Clinical Translation of a Novel Diagnostic Agent to Predict Immunotherapy Response in Solid Tumors

Over the past three years an entirely new cancer treatment paradigm has emerged following the FDA approval ofdifferent checkpoint inhibitors for a number of indications includingmetastatic melanoma and non small cell lung cancerThese new agents work by effectively releasing the brakes on the immune system that normally limit the body s natural responses to tumor cells and have generated long term remissionand even some curesHoweverthe developmentapplication and potential of these new treatments is hindered by relatively low response rates and the long times required to ascertain objective responsesImmunotherapy is expensive and comes with serious potential side effectsso early selection of the most effective therapy for each patient is criticalCurrentlythere is no effective way to measure responseas traditional methods such as biopsy and anatomic imaging have not been predictiveTo overcome these limitationswe have developed a molecular imaging agent for Positron Emission TomographyPETthat is targeted to granzyme Bthe enzyme released by activated immune cells to kill target tumor cellsBy non invasively measuring the tumor concentration of granzyme Bwe have shown the specificity and potential of our PET imaging agent to predict early response to checkpoint inhibitors with in vivo non clinical cancer modelsWe have extended our work ex vivo specificity analysis in human cancer tissue to demonstrate our target shows granzyme B levels are predictive of response in melanoma patient samplesGiven the preliminary success of our agent to determine immunotherapy response and the lack of effective alternativeswe believe an accelerated translation to human testing is warrantedThis SBIR proposal includes the preparation and completion of an exploratory IND study to demonstrate safety in a small group of Melanoma patients and to determine safetydistribution and imaging potential in humans undergoing checkpoint inhibitor therapyAlthoughthis study cannot be empowered to determine efficacyPET imaging data will be correlated with clinical follow up and melanoma biopsy data as a gold standard for Immuno Oncology responders vs non responders The greatest barrier to continued advances in Immuno OncologyI Otherapy is the absence of a test to measure early tumor response to the new Checkpoint inhibitor drugsImmune mediated tumor killing involves cytotoxic lymphocytesCTLsand a complex process of immune cell activationCTL activation results in release of cytotoxic granules containing granzyme Ba potent serine protease enzyme that degrades several critical proteins to induce apoptosis or cell deathWe propose to image extracellular Granzyme B concentrations in melanoma patients receiving checkpoint inhibitor therapy as an early indicator of tumor response