The recent advances in cancer immunotherapy have revitalized and expanded the entire field of cancer immunology. Long-term remissions in some of the deadliest cancers have given an incredible amount of hope to patients and oncologists. However, the reality of cancer immunotherapy is that most patients will not benefit. When deciding whether to begin immunotherapy, an oncologist is therefore faced with difficult dilemma of trying for a long-term remission with immunotherapy versus the likelihood that the patient will derive no benefit from an expensive treatment with potential for severe side effects. In addition, drug development in immunotherapy has also rapidly expanded, creating a large demand for patients whose outcomes from these trials will not be known for many months or longer. Current methods for stratifying patients both for standard of care immunotherapy and clinical trials have improved response, albeit only modestly. Most of these methods of characterization are focused around biopsy derived measures, which suffer from sampling only a small part of a single tumor at a single time point. For this proposal, I am proposing the development of a positron emission tomography (PET)- based diagnostic that has the potential to identify patients who will respond to immunotherapy, characterize their response after therapy has begun, and detect adverse events before clinical symptoms. All of this can be accomplished through a single agent, targeting granzyme B that I have discovered and is currently under investigational new drug status review at the FDA. Granzyme B is an enzyme released by immune cells that induces tumor killing, and it has been shown by myself and others to be present in high amounts in tumors that are undergoing response to immunotherapy. I have designed a PET imaging agent that only detects the active and released form of granzyme B, effectively distinguishing between immune cells that are present but exhausted and immune cells that are engaged in tumor killing. The goal of this work would be to use this agent to analyze patients before and after therapy to quantify levels of granzyme B and correlate them with overall response, as well as combine PET imaging with powerful tissue based genetic sequencing and histology. Because the scan covers the entire body, all of a patient?s tumor lesions would be analyzed, in addition to potential sites of adverse events. By monitoring both response and adverse events, a retrospective analysis of patients scanned with this agent could lead to clinical diagnostic parameters for early adverse event detection. Taken together, this approach represents an unconventional but potentially powerful way of investigating whole body immune cell activation, which has the potential to deliver immunotherapy to patients for whom it will benefit, while allowing those who would not benefit to pursue alternative options, including novel clinical trials.
Cancer immunotherapy can be highly effective, but it often is not and currently there is no way to predict its outcome until tumor progression. Granzyme B PET imaging represents a new method of non-invasively detecting sites of immune cell activation can provide an opportunity to improve patient selection, discover new mechanisms of resistance for second generation therapy, and detect sites of adverse events before they reach clinical symptoms.
