Immune Checkpoint Inhibitor Therapy for Kidney Transplant Recipients - A Review of Potential Complications and Management Strategies

Abstract

Immune checkpoint inhibitor (ICI) therapy has enabled a paradigm shift in Oncology, with the treatment of metastatic cancer in certain tumor types becoming akin to the treatment of chronic disease. Kidney transplant recipients (KTR) are at increased risk of developing cancer compared to the general population. Historically, KTR were excluded from ICI clinical trials due to concern for allograft rejection and decreased anti-tumor efficacy. While early post-marketing data revealed an allograft rejection risk of 40%-50%, 2 recent small prospective trials have demonstrated lower rates of rejection of 0%-12%, suggesting that maintenance immunosuppression modification prior to ICI start modulates rejection risk. Moreover, objective response rates induced by ICI for the treatment of advanced or metastatic skin cancer, the most common malignancy in KTR, have been comparable to those achieved by immune intact patients. Non-invasive biomarkers may have a role in risk-stratifying patients before starting ICI, and monitoring for rejection, though allograft biopsy is required to confirm diagnosis. This clinically focused review summarizes current knowledge on complications of ICI use in KTR, including their mechanism, risk mitigation strategies, non-invasive biomarker use, approaches to treatment of rejection, and suggestions for future directions in research.

Keywords: biomarkers; immunology; immunotherapy; kidney transplant; oncology; rejection risk.

FIGURE 1

Timeline of immune checkpoint inhibitor approvals by the United States Food and Drug Administration (FDA) from 2011 to 2023.

FIGURE 2

T-cell activation via the three-signal model. Cancer cells express tumor associated antigens which are captured by APCs. Signal 1: Antigen peptide presented by APC on MHC molecule binds to TC on -cell surface. Signal 2: Co-stimulation. The binding of CD28, expressed on T cells, to CD80/86 expressed on APC’s describes one of the necessary co- stimulatory signals. Signal 3: Once signal 1 and 2 have been completed, signal 3 denotes cytokine production by T cells, which allows ongoing T cell differentiation and proliferation. This includes the production of IL2 by T-cells leading to IL2-R stimulation on the surface of T cells. Il- Immune checkpoints provide a negative feedback mechanism in the setting of T cell activation. In lymphoid tissues, CTLA-4 binds to CD80/86 with higher affinity than CD28, leading to competitive inhibition of signal 2. In the peripheral tissue, PD-L1 which is expressed by epithelial cells (i.e., renal TEC, tumor cells) binds to PD-1, which is expressed by peripherally circulating T cells, inducing T-cell exhaustion. Abbreviations: APC, Antigen presenting cell; MHC, Major histocompatibility complex I/ll; TC, T-cell receptor; IL-2, Interleukin-2; IL2-R, Interleukin-2 receptor; CTLA-4, Cytotoxic -lymphocyte associated protein 4; PD-L1, Programmed cell death ligand 1; PD1, Programmed cell death protein 1; TEC, Tubular epithelial cell; JAK-3, Janus Kinase 3.

FIGURE 3

Immune checkpoint inhibitors including Anti CTLA-4, PDL-1 and PD-1 antibodies function by blocking the interactions between checkpoint proteins and their receptors. This disrupts the counter-regulatory negative feedback mechanism that suppresses T-cell activity, leading to persistent T-cell activation and proliferation, allowing T-cells to recognize and eliminate tumor cells. The tumor cells express LECtin, Gal-3, and FGL-1, which bind to LAG-3 expressed on the surface of T-cells and provoke T-cell anergy. Tumor tolerance is also promoted by the infiltration of Tregs within the tumor microenvironment. These Tregs express higher levels of CTLA-4, PD-1, LAG-3, and TIM-3, and they secrete elevated levels of IL-10 and TGF-ß, thus facilitating tumoral resistance. Abbreviations: CTLA-4, Cytotoxic T-Lymphocyte Antigen 4; PDL-1, Programmed cell death ligand 1; PD-1, Programmed cell death protein 1; LSECtin, Liver sinusoidal endothelial cell lectin; Gal-3, Galectin-3; FGL-1, Fibrinogen-like protein-1; LAG-3, Lymphocyte activation gene-3; Treg, Regulatory T-cell; TIM-3, T-cell immunoglobulin and mucin domain-containing protein 3; TGF-ß, Transforming growth factor- beta; CD 80/86 and CD 28, Cluster of differentiation 80/86 and 28; IL-10, Interleukin-10.

FIGURE 4

Immunoediting process represented by the dynamic interplay between the tumor micro-environment and the immune system in three phases. Phase I (Elimination): The host immune system initially recognizes the cancer cells as foreign (immune surveillance). Cytotoxic -cells and natural killer cells target tumor cells. Phase I (Equilibrium): A subset of tumor cells develop immune evasion mechanisms (reduced immunogenicity), but there is an overall balance between immune mediated tumor suppression and tumor outgrowth. Phase IIl (Tumor escape): Tumor cells evade the immune system’s surveillance and proliferate uncontrollably. This results in clinically apparent tumor, recurrence and/or metastases. Maintenance immunosuppression impedes initial immune surveillance. This reduces selective pressure on tumor cells which is necessary for the development of mechanisms that allow tumor immune evasion. As a result, tumors that develop in immunosuppressed individuals may be more likely to maintain their initial immunogenicity.