Developing a novel adjuvant system for therapeutic vaccines against lung cancer

DESCRIPTION provided by applicant Therapeutics is focused on the development of adjuvant systems with desired immune activities for targeted indications The Companyandapos s immune stimulatory adjuvant platform builds on combinatorial use of immune agonists with distinct immune targets and mechanisms of action for the generation of therapeutic immune responses Critical to this platform technology is the use of novel forms of tumor necrosis factor ligand TNFL costimulatory family agents that directly modulate innate adaptive and regulatory immunity and cross talk with pattern recognition receptors for sustained immune effector responses The Companyandapos s lead adjuvant system ISAS constitutes a novel form of BBL streptavidin chimeric molecule formulated with monophosphoryl lipid A MPL as an agonist of toll like receptor TLR The choice of BBL is based on the pleiotropic effects of BB costimulatory signaling in cells of innate NK cells NKT cells macrophages neutrophils and DCs adaptive CD and CD T cells and regulatory CD CD FoxP T regulatory Treg cells immunity and the critical role of coordinated responses of these cell populations in the eradication of cancer and control of recurrences MPL complements the immune activities of BBL by upregulating the BB receptor and ligand on antigen presenting cells and BBL physically interacts with TLRs for sustained innate immune responses Therefore the combined use of these two agents has the potential to generate robust immune effector responses and overcome immune evasion mechanisms culminating in the eradication of cancer and control of recurrences In support of this we have recently shown that ISAS as the adjuvant component of TAA based protein vaccines was effective in eradicating tumors in various preclinical models A mucin MUC TAA based vaccine tecemotide against non small cell lung cancer being developed by Merck KGaA has failed to meet its primary endpoint of improving overall patient survival in a phase III clinical study Factors contributing to the vaccie inefficacy are unknown We hypothesize that the lack of a potent adjuvant system able to generate a robust immune effector response as part of vaccine formulation as well as the need to overcome tumor immune evasion mechanisms may have contributed to the vaccine failure Therefore the main objective of this Phase I STTR application is to test if the ISAS adjuvant system generates robust cellular immune responses against MUC TAA and improves therapeutic efficacy of the tecemotide based vaccine formulation using MUC transgenic TG mice as a stringent preclinical tumor model Three specific Aims are designed to i establish a reformulated vaccine that generate robust Th responses to MUC TAA ii assess the therapeutic efficacy of the vaccine in eradicating lung carcinoma in MUC TG mice and iii investigate immune responses associated with vaccine efficacy failure A better efficacy for the reformulated vaccine over the tecemotide based vaccine formulation will indicate the need for further development of this vaccine and potential for entry into phase I clinical trials for lung cancer PUBLIC HEALTH RELEVANCE Cancer is a major public health problem in the United States and many other parts of the world One in deaths in the United States is due to cancer Standard treatments are not effective and often relatively toxic Research suggests that vaccines have the potential to treat cancer without the toxicity associated with standard treatments FasCure Therapeutics LLC is developing a novel immune adjuvant system ISAS that has shown therapeutic efficacy as a component of vaccines in several preclinical mouse models The overall goal of this project is to test if ISAS improves the therapeutic efficacy of a lead vaccine formulation against lung cancer that has failed in a phase III clinical trial