Cancer Immunotherapy in the Clinic: Dendritic Cells Present the Possibility
McMaster University ♦ Medical School of the Vrije Universiteit Brussel
Review Published in Molecular Therapy (npg), April 5, 2011
Dendritic cells play a vital role in the generation of T-cell responses to invading pathogens in the body. They fall into a class of cells known as antigen presenting cells (APCs), that display small protein segments, otherwise known as antigens, to T-cells such that an immune response may be mounted against foreign pathogens. There are three mechanisms of activation that lead to a rapid and efficient immune response. The first is the recognition of an antigen on the surface of APCs by T-cells. After a T-cell and APC meet one another, the second signal occurs by way of reinforcement through the interaction of costimulatory ligands on the extremity of both cells that work to enhance the first signal and ensure the T-cell acts upon its recognition of the foreign antigen. The third signal comes in the form of cytokines, small soluble chemical messengers released by APCs that promote T-cell polarization — immune activity geared towards foreign invaders. Dendritic cells are unique in their ability to trigger all three of these signaling mechanisms, and thus the proposition of using this cell type in immunotherapy vaccines is an interesting one.
Without knowing it, scientists have been moving towards utilizing immunotherapy in the clinic for more than 100 years. In the early 20th century researchers were already clueing in to the fact that there may exist some form of immune surveillance system allowing specific cell types to recognize and eradicate transformed cells from the body. In this recent review, written in part by researchers at McMaster University, the topic of immunotherapy is discussed in the context of manipulating dendritic cells to be amenable for use in immunotherapy vaccines. The general concept is to engineer dendritic cells such that they express small peptides known as tumour-associated antigens (TAAs). After being injected into the body TAAs elicit an immune response polarized towards tumour cells in the body. This is achieved with genetic manipulation in the petri dish prior to preparing the vaccination. During this process a single gene or multiple genes can be introduced to dendritic cells, resulting in the continuous production of native TAA peptides that are packaged and delivered to the cell surface on MHC class II molecules.
Each of the three signaling mechanisms that promote T-cell response may be exploited for immunotherapy in vivo. The foundation of this therapeutic approach to cancer is T-cell recognition of the tumour-specific antigen on the surface of engineered dendritic cells. This recognition is translated to action by receptor/ligand costimulation, which can be magnified by one of two means: enhancing the expression of costimulatory molecules, or downregulating molecules that inhibit or suppress T-cell response to dendritic cells. This is achieved by gene transfer or silencing mechanisms in vitro. Enhancing the CD40-CD40L receptor/ligand pair and downregulating the inhibitory zinc-finger protein A20 have proven effective in increasing overall costimulation at the T-cell/APC interface. Modifying the cytokine and chemokine milieu, the environment in which the immune cells reside, helps to direct the polarization of the ensuing immune response. Anticancer T-cell responses are best suited to occur in polarized niches established by type I IFN, IFN-γ, and IL-12p70. These niches are characterized by the presence of CD8+ T-cells (cytotoxic T-cells), CD4+ T-cells (helper T-cells), and natural killer cells. To achieve modification of the immune microenvironment dendritic cells are engineered to continuously express various cytokines and chemokines.
So where do we stand in the clinic? Protocols for the generation of dendritic cells from monocytes have been established and implemented to create immunotherapies for the clinic. Phase 1 studies illustrate that immunotherapy is well-tolerated. The preparation of dendritic cells for immunotherapy applications is somewhat of a recipe. Dendritic cells are first mixed with tumour-associated antigens, and then matured with the addition of a cocktail of cytokines including PDE-2, IL-β, IL-6, and TNF-α. Improvements upon this protocol using IFN I produce “DC1” dendritic cells that create a more highly polarized immune response following administration. One dendritic-cell based cellular vaccine has been approved by the FDA for the treatment of prostate cancer. This immunotherapy, Sipuleucel-T, was used to treat patients with castration-resistant prostate cancer and was reported to extend patient survival by 4.1 months. The authors of this review completed a clinical study involving 35 patients with metastatic melanoma. Roughly 60% of patients under therapy mounted an immune response against one or more of the vaccine antigens. Disease control of greater than 6 months with regression of metastases was noted in 35% of patients, while recurrence free survival was 23 months.
Things are looking promising in this emerging field with demonstrable safety and several clinical studies underway. While T-cell activation appears to be consistent, current engineered dendritic cells fail to provide strong enough costimulation to maintain a proinflammatory immune environment and recruit all of the necessary components necessary to eradicate transformed cells. As tumours maintain immunosuppressive environments successful immunotherapies will have to elicit persistent and aggressive responses to tumours in vivo. This will likely be achieved through the transfer of several genetic components that simultaneously enhance all three mechanisms of immune response activation.