Design and Modification of Allogeneic Cell Vaccines

Tumor cells are generally thought to be poorly immunogenic, although immunogenicity varies considerably between tumors of different backgrounds. Creative Biolabs is a world leader in the field of cancer vaccine development. We have a variety of strategies that are aimed at improving the immunogenicity of the vaccine including modification of vaccine cells to express costimulatory molecules or cytokines. With our extensive experience and advanced platform, we are therefore confident in offering the best modification services to improve the efficacy of allogeneic cell vaccines. We guarantee the finest results for our customers all over the world.

Modification of Allogeneic Cell Vaccines with Costimulatory Molecules

Poor immunogenicity is due at least partly to the heterogeneous expression of MHC and costimulatory molecules. The absence of costimulation raised concerns that vaccine cells might induce tolerance.

Fig.1 Costimulatory molecules and their ligands ^[1]

• B7.1/CD80 Costimulatory Molecules

The introduction of B7.1/CD80 costimulatory molecules into vaccine cells has been investigated in preclinical models. Several studies showed that expression of CD80 on autologous vaccine cells elicited CTL responses and improved protection against tumor challenge. However, results from one study suggested that CD80 expression is effective only when the vaccine cells are themselves immunogenic. In allogeneic models, effective protection against tumor was also demonstrated.

The apparent effectiveness of modification of vaccine cells with costimulatory molecules raises further questions concerning the mechanism by which whole-cell vaccines stimulate T cell responses. Introduction of costimulatory molecules into vaccine cells presumes that direct priming forms a component of the mechanism for T cell stimulation. Direct priming occurred when CD80 was introduced into the vaccine, suggesting that introduction of costimulation may influence the mechanism of T cell stimulation. It is interesting to note that many allogeneic cell vaccines used in humans are matched for at least one HLA allele, leaving the possibility that such vaccines work, at least in part, through direct presentation of antigen.

Modification of Allogeneic Vaccines to Secrete Cytokines

Cytokines have been used to treat advanced cancers, including renal cell carcinoma and metastatic melanoma with some success, but systemic administration is associated with marked toxicity. Recombinant cytokines expressed by modified tumor cells can be used to target the cytokine to tumor or vaccination sites where they can induce a proinflammatory environment, with the additional benefit of lowering the levels of circulating cytokine and therefore circumventing the toxicity related to high systemic doses.

Cytokine-secreting tumor cells have been tested extensively in mouse models for their efficacy in reducing tumorigenicity, protecting against tumor challenge and raising immune responses. Creative Biolabs is developing a range of cytokines, of which IL-2 and GM-CSF have been shown to have potential in allogeneic tumor cell vaccination models.

• IL-2: Interleukin 2 is produced by CD4⁺ T cells of the TH1 type. It supports recruitment, differentiation, and proliferation of T and NK cells and is frequently used systemically for the treatment of renal cell carcinoma and melanoma. In autologous IL-2-secreting cell vaccination models, there is a requirement for CD8⁺ T cells and/or NK cells to establish effective protection against tumor challenge. In a study, where allogeneic cell vaccines are shown to be protective against tumor challenge in a prophylactic treatment model, IL-2-secreting vaccine is more effective than unmodified cells. Furthermore, vaccination with IL-2-secreting allogeneic cells gave rise to a cytotoxic response that recognized syngeneic tumor.
• GM-CSF: Although GM-CSF has highly pleiotropic effects, it is involved principally in stimulation of proliferation and activation of granulocytes and monocytes. GM-CSF stimulates dendritic cell maturation and is able to augment APC function. Protective immunity is induced by vaccination with allogeneic GM-CSF-secreting cells, and stimulation of cytotoxic responses to tumor cells has been demonstrated.

Creative Biolabs is a leader in the field of vaccine development and has focused on the cancer vaccines for years. We have experienced experts and advanced platforms that are able to provide excellent services. If you are interested in our services, please contact us for more details.

Reference

1. Hubo, M. (2013). “Costimulatory molecules on immunogenic versus tolerogenic human dendritic cells.” Front Immunol 4, 82.

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