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 of 6 different checkpoint inhibitors for a number of indications including; metastatic melanoma and non-small cell lung cancer. These 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 remission, and even some cures, However, the development, application and potential of these new treatments is hindered by relatively low response rates and the long-times required to ascertain objective responses. Immunotherapy is expensive and comes with serious potential side effects, so early selection of the most effective therapy for each patient is critical. Currently, there is no effective way to measure response, as traditional methods such as biopsy and anatomic imaging have not been predictive. To overcome these limitations, we have developed a molecular imaging agent for Positron Emission Tomography (PET) that is targeted to granzyme B, the enzyme released by activated immune cells to kill target tumor cells. By non-invasively measuring the tumor concentration of granzyme B, we have shown the specificity and potential of our PET imaging agent to predict early response to checkpoint inhibitors with in vivo non-clinical cancer models. We 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 samples. Given the preliminary success of our agent to determine immunotherapy response and the lack of effective alternatives, we believe an accelerated translation to human testing is warranted. This 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 safety, distribution and imaging potential in humans undergoing checkpoint inhibitor therapy. Although, this study cannot be empowered to determine efficacy, PET 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-Oncology (I-O) therapy is the absence of a test to measure early tumor response to the new Checkpoint inhibitor drugs. Immune-mediated tumor killing involves cytotoxic lymphocytes (CTLs) and a complex process of immune cell activation. CTL activation results in release of cytotoxic granules containing granzyme B, a potent serine-protease enzyme that degrades several critical proteins to induce apoptosis or cell death. We propose to image extracellular Granzyme B concentrations in melanoma patients receiving checkpoint inhibitor therapy as an early indicator of tumor response.