COMBINATION OF CHECKPOINT INHIBITORS

COMBINATION OF CHECKPOINT INHIBITORSCheckpoint inhibitors such as anti PDand anti PD Lantibodies Abhave demonstrated considerable success in oncologyproviding both patient benefits and commercial successCombination immune therapeutic strategies can enhance the magnitude of the antitumor immune response over single agentsThis study focuses on in vivo model to study safety and efficacy of combination of CBTanti PDand CBTanti PD LAbs in solid tumors using a novel study designOne of the challenges in cancer drug development is the high failure rate in clinical trials and the associated high costsThis is reflective of the lack of predictive power of traditional preclinical modelswhere efficacy at preclinical setting fails to translate into clinical benefitThe need to reduce drug attrition is especially acute in the field of oncologywhere drugs fail not only because of toxicity but also lack of efficacyHuman CDhematopoietic stem cellHSCare engrafted into immunodeficient NOD SCID gammaNSGmicePatient derived xenograft tumors with high PD Lexpression will be implanted subcutaneously in these miceNow the mouse has both human PDand human PD Lin its system and can be used to study the combination effects of the two humanized antibodiesCBTand CBTWe propose a novel in vivo mouse study design that mimics human clinical trialcheckerboard method using two attributesPatient derived xenografts PDXandDonor HSCPDX tumors positive for PD Landdonor HSC will be interrogated in a ncheckerboard assay to yieldcombinations mimicking human clinical trial withsubjectsBy analyzing immune modulation in vivo in vehicle vs treated groups in this animal model can help identify useful biomarkers which can be developed as a companion diagnostic to help with commercializationPotentially overlapping safety and tolerability when combining two agents is important to discern prior to in human trialsBy characterizing differences in Mononuclear phagocyte system MPSinteractions and response we will be able to predict systemic PK differences and toxicities in Non human primates NHPsand humansCBT is in a unique position to study this combination and develop it further in the clinic as it holds the patents for both antibodies COMBINATION OF CHECKPOINT INHIBITORS Safetyefficacy and biomarker development are the three most important questions we need to answer before going into human trialsThis grant proposal will help us understand if the combination of immune checkpoint inhibitors CBTanti PDand CBTanti PD Lwill improve patient outcomes and help identify novel more useful biomarkers which can be developed as companion diagnostic to help with commercializationIt will also help us assess safety risk involved before administering these agents to patients