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By: Bernadette D’Souza

Bernadette D'SouzaImmunotherapy has gained focus for being a powerful and effective tool to fight cancer. As drug delivery experts strategize to utilize this mechanism to build a new generation of vaccines, the adjuvant, or costimulatory molecule, has emerged as a key player. Adjuvants could work in multiple ways to modulate the immune response that is specific to the tumor-associated antigen (TAA). TAAs include oncogenic proteins or glycoproteins synthesized by the tumor cell that are uniquely over-expressed either as membrane bound markers or within the cell.

An adjuvant is defined as a molecule that is added to a vaccine formulation to enhance the immune response towards the antigen. There are several types of adjuvants currently marketed, such as immune enhancing adjuvants that usually target APCs to increase cell-mediated and humoral immunity. A potential vaccine adjuvant target is the pattern recognition receptor, an example of which is the toll like receptors (TLRs), which augment the presentation and co-stimulation of TAAs. These receptors can be targeted through various TLR agonists to play a pivotal role in dendritic cell (DC) maturation and downstream signaling pathways. TLR agonists are potent drivers of TAA cross-presentation in DCs.

Another vaccine adjuvant is insoluble aluminum salt (broadly termed as alum), which functions by adsorbing the antigen to their surface—creating a depot effect and local inflammation. In doing this, the alum adjuvants recruit immune cells to promote uptake of the antigen around the injection site and in nearby draining lymph nodes. MF59, an oil-in-water emulsion, is one more successful vaccine adjuvant that activates tissue resident monocytes, macrophages, and dendritic cells to release cytokines and chemokines, resulting in migration of immune cells to the injection site. The amplification of chemical signals result in more efficient transport of the antigen to the lymph nodes.

Adjuvant stimulation strategies - blog visual aid

Schematic of adjuvant stimulation of dendritic cells that lead to T-cell activation (click on image for larger picture)

Liposomes and micro/nanoparticles have also been used as vaccine adjuvants. The ability of immune cells to preferentially phagocytose a particulate antigen has accentuated the importance of delivery systems as adjuvants. For antigen presenting purposes anionic liposomes have been found to be more potent than neutral or cationic liposomes. The biggest potential for nano or microparticles is the codelivery of antigens and one or more immune potentiators, such as TLRs in the same system. Zhu and colleagues have shown that polylactide-co-glycolide (PLG) nanoparticles encapsulated with the TAA and TLR agonists and administered orally, generated significantly stronger T-cell responses in the large intestine of mice, which could hold potential in the treatment of colorectal tumors cancers and other regions of the gastrointestinal tract. PLG particles are made up of simple biodegradable polymers that can encapsulate multiple antigens and/or adjuvants. Another study showed that active isolates of bacterial strains containing TLR-2, 3, and 4 agonists resulted in effective antitumor activity.

Effective immunotherapy for cancer therapy entails recruitment of potent cells from the innate as well as adaptive immune system to generate specific and long-term immune responses. Using appropriate strategies to improve delivery of TAAs along with adjuvants to lymph nodes to activate the adaptive immune system could achieve successful tumor regression. The potential for research in this field is immense and it is exciting to be at the forefront of new approaches that focus on enhancing cytotoxic T-cells and memory lymphocytes that would home to tumor sites.

Bernadette D’Souza, Ph.D., is an assistant professor in the Department of Pharmaceutical, Social and Administrative Sciences at Samford University –Birmingham, AL. Her research focuses on immunotherapy and using novel formulation strategies to deliver tumor associated antigens to dendritic cells.