Intravital Imaging of Melanoma Tumors for Mechanism Discovery and Patient Surveillance After Checkpoint Blockade Immunotherapy
Abstract
This research project addresses these two FY22 MRP Focus Areas: identify how the tumor microenvironment impacts response to therapy and progression and develop prediction and surveillance tools for distinguishing patient populations at risk for second primary/recurrence and/or metastasis. Our research also tackles some objectives of the FY22 MRP Challenge Statement, particularly the need for improved tools and improved outcomes for melanoma patients. The central problem addressed in this application is that although many patients with metastatic melanoma greatly benefit, and in some cases are cured, by checkpoint blockade immunotherapy (CBI), most of them do not respond. Thus, there is a pressing need for more efficacious CBI and tools that help physicians monitor how well CBI works in patients. Indeed, it is of paramount importance to learn as early as possible if a therapy is not working so that treatment can be changed before the tumor has the opportunity to grow. The objective of this proposal is to apply intravital microscopy to aid the examination of melanoma patients treated with CBI. Intravital microscopy is a technique that allows us to record movies of immune cells as they move within the melanoma tumor inside a patient. From immune cell movement, we can deduce lots of information, including if the CBI is triggering an immune response that will benefit the patient or not. Thus, our intravital microscopy tool has the potential to give early indications of the efficacy of immunotherapy. To reach this goal, we divided our proposal into three Aims. In the first Aim, we will study mouse melanoma by intravital microscopy to construct an atlas matching immune cell types with their shape, size, and how they move in the melanoma environment. Such an atlas is of paramount importance because it allows the identification of immune cells in all scenarios where their specific labeling with fluorescence dyes is impossible, including patients. In the second Aim, we will study the immune reactions unleashed by CBI in mouse melanomas and how variations in immune cell movements accompany these responses. This knowledge is essential to pair specific immune cell dynamics and the efficacy of CBI. In addition, Aim 2 will also deepen our understanding of the immune reactions triggered by CBI. In Aim 3, we will run intravital microscopy on melanoma patients treated with CBI and make predictions on how immunotherapy is working using the information from the previous two Aims. When intravital microscopy is available to melanoma patients, it will greatly aid physicians in making timely corrections to the administered therapy based on predictions on whether the current treatment is working or not. This tool thus may benefit more than half of melanoma patients in which CBI does not work, which will be directed to other types of therapy before it is too late. Notably, intravital imaging is safe, as it does not expose patients to radioactivity, and no contrast agent is administered. Human intravital microscopy bids fair to benefit all patients with metastatic melanoma. However, the melanoma rate is higher in the military above 45 years of age compared to the general population. Moreover, melanoma incidence has increased rapidly among younger men in the military, with the highest rates in the Air Force. Thus, the new surveillance tool we are developing will be particularly useful to active-duty Service Members.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311027
Entities
People
- Anand Ganesan
Organizations
- United States Army
- University of California, Irvine