Combination Strategies to Optimize Efficacy of Dendritic Cell-Based Immunotherapy

Abstract

Dendritic cells (DCs) are antigen-presenting cells (APCs) that are essential for the activation of immune responses. In various malignancies, these immunostimulatory properties are exploited by DC-therapy, aiming at the induction of effective anti-tumor immunity by vaccination with ex vivo antigen-loaded DCs. Depending on the type of DC-therapy used, long-term clinical efficacy upon DC-therapy remains restricted to a proportion of patients, likely due to lack of immunogenicity of tumor cells, presence of a stromal compartment, and the suppressive tumor microenvironment (TME), thereby leading to the development of resistance. In order to circumvent tumor-induced suppressive mechanisms and unleash the full potential of DC-therapy, considerable efforts have been made to combine DC-therapy with chemotherapy, radiotherapy or with checkpoint inhibitors. These combination strategies could enhance tumor immunogenicity, stimulate endogenous DCs following immunogenic cell death, improve infiltration of cytotoxic T lymphocytes (CTLs) or specifically deplete immunosuppressive cells in the TME, such as regulatory T-cells and myeloid-derived suppressor cells. In this review, different strategies of combining DC-therapy with immunomodulatory treatments will be discussed. These strategies and insights will improve and guide DC-based combination immunotherapies with the aim of further improving patient prognosis and care.

Dendritic cell vaccine immunotherapy; the beginning of the end of cancer and COVID-19. A hypothesis

“…However, as discussed earlier several issues should be addressed before becoming mainstream in cancer therapy. Current clinical trials involving different types of tumors (as in Table 1 ) are currently exploring the significance of the DC vaccine as a monotherapy or in combination with other interventions in different types of tumors as metastatic melanoma [41] , breast cancer [42] , and prostate cancer [36] .…”

Prostaglandin E Receptor 4 Antagonist in Cancer Immunotherapy: Mechanisms of Action

“…Animal experiments support the combination of the EP4 antagonist E7046 (ER0886046) with anti-CTLA4 in a mouse melanoma B16F10 model and with anti-PD-1 or anti-PD-L1 antibodies in a mouse colon cancer CT26 model. Higher antitumor efficacies were demonstrated in combination, compared with E7046 or the ICI antibody alone (44). Figure 2 illustrates the opportunity to introduce EP4 antagonist therapy with ICIs, which may cooperatively interact leading to an efficient C-IC.…”

“…The combination of radiotherapy and/or chemotherapy with the EP4 antagonist is thought to synergistically accelerate the C-IC. Simultaneous increases in the cDC population by EP4 therapy and the production of DAMPs through therapy-producing ICD in tumors are essentially required for the effective production of tumor-specific effector CD8 + T cells (44) (Figure 2).…”

Emerging Treatments for Malignant Pleural Mesothelioma: Where Are We Heading?

“…Several sources of tumor antigens (mRNA, peptides, proteins or whole tumor cell lysate) can be used to load DCs (107). Because TAAs are difficult to identify in mesothelioma (thus excluding peptides as best source), and adequate tumor tissue is rarely obtained from mesothelioma patients (108,109), an allogenic tumor lysate has been developed (110). Results from a first-inhuman clinical trial involving nine MPM (non-progressive after at least 4 cycles of chemotherapy) showed that this approach is safe (no dose-limiting toxicities were established) and led to radiological responses and promising survival data, with median PFS of 8.8 months and median OS not reached (110).…”