Efficacy and Tolerance of Immune Checkpoint Inhibitors in Transplant Patients With Cancer

A Systematic Review

Thibaut d'Izarny-Gargas; Antoine Durrbach; Mohamad Zaidan

Disclosures

American Journal of Transplantation. 2020;20(9):2457-2465. 

In This Article

Abstract and Introduction

Abstract

Solid organ transplant (SOT) is frequently complicated by cancers, which render immunosuppression challenging. Immune checkpoint inhibitors have emerged as treatments for many cancers. Data are lacking regarding efficacy and rejection risk in the SOT population. We conducted a systematic literature review and analyzed 83 cases of immune checkpoint inhibitor use for cancer in SOT. Two thirds of these patients received anti–programmed death ligand 1 therapy, 15.7% received anti–cytotoxic T lymphocyte–associated protein 4 therapy, and 10.8% received a combination. Allograft rejection occurred in 39.8% of patients, leading to end-stage organ failure in 71.0% of cases. Outcomes were similar across organs and immunotherapy regimens. The use of immunosuppressants other than steroids, time since transplant, and prior episodes of rejection were associated with the risk of rejection. The median overall survival of patients was 36 weeks. Most of the deaths were related to cancer progression. In nonkidney recipients, graft rejection was strongly associated with worse survival. At the end of the study, 19.3% of the patients were alive, free from rejection and tumor progression. This study highlights the difficult tradeoff facing oncologists and transplant specialists managing transplant recipients with cancer, and the need for prospective data and novel biomarkers for identifying the patients likely to benefit from immunotherapy in the SOT setting.

Introduction

Cancer development in solid-organ transplant recipients (SOTRs) is a major concern, because many tumors have a higher frequency in such patients than in the general population[1,2] and cancer is the second leading cause of mortality in these patients.[3] Immunosuppression is essential to ensure allograft tolerance, but it also increases the risk of tumor emergence and progression.[4]

Immunotherapy has recently emerged as a treatment option for many cancers.[5–9] Pathology studies have shown that tumor cells or the surrounding tumor-infiltrating lymphocytes express programmed cell death protein 1 (PD1)/programmed death ligand (PD-L1) and/or cytotoxic T lymphocyte–associated protein 4 (CTLA-4), which may hinder full T lymphocyte activation by inhibiting the second signal pathway. Immune checkpoint inhibitors (CPIs) targeting these molecules can be used to restore T lymphocyte activation and antitumor activity. CPIs have gained US Food and Drug Administration approval following randomized controlled trials showing benefit for patient survival.[5] However, SOTRs were excluded from these trials, due to concerns that such treatment strategies might trigger allograft rejection and that the immunosuppressive drugs might decrease antitumor efficacy.[9]

In solid organ transplant, immune checkpoint pathways also play an important role in controlling the immune response. For example, belatacept, a CTLA-4–immunoglobulin fusion protein inhibiting T cell coactivation, is used instead of calcineurin inhibitors for some kidney transplant patients. It has been shown to be effective for preventing acute rejection in kidney transplant patients,[10] by inhibiting the interaction between CD80/86 on presenting cells with their ligands CD28 or CTLA-4. However, a higher rate of acute rejection has been observed in patients treated with belatacept than in controls in phase 3 studies, and this rejection is associated with a higher proportion of CD8+CD28+ or CD4+CD57+PD-1 memory T cells.[11,12] Conversely, the impairment of T cell activation by belatacept is associated with a higher risk of lymphoma after transplant in Epstein-Barr virus (EBV)-negative patients receiving an organ from EBV-positive donors.[13] Moreover, there is experimental evidence to suggest that the immunoregulatory pathways controlling the second signal are involved in graft tolerance, resulting in a probable risk of organ rejection in cases of blockade.[14–18] These findings highlight the complexity of the role of checkpoint pathways in graft acceptance and the control of tumor development and drug response in SOTRs.

Case reports and short series documenting the use of CPIs in SOTRs have yielded conflicting results for organ rejection and antitumor efficacy.[19–21] The true benefits and pitfalls of CPI use in SOTRs with cancer remain to be determined. The concomitant management of immunosuppression also remains a major concern. This systematic literature review addresses these issues.

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