Title: Pre-clinical Evaluation of a Novel Immune Modulator, Alpha-TEA in Combination with Immune Checkpoint Blockade

Triple negativePRERHERbreast cancerTNBCwhich disproportionately afflicts premenopausal and minority womenhas a very poor prognosisCurrent TNBC treatment consists of combination chemotherapy which is toxic to the patientincreases morbidity and decreases quality of lifeConsidering these limitationsand high relapse rateTNBC poses a major clinical challengeand developing new agents that are effective and safe is a critical unmet needVeana Therapeutics has developed a novel compoundalpha tocopheryloxyacetic acida TEAwhich kills cancer cells and stimulates the immune systemVeana is conducting a first in human safety trial of oral a TEA in patients with advanced cancerAt the lowest doses tested so fara TEA is safeand has stopped tumor from growing inof patientsCancer treatment has been revolutionized by a new class of antibodies known as immune checkpoint inhibitorswhichrelease the brakesso that immune cellsT cellscan more effectively destroy cancer cellsThe safest of this classanti Programmed Deathanti PDdemonstrated objective clinical responses in patientswhich led to FDA approval for the treatment of melanomakidneybladder and head and neck cancersUnfortunatelyanti PDhas not demonstrated the same activity in advanced TNBC patientsThe finding that only a few patients obtain long term benefit with anti PDtherapy has fueled combinations with other agents with the goal of increasing curative responses in more patientsHowevera major obstacle to achieving this goal is determining the best dosing and sequence of these combination therapiesDue to its unique property toprimethe immune systema TEA is an ideal candidate to combine with anti PDin TNBCThe goal of this application is to conduct pre clinical studies to determine the optimum dose of a TEA and schedule of anti PDthat will deliver the best therapeutic outcomeWe will pursue three specific aims to achieve this goalAimwill assess the impact of varying doses of a TEA and timing of anti PDon tumor growthmetastasisand survivalAimwill identify surrogate immunologic biomarkers of effective combination therapy by assessing expression of T cell activation andexhaustionmarkerscell proliferationcytokine productionfrequency of tumor infiltrating T cells and expression of the PDligandPDLby immunohistochemical staining of tumor tissueAimwill compare the antitumor activity and toxicity profile of a TEAdoxorubicinand paclitaxel in combination with anti PDby assessing tumor growth and survivaland performing hematological analysiscomplete blood countsblood chemistry analysisnecropsy and examination of tissues and organsSuccessful completion of the studies and realization of the milestones will lay the groundwork for a Phase II grant application to evaluate safety of a TEA plus anti PDin a first in human combination trial in patients with TNBCDemonstration of efficacy in subsequent Phase II III trials could lead to FDA approval which would pave the way for commercialization of a TEA as a companion drug with anti PDfor treating TNBC PROJECT NARRATIVE Triple negative breast cancerTNBCis a very aggressive type of breast cancer that disproportionately afflicts pre menopausal and minority women and for which treatment options are limitedIntensive combination chemotherapywhich is standard of care for these patientsis associated with significant toxicity and morbidityThis project will assess the efficacy and toxicity profile of a TEA as a novel drug candidate in combination with anti PDfor the treatment of TNBCThe lack of toxicity coupled with the immune adjuvant activity of a TEA position it strongly as an attractive alternative for TNBC patients that are ineligible for treatment with current drugs due to safety concerns