PRESENTED BY
BEN SPRANGERS

Presentation Summary

Written by Jasna Trbojevic-Stankovic
Reviewed by Ben Sprangers

The introduction of immune-checkpoint modulators to the oncology field nearly a decade ago has indeed revolutionized cancer therapy. The first authorized antibody blocking an immune checkpoint was ipilimumab, which was released in 2011 and directed against CTLA4. It was later followed by PD-1 inhibitors nivolumab, pembrolizumab, and cemiplimab, and PD-L1 inhibitors atezolizumab, avelumab, and durvalumab (1).

Mechanisms of action of immune checkpoint inhibitors
Several regulatory mechanisms normally maintain an immune response within a desired physiologic range and protect the host from excessive immune response.In the cancer setting, removing inhibitory signals of T-cell activation enables tumor-reactive T cells to overcome regulatory mechanisms and establish an effective antitumor response. Two signals are necessary for efficient CD4 T cell activation. One is provided by the recognition of antigen presented to the T cell receptor by the major histocompatibility complex class II molecules in the antigen-presenting cells. The other is co-stimulatory signaling through CD28 present on T cells which ligates to CD80 or CD86 receptors on antigen-presenting cells. Overactivation of this process is prevented by the negative feedback loop involving anti-CTLA4 which binds to CD80 and CD86 with a much higher affinity than CD28. Administering antibodies against anti-CTLA4 inhibits this inhibitory signal, thus resulting in prolonged reactivation of T cells (2).
The PD-1/PD-L1 system, which is set to maintain T-cell responses within a desired physiologic range, is activated by immune responses to inflammatory cytokines. Upon engagement with PD-L1, PD-1 primarily transmits a negative costimulatory signal to attenuate T-cell activation (Figure 1). Recent evidence also suggests that CD28 is a primary target for PD-1–induced attenuation, implying that both, CTLA4 and PD-1, at least in part, act through a similar molecular mechanism of attenuating CD28-mediated costimulation (2).

Figure 1. Mode of action of checkpoint inhibitors (2, 3)

CPI-induced immune-related adverse events
Checkpoint inhibitors (CPIs) undoubtedly represent the paramount achievement in cancer treatment. Unlike the previous genomically-targeted therapies to which cancer cells eventually develop resistance mechanisms, the CPIs rely on inhibiting the randomly generated antigen receptors, followed by a selective process that generates a vast repertoire of T cell clones, providing sufficient diversity and adaptability to match the complexity of tumors (4). Hence, they provide significantly higher survival rates even in patients with metastatic disease (5).
Nevertheless, similar to other cancer therapies, CPIs may lead to side effects and toxicities. They can cause a unique spectrum of autoimmune phenomena, known as immune-related adverse events, generally manageable with immunosuppressive agents (4). The mechanisms of these immune-related adverse events vary related to the specific agent used (Figure 2). CTLA4 inhibitors induce T cells overactivation and proliferation, impaired regulatory T cells survival, overproduction of T helper 17 cells, cross-reactivity between anti-tumor T cells and antigens on healthy cells, and increased autoantibody production (2). PD-1 and PD-L1 inhibitors reduce the survival and inhibitory function of regulatory T cells and increase cytokine production (2).

Figure 2. The mechanisms of immune-related adverse events from CPIs (2, 3)

The frequency of immune-related adverse events is mainly dependent on the agents used. There are emerging data suggesting that adverse events are slightly more frequent with CTLA4 inhibitors than with PD1/PDL1 inhibitors. A recent network meta-analysis evaluated the safety profiles of the currently used CPIs concluding that atezolizumab had the best safety profile in general, and nivolumab the best safety profile in lung cancer when taking and integrated approach. Based on this analysis, tremelimumab exhibits the most toxic profile (6). Ironically, the higher occurrence of immune-related adverse events, especially cutaneous, is associated with better tumor outcomes (7).

Besides the type of CPI, other factors associated with the frequency of immune-related adverse events are the exposure time, the administered dose, and specific characteristics of individual patients (6). The most often affected systems are the skin, the gastrointestinal tract, the lungs, the liver, and the endocrine system (8). Renal involvement is less common but can be significant. The most frequent renal immune-related adverse event of CPI therapy is acute tubulointerstitial nephritis. The risk for its presentation increases when a combination of CPIs is used, as well as with concomitant use of proton pump inhibitors (1). A very recently published paper presented the results of a multicenter study of 138 patients with immune CPI-associated acute kidney injury identifying baseline estimated glomerular filtration rate <30ml/min, use of proton pump inhibitors, and combination of CPIs as major risk factors for developing acute tubulointerstitial nephritis (9). Fortunately, the majority of patients responded well to corticosteroid treatment and achieved complete or partial recovery of renal function Although there is uncertainty about the optimal dosing and duration of the corticosteroid treatment. Besides acute tubulointerstitial nephritis, certain patterns of glomerular involvement have also been associated with specific CPIs, as presented in Table 1 (10, 15). [/av_textblock] [av_image src='https://www.era-edta.org/en/nep/wp-content/uploads/sites/9/2021/01/sprangers3.jpg' attachment='2599' attachment_size='full' align='center' styling='' hover='' link='' target='' caption='' font_size='' appearance='' overlay_opacity='0.4' overlay_color='#000000' overlay_text_color='#ffffff' copyright='icon-reveal' animation='no-animation' av_uid='av-k21xyois' custom_class='' admin_preview_bg=''] Figure 1: Potential interventions in CKD [17] [/av_image] [av_textblock size='11' font_color='' color='' av-medium-font-size='' av-small-font-size='' av-mini-font-size='' av_uid='av-k20b1b35' custom_class='' admin_preview_bg='']

Table 1. Renal immune-related adverse events from CPIs besides tubulointerstitial nephritis (3, 10)

CPIs in patients with CKD/dialysis, systemic diseases with renal involvement, and solid organ transplant recipients
CPIs are large molecules, not removed by the kidneys, and thus not requiring dose adjustment related to the level of renal function. Nevertheless, there is a notable paucity of studies on the effects of CPIs in patients with renal dysfunction thus necessitating further investigations of this subject.

Other important issues to consider with CPIs are their safety and efficacy in patients with preexisting autoimmune disease. One nationwide multicenter study which included 112 patients with psoriasis, rheumatoid arthritis, and inflammatory bowel disease receiving CPIs indicated that flares or immune-related adverse events occur frequently, but are mostly manageable without discontinuation of cancer therapy. Immunosuppressive therapy at baseline was associated with poorer outcomes in this study (11). A more recent review suggests that the risk of developing immune-related adverse events depends on the underlying systemic disease. Patients with polymyalgia rheumatica, myasthenia and/or myositis, rheumatoid arthritis and psoriasis seem to be most affected, while those with lupus and ANCA-associated vasculitis are less inclined to experience immune-related adverse events with CPIs (2). However, larger studies are needed to substantiate this evidence.

Solid organ transplant recipients exhibit two to three-fold higher mortality and cancer risks than the general population. Nonetheless, anti-cancer treatment with CPIs in these patients is highly challenging. CPIs target The PD1/PDL1 axis involved in graft maintenance and may lead to stimulation of T-cells in peripheral tissues beyond cancer, thus affecting graft survival. Indeed, the use of CPIs has been associated with acute rejections of solid organ transplants in nearly half of the treated patients, with a slightly higher risk associated with PD1/PDL1- than with CLTA4 inhibitors. Conversely, immune-related adverse events are more often associated with CTLA4 CPIs (12, 13). Nevertheless, careful patient selection might improve the prospects and obtain a favorable antitumor response while avoiding rejection, but more studies are needed to define guidance on how to identify these patients (14, 16).

References

1. Gupta S, Cortazar FB, Riella LV, Leaf DE. Immune Checkpoint Inhibitor Nephrotoxicity: Update 2020. Kidney360 2020;1(2):130-140.

2. Ramos-Casals M, Brahmer JR, Callahan MK, et al. Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers. 2020;6(1):38. doi: 10.1038/s41572-020-0160-6.

3. Sprangers B. Checkpoint inhibitors: Should CPI be administered after KT/CKD patients? Presented at the 57th European Renal Association – European Dialysis Transplantation Association congress (fully virtual). June 6, 2020. Available at Virtual Meeting

4. Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161(2):205-14. doi: 10.1016/j.cell.2015.03.030.

5. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373(1):23-34. doi: 10.1056/NEJMoa1504030.

6. Xu C, Chen YP, Du XJ, et al. Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis. BMJ. 2018;363:k4226. doi: 10.1136/bmj.k4226.

7. Eggermont AMM, Kicinski M, Suciu S. Management of Immune-Related Adverse Events Affecting Outcome in Patients Treated With Checkpoint Inhibitors-Reply. JAMA Oncol. 2020;6(8):1301. doi: 10.1001/jamaoncol.2020.1935.

8. Martins F, Sofiya L, Sykiotis GP, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019;16(9):563-580. doi: 10.1038/s41571-019-0218-0.

9. Cortazar FB, Kibbelaar ZA, Glezerman IG, et al. Clinical Features and Outcomes of Immune Checkpoint Inhibitor-Associated AKI: A Multicenter Study. J Am Soc Nephrol. 2020;31(2):435-446. doi: 10.1681/ASN.2019070676.

10. Herrmann SM, Perazella MA. Immune Checkpoint Inhibitors and Immune-Related Adverse Renal Events. Kidney Int Rep. 2020;5(8):1139-1148. doi: 10.1016/j.ekir.2020.04.018.

11. Tison A, Quéré G, Misery L; Groupe de Cancérologie Cutanée, Groupe Français de Pneumo-Cancérologie, and Club Rhumatismes et Inflammations. Safety and Efficacy of Immune Checkpoint Inhibitors in Patients With Cancer and Preexisting Autoimmune Disease: A Nationwide, Multicenter Cohort Study. Arthritis Rheumatol. 2019;71(12):2100-2111. doi: 10.1002/art.41068.

12. Delyon J, Zuber J, Dorent R, et al. Immune Checkpoint Inhibitors in Transplantation-A Case Series and Comprehensive Review of Current Knowledge. Transplantation. 2020. doi: 10.1097/TP.0000000000003292.

13. d’Izarny-Gargas T, Durrbach A, Zaidan M. Efficacy and tolerance of immune checkpoint inhibitors in transplant patients with cancer: A systematic review. Am J Transplant. 2020;20(9):2457-2465. doi: 10.1111/ajt.15811.

14. De Bruyn P, Van Gestel D, Ost P, et al. Immune checkpoint blockade for organ transplant patients with advanced cancer: how far can we go? Curr Opin Oncol. 2019;31(2):54-64. doi: 10.1097/CCO.0000000000000505.

15. Cortazar FB et al. Clinical Features and Outcomes of Immune Checkpoint Inhibitor-Associated AKI: A Multicenter Study. J Am Soc Nephrol. 2020 Feb;31(2):435-446. doi: 10.1681/ASN.2019070676.

16. Murakami N et al; Immune Checkpoint Inhibitors in Solid Organ Transplant Consortium. A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant. Kidney Int. 2020 Dec 23:S0085-2538(20)31534-9. doi: 10.1016/j.kint.2020.12.015

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