Dendritic cell (DC)-based vaccination for cancer treatment has seen considerable development over recent decades. However, this field is currently in a state of flux toward niche-applications, owing to recent paradigm-shifts in immuno-oncology mobilized by T cell-targeting immunotherapies. DC vaccines are typically generated using autologous (patient-derived) DCs exposed to tumor-associated or -specific antigens (TAAs or TSAs), in the presence of immunostimulatory molecules to induce DC maturation, followed by reinfusion into patients. Accordingly, DC vaccines can induce TAA/TSA-specific CD8+/CD4+ T cell responses. Yet, DC vaccination still shows suboptimal anti-tumor efficacy in the clinic. Extensive efforts are ongoing to improve the immunogenicity and efficacy of DC vaccines, often by employing combinatorial chemo-immunotherapy regimens. In this Trial Watch, we summarize the recent preclinical and clinical developments in this field and discuss the ongoing trends and future perspectives of DC-based immunotherapy for oncological indications. 

https://www.tandfonline.com/doi/pdf/10.1080/2162402X.2022.2096363?needAccess=true

Trial watch: Dendritic cell (DC)-based immunotherapy for cancer

The immune checkpoint inhibitors have revolutionized cancer immunotherapy. These inhibitors are game changers in many cancers and for many patients, sometimes show unprecedented therapeutic efficacy. However, their therapeutic efficacy is largely limited in many solid tumors where the tumor-controlled immune microenvironment prevents the immune system from efficiently reaching, recognizing, and eliminating cancer cells. The tumor immune microenvironment is largely orchestrated by immune cells through which tumors gain resistance against the immune system. Among these cells are mast cells and dendritic cells. Both cell types possess enormous capabilities to shape the immune microenvironment. These capabilities stage these cells as cellular checkpoints in the immune microenvironment. Regaining control over these cells in the tumor microenvironment can open new avenues for breaking the resistance of solid tumors to immunotherapy. In this review, we will discuss mast cells and dendritic cells in the context of solid tumors and how these immune cells can, alone or in cooperation, modulate the solid tumor resistance to the immune system. We will also discuss how this modulation could be used in novel immunotherapeutic modalities to weaken the solid tumor resistance to the immune system. This weakening could then help other immunotherapeutic modalities engage against these tumors more efficiently.

/pdf/mast-cells-and-dendritic-cells-as-cellular-immune-1j6e797c.pdf

Mast Cells and Dendritic Cells as Cellular Immune Checkpoints in Immunotherapy of Solid Tumors

Dendritic cells (DCs) have received considerable attention as potential targets for the development of novel cancer immunotherapies. However, the clinical efficacy of DC-based vaccines remains suboptimal, largely reflecting local and systemic immunosuppression at baseline. An autologous DC-based vaccine (DCVAC) has recently been shown to improve progression-free survival and overall survival in randomized clinical trials enrolling patients with lung cancer (SLU01, NCT02470468) or ovarian carcinoma (SOV01, NCT02107937), but not metastatic castration-resistant prostate cancer (SP005, NCT02111577), despite a good safety profile across all cohorts. We performed biomolecular and cytofluorometric analyses on peripheral blood samples collected prior to immunotherapy from 1000 patients enrolled in these trials, with the objective of identifying immunological biomarkers that may improve the clinical management of DCVAC-treated patients. Gene signatures reflecting adaptive immunity and T cell activation were associated with favorable disease outcomes and responses to DCVAC in patients with prostate and lung cancer, but not ovarian carcinoma. By contrast, the clinical benefits of DCVAC were more pronounced among patients with ovarian carcinoma exhibiting reduced expression of T cell-associated genes, especially those linked to TH2-like signature and immunosuppressive regulatory T (TREG) cells. Clinical responses to DCVAC were accompanied by signs of antitumor immunity in the peripheral blood. Our findings suggest that circulating signatures of antitumor immunity may provide a useful tool for monitoring the potency of autologous DC-based immunotherapy. 

https://www.tandfonline.com/doi/pdf/10.1080/2162402X.2022.2101596?needAccess=true

Peripheral gene signatures reveal distinct cancer patient immunotypes with therapeutic implications for autologous DC-based vaccines

Simple Summary With an overall 5-year survival of only 20% for advanced-stage ovarian cancer patients, enduring and effective therapies are a highly unmet clinical need. Current standard-of-care therapies are able to improve progression-free survival; however, patients still relapse. Moreover, immunotherapy has not resulted in clear patient benefits so far. In this situation, dendritic cell vaccines can serve as a potential therapeutic addition against ovarian cancer. In the current review, we provide an overview of the different dendritic cell subsets and the roles they play in ovarian cancer. We focus on the advancements in dendritic cell vaccination against ovarian cancer and highlight the key outcomes and pitfalls associated with currently used strategies. Finally, we address future directions that could be taken to improve the dendritic cell vaccination outcomes in ovarian cancer. Abstract Ovarian cancer (OC) is the deadliest gynecological malignancy in developed countries and is the seventh-highest cause of death in women diagnosed with cancer worldwide. Currently, several therapies are in use against OC, including debulking surgery, chemotherapy, as well as targeted therapies. Even though the current standard-of-care therapies improve survival, a vast majority of OC patients relapse. Additionally, immunotherapies have only resulted in meager patient outcomes, potentially owing to the intricate immunosuppressive nexus within the tumor microenvironment. In this scenario, dendritic cell (DC) vaccination could serve as a potential addition to the therapeutic options available against OC. In this review, we provide an overview of current therapies in OC, focusing on immunotherapies. Next, we highlight the potential of using DC vaccines in OC by underscoring the different DC subsets and their functions in OC. Finally, we provide an overview of the advances and pitfalls of current DC vaccine strategies in OC while providing future perspectives that could improve patient outcomes.

/pdf/dendritic-cell-vaccines-a-promising-approach-in-the-fight-2mgznr16.pdf

Dendritic Cell Vaccines: A Promising Approach in the Fight against Ovarian Cancer

Ovarian cancer is the most lethal gynecologic tumor, with the highest mortality rate. Numerous studies have been conducted on the treatment of ovarian cancer in the hopes of improving therapeutic outcomes. Immune cells have been revealed to play a dual function in the development of ovarian cancer, acting as both tumor promoters and tumor suppressors. Increasingly, the tumor immune microenvironment (TIME) has been proposed and confirmed to play a unique role in tumor development and treatment by altering immunosuppressive and cytotoxic responses in the vicinity of tumor cells through metabolic reprogramming. Furthermore, studies of immunometabolism have provided new insights into the understanding of the TIME. Targeting or activating metabolic processes of the TIME has the potential to be an antitumor therapy modality. In this review, we summarize the composition of the TIME of ovarian cancer and its metabolic reprogramming, its relationship with drug resistance in ovarian cancer, and recent research advances in immunotherapy.

/pdf/metabolic-reprogramming-of-the-tumor-immune-microenvironment-2rykhikv.pdf

Metabolic reprogramming of the tumor immune microenvironment in ovarian cancer: A novel orientation for immunotherapy

Abstract Purpose: The successful implementation of immune checkpoint inhibitors (ICI) in the clinical management of various solid tumors has raised considerable expectations for patients with epithelial ovarian carcinoma (EOC). However, EOC is poorly responsive to ICIs due to immunologic features including limited tumor mutational burden (TMB) and poor lymphocytic infiltration. An autologous dendritic cell (DC)-based vaccine (DCVAC) has recently been shown to be safe and to significantly improve progression-free survival (PFS) in a randomized phase II clinical trial enrolling patients with EOC (SOV01, NCT02107937). Patients and Methods: We harnessed sequencing, flow cytometry, multispectral immunofluorescence microscopy, and IHC to analyze (pretreatment) tumor and (pretreatment and posttreatment) peripheral blood samples from 82 patients enrolled in SOV01, with the aim of identifying immunologic biomarkers that would improve the clinical management of patients with EOC treated with DCVAC. Results: Although higher-than-median TMB and abundant CD8+ T-cell infiltration were associated with superior clinical benefits in patients with EOC receiving standard-of-care chemotherapy, the same did not hold true in women receiving DCVAC. Conversely, superior clinical responses to DCVAC were observed in patients with lower-than-median TMB and scarce CD8+ T-cell infiltration. Such responses were accompanied by signs of improved effector functions and tumor-specific cytotoxicity in the peripheral blood. Conclusions: Our findings suggest that while patients with highly infiltrated, “hot” EOCs benefit from chemotherapy, women with “cold” EOCs may instead require DC-based vaccination to jumpstart clinically relevant anticancer immune responses. 

/pdf/an-autologous-dendritic-cell-vaccine-promotes-anticancer-3dy8557m.pdf

Frank-Michael Dittes

Papers

An Autologous Dendritic Cell Vaccine Promotes Anticancer Immunity in Patients with Ovarian Cancer with Low Mutational Burden and Cold Tumors