Case report: Predictability of clinical response and rejection risk after immune checkpoint inhibition in liver transplantation

Abstract

Background: The approval of Atezolizumab / Bevacizumab therapy (Atezo/Bev) in 2020 opened up a promising new treatment option for patients with end-stage hepatocellular carcinoma (HCC). However, liver transplant (LTx) patients with HCC are still denied this therapy owing to concerns about ICI-induced organ rejection and lack of regulatory approval.

Methods: A prospective observational study at a tertiary liver transplant centre monitored the compassionate, off-label use of Atezo/Bev in a single, stable LTx recipient with non-resectable HCC recurrence. Close clinical, laboratory and immunological monitoring of the patient was performed throughout a four-cycle Atezo/Bev treatment. Measured parameters were selected after a systematic review of the literature on predictive markers for clinical response and risk of graft rejection caused by ICI therapy.

Results: 19 articles describing 20 unique predictive biomarkers were identified. The most promising negative prognostic factors were the baseline values and dynamic course of IL-6, alpha-fetoprotein (AFP) and the AFP/CRP ratio. The frequency of regulatory T cells (Treg) reportedly correlates with the success of ICI therapy. PD-L1 and CD28 expression level with the allograft, peripheral blood CD4⁺ T cell numbers and Torque Teno Virus (TTV) titre may predict risk of LTx rejection following ICI therapy. No relevant side effects or acute rejection occurred during Atezo/Bev therapy; however, treatment did not prevent tumor progression. Absence of PD-L1 expression in pre-treatment liver biopsies, as well as a progressive downregulation of CD28 expression by CD4⁺ T cells during therapy, correctly predicted absence of rejection. Furthermore, increased IL-6 and AFP levels after starting therapy, as well as a reduction in blood Treg frequency, correctly anticipated a lack of therapeutic response.

Conclusion: Atezo/Bev therapy for unresectable HCC in stable LTx patients remains a controversial strategy because it carries a high-risk of rejection and therapeutic response rates are poorly defined. Although previously described biomarkers of rejection risk and therapeutic response agreed with clinical outcomes in the described case, these immunological parameters are difficult to reliably interpret. Clearly, there is an important unmet need for standardized assays and clinically validated cut-offs before we use these biomarkers to guide treatment decisions for our patients.

Keywords: biomarker; clinical response; hepatocellular carcinoma; immune checkpoint inhibition; immune monitoring; liver transplantation; rejection risk.

Figure 1

Contrast-enhanced CT scans before initiation of ICI therapy and as interim examination after 3 cycles of atezolizumab / bevacizumab treatment. Both intrahepatic (A + C) and intrapulmonary (B + D) HCC metastases are marked in colour. (A) Pretherapeutic axially reconstructed abdominal CT scan showing a large recurrence of HCC in the left liver lobe. (B) Pretherapeutic coronary reconstructed thoracic CT scan showing a pulmonary metastasis of HCC. (C) Axially reconstucted abdominal interim CT scan showing an example of a pronounced progression of intrahepatic HCC. (D) Coronary reconstucted thoracic interim CT scan showing marked progression of pulmonal HCC metastases.

Figure 2

Routine biochemical liver parameters in the course of ICI therapy. (A,B) Liver enzymes (GOT & GPT) to assess the vitality of the hepatocytes. (C–E) Cholestasis parameters (γGT, GLDH & AP) to assess the vitality of the cholangiocytes. (F,G) Bilirubin and CHE for assessing metabolic functionality of the transplanted liver.

Figure 3

Histopathology of biopsies of the transplant liver (A–C) as well as intrahepatic HCC foci (D,E) prior to initiation of immune checkpoint therapy (200x magnification). (A) HE-stained representative section of the transplant liver biopsy. * intrahepatic fat vacuoles, → inflammatory infiltrate. (B) Corresponding immunohistochemical staining for PD-L1. (C) Corresponding immunohistochemical staining for PD-1. → inflammatory infiltrate with scattered PD-1 positive lymphocytes. (D) HE-stained representative section of HCC-infiltrated liver biopsy. (E) Corresponding immunohistochemical staining for PD-L1. (F) Immunohistochemical staining for CD3.

Figure 4

Immunomonitoring data in the course of ICI therapy. (A–C) Clinical routine Inflammatory parameters. (D) Torque Teno Virus level (TTV) as a surrogate parameter for the patient's immunocompetence. (E) AFP tumor marker level. (F) CD28 expression level in CD4⁺ T cells in peripheral blood. (G) Frequency of Tregs in the peripheral blood.