vaccines as a promising strategy in cancer immunotherapeutics

Abstract The development of cancer vaccines is based on the premise that tumor cells are potentially targetable by host immunity through the effective presentation of tumor‐associated antigens to reactive T‐cell populations. Vaccine efficacy may be limited by the functional properties of effector cells including the lack of high‐affinity T cells to target self‐antigens. In contrast, neoantigens arise from tumor‐specific mutational events that generate epitopes that are potentially seen as foreign by host immunity. As such, neoantigen‐targeted vaccination provides a high level of tumor specificity, promotes greater T‐cell effector function, and minimizes off‐target toxicities. Next‐generation sequencing and high‐throughput computational algorithms have allowed for the identification of neoantigens in solid tumor and hematologic malignancies. Vaccine generation involves the screening of potential epitopes based on HLA restriction and reactivity by the T‐cell repertoire. Early phase studies have demonstrated feasibility of vaccine production and resultant potent immunologic responses. The clinical impact of neoantigen vaccination and its incorporation into combinatorial immunotherapeutic strategies is currently being explored