Granzyme B PET as a Novel Means to Assess T-Cell Activation in Response to 177Lu-PSMA-617 Priming in Metastatic Castration-Resistant Prostate Cancer
Abstract
Cancer immunotherapies that mobilize patients’ own immune system to ablate tumors are among the most promising new classes of anticancer therapies. However, the profound remissions seen in patients with cancers like bladder, melanoma, or non-small cell lung cancer have not been commonly observed in prostate cancer patients. On this basis, the prostate cancer research community is now working aggressively to understand why prostate cancer is poorly responsive to first generation cancer immunotherapies to identify new therapeutic approaches to overcome resistance. Data from our research program is beginning to suggest that radiation therapy may prime prostate cancer tumors to experience better tumor responses to cancer immunotherapies. To test this idea, we recently launched the first clinical trial in the United States, investigating whether a single dose of 177Lu-PSMA effectively primes prostate cancers to respond to pembrolizumab immunotherapy (NCT03805594). We have observed very promising durable responses in nearly half of patients, opening up possibilities for further combinations of radiation plus immunotherapy in prostate cancer. Yet, importantly, using traditional genetic sequencing tools, we have been unable to identify which patients are most likely to respond to this approach. To respond to this unmet need to identify whose tumors are responding to this combination of radiation and immunotherapy, we developed a new imaging technology that specifically detects immune cells actively engaged in the process of tumor cell killing. We developed this technology because it is currently very challenging to observe on conventional imaging (e.g., CT, nuclear bone scan, PSMA PET) death of prostate cancer caused by immune cells. Moreover, acquiring prostate cancer biopsies after starting treatment to look for evidence of tumor response is challenging and often unsuccessful. Even when successful, trying to predict patient response based on the biological features of one tumor biopsy is problematic, as one patient typically has over 20 metastases in different sites (e.g., bone, liver), and prostate cancer metastases are biologically different, even within the same patient. Thus, we hypothesize that our imaging assay will provide a non-invasive and more holistic indication that a patient is responding to therapies designed to active the immune system compared to contemporary diagnostic techniques. We have completed and published proof of concept studies showing that the imaging technology (termed 64Cu-GRIP B) can detect tumors responding to immune checkpoint inhibitors in clinically relevant mouse models of cancer. Since this milestone, we have received grant support from the National Cancer Institute to translate 64Cu-GRIP B into humans, and a first in human study is planned for early 2022. Thus, we are well positioned to perform the first-ever patient studies of 64Cu-GRIP B in prostate cancer patients enrolled in our combination trial of 177Lu-PSMA plus pembrolizumab immunotherapy. After modifying the existing clinical trial to include 64Cu-GRIP B PET, we will conduct serial imaging with 64Cu-GRIP B PET/CT pre- and post-treatment to determine whether early tumor responses can be captured on imaging. We will analyze the PET imaging data to evaluate whether early post-treatment changes in tumor uptake of 64Cu-GRIP B relate to immune-related changes in the tumor and/or blood and to forecast whether a patient experiences survival benefit from treatment. Since this project is focused on implementing a new imaging technique to reveal how to more effectively mobilize a productive immune response against prostate cancer, the project is mutually responsive to the overarching challenges to Define the biology of lethal prostate cancer to reduce death and Develop treatments that improve outcomes for men with lethal prostate cancer. This project is primarily focused on patients with metastatic hormone resistant prost
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210513
Entities
People
- Rahul Aggarwal
Organizations
- United States Army
- University of California, San Francisco