Harnessing dendritic cells to generate cancer vaccines

Abstract

Passive immunotherapy of cancer (i.e., transfer of T cells or antibodies) can lead to some objective clinical responses, thus demonstrating that the immune system can reject tumors. However, passive immunotherapy is not expected to yield memory T cells that might control tumor outgrowth. Active immunotherapy with dendritic cell (DC) vaccines has the potential to induce tumor-specific effector and memory T cells. Clinical trials testing first-generation DC vaccines pulsed with tumor antigens provided a proof-of-principle that therapeutic immunity can be elicited. Newer generation DC vaccines are built on the increased knowledge of the DC system, including the existence of distinct DC subsets and their plasticity all leading to the generation of distinct types of immunity. Rather than the quantity of IFN-gamma-secreting CD8(+) T cells, we should aim at generating high-quality, high-avidity, polyfunctional effector CD8(+) T cells able to reject tumors and long-lived memory CD8(+) T cells able to prevent relapse.

Figure 1. Three approaches to DC-based immune intervention in cancer

1) Vaccines based on antigen with or without adjuvant that target DCs randomly. That might result in vaccine antigens being taken up by a “wrong” type of DCs in the periphery which might lead to “unwanted” type of immune response. Vaccine antigens could also flow to draining lymph nodes where they can be captured by resident DCs; 2) Vaccines based on ex-vivo generated tumor antigen-loaded DCs that are injected back into patients; and 3) specific in vivo DC targeting with anti-DC antibodies fused with antigens and with DC activators.

Figure 2. BIIR dendritic cell vaccine trials

Illustrated are early trials conducted at BIIR. Early trials (#1-3) tested the immune and clinical efficacy of DC vaccines loaded with short peptides representing tumor associated antigens (TAA) and control antigens. These trials tested the immunogenicity of composite DC vaccines (containing Langerhans cells and interstitial DCs) (#1), activation of CD34+ HPCs-derived DCs (#2) and the activity of composite monocyte-derived DCs generated with GM-CSF and TNF (3#). Trial #4 tested the immune and clinical efficacy of monocyte-derived DCs loaded with killed allogeneic melanoma cells. Newer trials (#5 and beyond) are testing the immunogenicity of GM-CSF/IFN-DCs derived from monocytes.

Figure 3. Distinct DC subsets generate distinct types of T cell immunity

DC system has two cardinal features: 1) subsets; and 2) plasticity. This yields distinct types of immunity thereby allowing DCs to cope with protection against a variety of microbes and maintenance of tolerance to self. Understanding these two features is fundamental to develop vaccines that elicit the desired type of immune responses.

Figure 4. Loading DCs with tumor antigens

In our initial trials, DCs were loaded with short synthetic peptides, the major limitations of which are MHC restriction and the lack of cognate CD4⁺ T cell epitopes. Next step was to test loading DCs with killed tumor cells. These are able to generate a broad repertoire of CD4⁺ and CD8⁺ T cells. Long synthetic peptides might overcome MHC restriction and allow us to better control T cell repertoire. These studies will lay the ground for selection of long peptides that can be fused with anti-DC antibodies for ex vivo and in vivo DC targeting.