Tumor location as a risk factor for severe immune-related adverse events

Abstract

Immune-related adverse events (irAEs) can cause severe morbidity and mortality, and they impair treatment with immune checkpoint inhibitors (ICI). Risk factors for irAEs are not well understood.We observed cases of patients having tumor deposits in their liver and lung during a workup of irAEs, which led us to hypothesize that the presence of tumor in an organ would increase the odds of developing severe irAEs in that organ. We then performed a retrospective cohort study that included patients who received an ICI for the treatment of cancer and were hospitalized between February 2011 and November 2021 at the Massachusetts General Hospital.We reviewed 384 patients hospitalized with concern for any irAE. A clinical diagnosis of ICI-related hepatitis occurred in 18% of patients with liver tumor deposits versus 8% of those without (OR 2.23, 95% CI (1.10 to 4.43), p=0.02). ICI-related pneumonitis occurred in 10% of patients with lung tumor deposits versus 4.4% of those without (OR 2.45, 95% CI (1.06 to 6.36), p=0.047). A combined analysis for liver and lung lesions demonstrated that the presence of tumor deposits in an organ increased the odds of having an irAE in that organ by over twofold (OR 2.31, 95% CI (1.34 to 3.99), p=0.002).Our results suggest that the presence of tumor deposits may represent a novel risk factor for severe irAEs in that organ.

Keywords: Biomarker; Immune Checkpoint Inhibitor; Immune related adverse event - irAE; Immunotherapy.

Figure 1. Clinical cases of tumor infiltration in the organs affected with immune-related adverse events. (A, B) Pathologic correlates of Case 1. In (A) H&E of a liver biopsy from Case 1 at (left) 100x magnification and (right) 400x magnification shows infiltration of liver parenchyma with uveal melanoma and lymphocytes. In (B) a repeat biopsy from Case 1 collected 2 months later shows findings consistent with ICI-related hepatitis and no metastases at (left) 100x and (right) 400x magnification. Areas enriched with clusters of cancer cells with large nuclei and nucleoli (yellow circles) and lymphocytes (black circles) are highlighted to demonstrate examples of cell populations that are interspersed in the tissue. (C, D) Radiographic correlates of Case 2. In (C) contrast-enhanced CT imaging shows areas of (left) metastatic melanoma and (right) lung parenchyma prior to ICI initiation. In (D) non-contrast CT imaging 6 months after ICI treatment initiation shows the same regions as in (C) to highlight evidence of (left) antitumor response and (right) ICI-related pneumonitis, respectively. ICI, immune checkpoint inhibitor.

Figure 2. Patient inclusion and exclusion analyses. A flow diagram showing the number of patients excluded from the study for meeting the listed clinical criteria as well as those with the irAEs and tumor deposits in the organs of interest. ICI, immune checkpoint inhibitor; irAE, immune-related adverse event; irHepatitis, ICI-related hepatitis; irPneumonitis, ICI-related pneumonitis.

Figure 3. irAEs in livers and lungs with tumors. (A), (B) 2×2 tables of tumors and irAEs in the (A) liver and (B) lung. In each group, the patients with and without tumors in that organ and with and without a diagnosis of (A) ICI-related hepatitis and (B) ICI-related pneumonitis are shown. (C) A meta-analysis using a random-effects model of the risk of irAEs in these individual organs shows that the presence of tumor in an organ was associated with an increased risk of developing an irAE in that organ. ICI, immune checkpoint inhibitor; irAE, immune-related adverse event.