The Challenge of Cancer Immunotherapy

The Revised Authoritative Guide To Vaccine Legal Exemptions

Vaccines Have Serious Side Effects

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Effective cancer immunotherapy induces the killing of tumor cells by cytotoxic T lymphocytes (CTLs), resulting in tumor regression and a survival benefit for patients. Malignant tumors are often characterized by an intense proliferative capacity, and local to systemic invasiveness (Mbeunkui and Johann 2009; Curiel and Curiel 2002), and these lethal characteristics have rendered surgical resection, radiation treatment, and chemotherapy ineffective for many cancer patients. Tumors are also replete with antigens, resulting in immune recognition and significant immune-cell infiltrates, but tumor cells create microenvironments (e.g., production of immunosuppressive cytokines) that suppress anticancer activity (Mbeunkui and Johann 2009; Curiel and Curiel 2002). The potential for the innate immune system to react specifically and systemically against local and metastatic lesions (Curiel and Curiel 2002), and to obtain memory that may prevent tumor recurrence (Klebanoff et al. 2006) has inspired the development of immunotherapies that seek to reprogram anticancer responses (Curiel and Curiel 2002; Klebanoff et al. 2006). A key challenge is to formulate treatment modalities that provide specific and persistent immunostimulation to sustain immune attack against tumor cells (predominantly by CTLs) until patients' tumors are completely cleared (Curiel and Curiel 2002; Klebanoff et al. 2006; Banchereau and Steinman 2007; Schuler et al. 2003).

Current immunotherapeutic approaches are of two main types: cancer vaccines and adoptive T cell transfer (Curiel and Curiel 2002; Klebanoff et al. 2006; Banchereau and Steinman 2007; Schuler et al. 2003). Cancer vaccines introduce tumor-associated antigens at the vaccine site and seek to cause tumor regression by relying on a cascade of events that are orchestrated by dendritic cells (DCs) (Banchereau and Steinman 2007; Schuler et al. 2003). Innate antigen recognition and processing is the responsibility of DCs, which, upon activation, have a potent ability to present tumor-antigens processed onto major histocompatibility complexes (MHC), and to translate pathogenic danger signals (e.g., lipopolysaccharides and bacterial DNA) into the expression of specific stimulatory molecules and cytokines (Banchereau and Steinman 1998, 2007; Mellman and Steinman 2001; Holger et al. 2007). Activated DCs then migrate to lymphoid tissues to interact with naive T cells by presenting MHC-antigen peptides and immunostimulatory cytokines, which signal and propagate antigen-specific T cell differentiation and expansion (Banchereau and Steinman 1998, 2007; Mellman and Steinman 2001; Holger et al. 2007; Sozzani et al. 1998). The type and potency of the T cell response elicited by activated DCs, and, by extrapolation, cancer vaccines, depends on several factors: the type of antigen (endogenous versus exogenous), the microenvironment of the DC-antigen encounter, the extent of DC activation and the number of DCs that stimulate CTL differentiation and expansion (Curiel and Curiel 2002; Klebanoff et al. 2006; Banchereau and Steinman 1998, 2007; Schuler et al. 2003; Mellman and Steinman 2001; Holger et al. 2007; Sozzani et al. 1998). In contrast to vaccines, adoptive T cell transfer bypasses antigen delivery and mediators of T cell activation, by transfusing autologous or allogenic T cells that have been modified in ex vivo cultures and selected to target specific cancer antigens (Klebanoff et al. 2006; Celluzzi et al. 1996; Jenne et al. 2000; Plautz et al. 1998; Hinrichs et al. 2009).

Although cancer vaccines and adoptive T cell transfers have induced CTL responses to specific tumor-associated antigens, and tumor regression in a subset of cancer patients (Curiel and Curiel 2002; Klebanoff et al. 2006; Banchereau and Steinman 2007; Schuler et al. 2003; Celluzzi et al. 1996; Jenne et al. 2000; Plautz et al. 1998; Hinrichs et al. 2009; Yu et al. 2004), these treatments have failed to confer reproducible survival benefit (Klebanoff et al. 2006; Rosenberg et al. 2004). Clinical tests of cancer vaccines have utilized a variety of methods to deliver antigen, including delivery of bulk antigen in the form of tumor lysates (Jenne et al. 2000; Nestle et al. 1998) and irradiated tumor cells (Jinushi et al. 2008; Nemunaitis et al. 2006) or patient-derived DCs pulsated with tumor antigen in ex vivo cultures (Celluzzi et al. 1996). Adjuvants and toll-like receptor (TLR) agonists are often mixed into vaccines to provide danger signals (factors associated with infectious microenvironments) in order to enhance DC maturation and amplify effector responses (Banchereau and Steinman 2007; Holger et al. 2007). However, the limitations of current approaches include short term antigen presentation and immunostimulation due to short, in vivo half-lives (within tissues and immune cells), and in the case of DC or T cell transplantation therapies, there is a rapid loss in cell viability and no control over cell function upon transplantation (Curiel and Curiel 2002; Klebanoff et al. 2006; Banchereau and Steinman 2007; Schuler et al. 2003). The indiscriminate targeting and rapid loss of bioavailability and bioactivity in relation to current therapies likely reduces their efficiency, which limits DC and CTL activation resulting in transient to ineffective tumor attack. Intuitively, persistent induction of antitumor CTL activity is required to mediate tumor regression, and to clear large tumor burdens (Curiel and Curiel 2002; Klebanoff et al. 2006; Banchereau and Steinman 2007; Schuler et al. 2003; Rosenberg et al. 2004).

This review will discuss the development and application of immunologically active biomaterials that specifically target DCs and T cells, and regulate their responses to antigens and tumors. We specifically focus on two biomaterial approaches that enable specific and sustained regulation of immune activity, and controlled immunostimulation: drug delivery and three-dimensional cell niches. Biopolymers of many different types have been formulated into particulate systems that control the bioavailability, the pharmacokinetics and the localization of proteins and nucleic acids, and we will discuss work to develop material vectors for antigen and adjuvants with DC targeting ability. Moreover, as an alternative to approaches that utilize ex vivo cell manipulation (e.g., DC-based vaccines and Adoptive T cell transfer), biomaterials have been fashioned into biofunctional, three-dimensional matrices that create distinct, immunostimulatory microenvironments and regulate DC and T cell trafficking and activation in situ. We also highlight the use of these delivery systems and niches to prime DC and T cell responses to tumors in animal models, and the prospects for their clinical impact in cancer immunotherapy.

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