R01HL159187

Immune Checkpoint Inhibitors and Accelerated Coronary Atherosclerosis - Project Summary/Abstract

Immune checkpoint inhibitors (ICI's) represent a paradigm shift in cancer care, leveraging the immune system to target cancer cells. In animal and basic studies, these pathways (PD-1, PD-L1, and CTLA-4) are also critical negative regulators of atherosclerosis. Blockade of PD-1, PD-L1, and CTLA-4 in animal studies activates T cells, leading to T cell infiltration and increased atherosclerosis.

We provide retrospective clinical and imaging data to support our hypothesis that ICI's will increase coronary atherosclerosis in a prospective study. We will test this hypothesis by performing a prospective observational coronary CTA study. Initially enrolling 300 patients with melanoma, with and without the BRAF mutation (2:1 ratio, ICI/BRAF), 135 patients will undergo serial coronary CTA at baseline, 12 months (sub-group), and 2 years. Patients with melanoma with a BRAF mutation receive BRAF inhibitors and will act as the control group, while BRAF negative patients are treated with an ICI.

In Aim 2, based on prior work, we will test whether pre-specified plausible biological factors with established associations with plaque progression (e.g. PD-1, PD-L1, SCD163, SCD14, MCP-1, IL-6, IL-1B) mediate the accelerated atherosclerosis with ICI's. For example, lower PD-1 and PD-L1 levels associate with higher coronary atherosclerotic plaque, where both PD-1 and PD-L1 suppress T cell-driven inflammation in plaques and plaque progression.

In Aim 3, we will perform unbiased exploratory analyses applying single-cell RNA technologies to systematically decipher the immune cells that contribute. In patients not on an ICI, specific T cell subsets have been linked to atherosclerosis, and in preliminary data, we show activation of specific T cells (CD8+) with other ICI toxicities.

The use of ICI's has increased and continues to rapidly expand. It is estimated that 36% of cancer patients are currently eligible for an ICI, and the number of active clinical trials leveraging ICI's is extraordinary. Therefore, there is an urgent need to test in a clinical study whether ICI's lead to accelerated coronary atherosclerosis and to provide insight into the mechanisms involved.

The General Hospital Corporation

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Boston, Massachusetts 021142750 United States

Single Zip Code

Improving Outcomes in Cancer Treatment-Related Cardiotoxicity (R01 Clinical Trial Optional) (PA-19-112)

Amendment Since initial award the total obligations have increased 286% from $1,041,129 to $4,014,114.