Immune Checkpoint Inhibitor Therapy May Induce Inflammatory Activity in Large Arteries

Study findings published in the journal Circulation suggest that immune checkpoint inhibitor therapy in patients with cancer could aggravate cardiovascular inflammation and subsequent cardiovascular or cerebrovascular events.¹

Researchers retrospectively evaluated 20 patients with known melanoma treated with immune checkpoint inhibitors (80% PD-1 inhibitors, 5% CTLA-4 inhibitors, 15% combination of PD-1 and CTLA-4 inhibitors, 85% as first-line treatment) and available FDG positron emission tomography/computed tomography scans before and during treatment. An active segment analysis (target-to-background ratio [TBR] ≥ 1.6) at both scans was performed and subsequently assessed. Further, FDG maximum standardized uptake values (SUV^max) were derived by placing 1-cm3 volumes of interest along 6 artery segments (ascending, descending, and abdominal aorta, aortic arch, iliac arteries).

Cancer immunotherapy with immune checkpoint inhibitors resulted in a significant increase of inflammatory activity in each active segment (mean SUV^max and TBR of all segments were compared; mean SUV^max_pre = 2.85 ± 0.17 vs mean SUV^{max_ post} = 3.48 ± 0.17; P < .001 and TBR^_pre = 1.76 ± 0.06 vs mean TBR^_post = 2.05 ± 0.06; P < .001). However, FDG uptake measured before and after immune checkpoint inhibitor therapy in bone marrow and spleen did not show statistical differences (SUV^{max_bonemarrow_pre} = 2.38 ± 0.23 vs SUV^{max_bonemarrow_pos}t = 2.55 ± 0.23; P = .10; SUV^{max_spleen_pre} = 3.76 ± 0.24 vs SUV^{max_spleen_post} = 3.67 ± 0.24; P = .02).

Moreover, segmental SUVmax values were found to be significantly elevated after therapy in noncalcified and mildly calcified segments (P < .001), but not in moderate to severely calcified lesions (P = .11). The inflammatory blood biomarker CRP (C-reactive protein) also did not show significant differences before and after therapy (CRP^pre = 0.47 ± 0.64 vs CRP^post = 0.90 ± 2.22; P = 0.39).

“Because of unchanged FDG activity in the spleen and bone marrow, we assumed there is nonsignificant extramedullary monocytopoiesis/hematopoiesis after [immune checkpoint inhibitor therapy], whereas the specific activation of less calcified lesions may suggest [immune checkpoint inhibitors] could profoundly impact local innate immune cells, particularly in patients experiencing early/vulnerable atherosclerotic phase but not in advanced segments presenting demoted immune cells,” the study authors concluded.

Importantly, this study does not suggest patients with cancer – even those with pre-existing cardiovascular disease – should forego immune checkpoint inhibitor therapy.² Instead, these study findings suggest oncologists should consider strategies which may mitigate any impact on the heart and consult with a cardio-oncologist to evaluate a specific patient's cardiovascular disease risk.

Senior study author, Marcus Hacker, MD, of the division of nuclear medicine at the Medical University, indicated that though this study only included patients with known melanoma, his team has since expanded the study to include patients with lymphoma, observing similar results that have not yet been published. Moving forward, he indicated that studies need to look at whether the increased arterial inflammation observed in patients receiving immune checkpoint inhibitors leads to heart complications later in life.

"If our study results can be replicated in prospective settings, we should think about future combination therapies with atherosclerosis-stabilizing agents like statins to potentially protect patients at cardiovascular risk from unfortunate events after therapy,” Hacker said in a press release.

References:

1. Calabretta R, Hoeller C, Pichler V, et al. Immune Checkpoint Inhibitor Therapy Induces Inflammatory Activity in Large Arteries. Circulation. doi: 10.1161/circulationaha.120.048708

2. Immune-boosting cancer treatment may pose cardiovascular risk [news release]. American Heart Association. Published September 8, 2020. Accessed September 24, 2020. https://www.heart.org/en/news/2020/09/08/immune-boosting-cancer-treatment-may-pose-cardiovascular-risk