Manipulating Dendritic Cells for Cancer Immunity

Karolina Palucka, MD, PhD

Dendritic cells (DCs) are an essential target for generating immunity against cancer due to their ability to manipulate the immune system and there are a number of potential methods by which DCs can be utilized for cancer immunotherapy, according to Karolina Palucka, MD, PhD.

In a presentation during the “Primer on Tumor Immunology and Cancer Immunotherapy™” session yesterday morning, Palucka, a professor at the Jackson Laboratory for Genomic Medicine in Farmington, Connecticut, explained the role of DCs in the immune system and how they can be incorporated into cancer therapeutics.

DCs are antigen-presenting cells (APCs) that convert proteins to peptides that are then presented on major histocompatibility complex class I and II molecules with costimulatory signals and are recognized by T cells.^1,2They can control elements of both the innate and adaptive immunity, so they act as a link between them,²Palucka said. Not only do they activate lymphocytes, for example, but they also induce immunologic tolerance to self-antigens, which minimizes autoimmune reactions.³

There are many potential avenues for using DCs in cancer therapy, Palucka explained: 1) endogenous vaccination with immunogenic chemotherapy, radiotherapy, antitumor antibodies, and T-cell checkpoint blockade; 2) ex vivo-generated cytokine- driven DCs using ex vivo instruction to elicit cytotoxic effectors and helper T cells; 3) reprogramming inflammation by targeting DCs with Toll-like receptor ligands and cytokine blockade; and 4) endogenous vaccination by targeting antigens to DC subsets in vivo, in which the anti-DC antibody is linked to a pathogen and/or a cancer antigen and DC activator.

DC-based vaccines are an area of particular interest in immunotherapy. With these vaccines, APCs are reinjected into the tissue which are captured by DCs, leading to activation of the DCs by the adjuvant. These antigen-loaded DCs are then migrated to tumor-draining lymph nodes to present the vaccine antigens.⁴In a phase I clinical trial of an autologous, functionally mature interleukin-12 DC vaccine in 3 patients with stage III resected cutaneous melanoma, researchers found that the vaccine increased the presence of HLA class I-restricted neoantigens. The study authors believed that the vaccination broadened the breadth and clonal composition diversity of the antitumor immunity in these patients.⁵One strategy emerging in clinical trials for potentiating immunity with DCs is by targeting antigens directly to DCs in situ. “The targeting of the antigens to the dendritic cells in vivo is a very interesting option, rather than generating dendritic cells outside of it,” Palucka said during her presentation, and pointed out several trials investigating this approach.

A fully human anti-DEC205 (DC receptor) monoclonal antibody conjugated to the full-length NYESO1 tumor antigen was given to 45 patients with advanced cancer in an early-phase clinical trial.⁶NYESO1-specific antibodies were detected in 79% of the patients following vaccination. Two patients demonstrated a small tumor regression and 13 patients had stable disease for a median of 6.7 months. The researchers determined that the vaccine induce strong cellular and humoral responses, but also that combined targeting of multiple human DC subsets could potentially improve the efficacy of DC targeting.

Moving forward, immunotherapy targeting DCs can be combined with other cancer therapeutics, including with chemotherapy and/or targeted therapy. “Combination in the proper timing could be a very efficient treatment,” Palucka said, adding that combinations of different approaches of immunotherapy especially require further study. These combinations will likely be the next steps in exploring targeting DCs for greater cancer immunity.

References:

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3. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245-252. doi: 10.1038/32588.
4. Palucka A, Banchereau J. SnapShot: cancer vaccines. Cell. 2014;157(2):516-516. e1. doi: 10.1016/j.cell.2014.03.044.
5. Carreno BM, Magrini V, Becker-Hapak M, et al. Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science. 2015;348(6236):803-808. doi: 10.1126/science.aaa3828.
6. Dhodapkar MV, Dhodapkar KM. Recent advances and new opportunities for targeting human dendritic cells in situ. Oncoimmunology. 2014;3(8):e954832. doi: 10.4161/21624011.2014.954832.