Improving Immunotherapy: Boosting Immune Response and Functional Immune Cell Imaging
Abstract
Project Description: Colorectal cancer (CRC) is the third most common cause of cancer-related death in the United States. Approximately 50% of all patients develop metastases, which is associated with poor survival. Recently, a new drug group, immune checkpoint blockers such as "anti-CTLA-4" or "anti-PD-1," have been introduced for the effective treatment of many cancers. Their mode of action is to promote the activation and recruitment of anticancer active immune cells such as CD8+ T-effector cells to the tumor for effective treatment. Yet, the treatment success in patients with CRC is lacking behind expectations, which is believed to be associated with the low "immunogenicity" resulting in an overall lower anticancer immune system activation. However, increasing the immunogenicity can be achieved by e.g., thermal tumor ablation acting as an in situ immunostimulatory process. Thus, we hypothesize that augmenting the immunogenicity of CRC via thermal ablation may increase tumor response to immune checkpoint inhibition treatment initiating a powerful antitumor immune reaction, which exceeds the anticancer treatment effect of either thermal ablation or immune checkpoint inhibition alone. We will test this hypothesis in the "CT26 - BALB/c" CRC mouse model. Besides increasing the treatment response, strategies for treatment response prediction and assessment are key to deliver the best possible care for each patient. However, currently applied response criteria used to decide for a successful or unsuccessful therapy are based on tumor shrinkage or growth, which can only be assessed meaningful at a relatively late stage (~3 months) after treatment start, possibly delaying alternative treatment. In several preclinical and clinical investigations, increased intratumoral CD8+ cells before treatment as well as ~3-6 weeks after treatment correlated with better therapy response. Thus, the monitoring of active intratumoral CD8+ cells may be an effective strategy for response prediction and early treatment response assessment: With our newly developed dual pre-targeted PET imaging strategy, aimed at imaging CD8+ immune cells co-localized with cancer cells, we intend to quantify intratumoral CD8+ immune cells. To estimate immune cell activity, we propose to measure the extracellular pH, which is known to correlate with immune cell activity (e.g., low activity in acidic environment). Extracellular pH will be measured via Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) Magnetic Resonance Imaging (MRI). We hypothesize that the combination of the dual pre-targeted PET Imaging and the BIRDS MRI technique will allow for an accurate quantification of active antitumor CD8+ T-effector cells within the tumor. In summary, with our proposed research, we aim at improving the treatment efficacy of immune checkpoint blockers in CRC and to develop a new strategy for functional immune response prediction and assessment. Career Goals in Cancer Research: The Principal Investigator (PI) is an interventional radiologist who has a vast experience in treatment and imaging of cancers including CRC. Treatment with immune checkpoint inhibitors is rapidly emerging for many cancers such as e.g., melanoma with great response rates, whereas for other tumors such as e.g., CRC, success is lacking behind expectations. The proposed research aims at improving treatment response and response assessment from an (interventional) radiology perspective, which will allow the PI to go new paths to investigate and to promote the role of radiology in the field of immunotherapy. The research and career development plan will allow the PI to test the concept and to lay the groundwork for future evaluations of the proposed project. Applicability of the Proposed Research: Thermal ablation as an in situ immunostimulatory process bears a promising potential to improve response to immune checkpoint inhibition therapy in patients with CRC. Since
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710505
Entities
People
- Hyun Kim
Organizations
- United States Army
- Yale University