Will it be possible to find predictive genetic markers of immune checkpoint inhibitor toxicity that are not also predictive of survival?

Immuno-Oncology Insights 2024; 5(1), 7–16

DOI: 10.18609/ioi.2024.002

Published: 17 January
Commentary
Claire Palles, Ik Shin Chin

A durable response to immune checkpoint inhibitor therapy is observed in 20–30% of patients, however, approximately 10–55% experience one or more grade 3+ immune related adverse events, depending upon whether they were treated with single-agent or combination checkpoint blockade therapy. In 2022, the first genome-wide association study of immune checkpoint inhibitor-induced immune related adverse events was published. We could now begin to predict which patients will experience serious immune-related adverse events requiring urgent treatment with immunosuppressive agents. There is a growing body of evidence that those who experience immune related adverse events have a better treatment response and survival outcome. This Commentary article reviews the evidence for the link between immune related adverse events induced by immune checkpoint inhibitors and efficacy. It summarizes the evidence for the interleukin-7 single nucleotide polymorphism, the first genome-wide significant biomarker of immune-related adverse effects.

Introduction

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1), programmed cell death 1 ligand (PD-L1), or cytotoxic T cell associated protein 4 (CTLA-4) were first approved as anti-cancer treatments in 2011 [1]Mansh M. Ipilimumab and Cancer Immunotherapy: A New Hope for Advanced Stage Melanoma. Yale J. Biol. Med. 2011; 84(4), 381. and their use has increased rapidly since. In the US alone there were 462,049 prescriptions for six ICI agents in 2021 [2]Shin YE, Kumar A, Guo JJ. Spending, Utilization, and Price Trends for Immune Checkpoint Inhibitors in US Medicaid Programs: An Empirical Analysis from 2011 to 2021. Clin. Drug Investig. 2023; 43(4), 289.. ICIs are used in the first or second lines of treatment for approximately 50 cancer types because of their ability to reactivate immune T cells to mount strong anti-tumor responses [3]Robert C. A decade of immune-checkpoint inhibitors in cancer therapy. Nat. Commun. 2020; 11(1), 1–3.. One of the major problems of ICI treatments, however, are the unwanted auto-immune-like immune-related adverse effects (irAEs) that can affect multiple organs. Whilst the majority of irAEs are mild, 10–55% of patients can experience severe events requiring steroid or immune modulatory treatment [4]Balducci D, Quatraccioni C, Benedetti A, Marzioni M, Maroni L. Gastrointestinal disorders as immune-related adverse events. Explor. Target Antitumor Ther. 2023; 4(5), 1095–1103. [5]Arnaud-Coffin P, Maillet D, Gan HK, et al. A systematic review of adverse events in randomized trials assessing immune checkpoint inhibitors. Int. J. Cancer 2019;145(3), 639–648. [6]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. [7]Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations. Front. Oncol. 2018; 8, 86. [8]Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N. Engl. J. Med. 2017; 377(14), 1345–1356. [9]Khoja L, Day D, Wei-Wu Chen T,
Siu LL, Hansen AR. Tumor- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2017; 28(10), 2377–2385.
. The toxicity profile of the ICI therapies can also vary depending on the ICI agent used. Egeler et al reported hypophysitis and fatigue as the most common serious irAE for anti-CTLA-4 agents, asthenia in anti-PD1 agents, and diarrhea and rash in combined anti-PD1 and anti-CTLA4 regimes. Deranged liver function tests were also commonly reported from all three ICI regimes [10]Egeler MD, van Leeuwen M, Fraterman I, et al. Common toxicities associated with immune checkpoint inhibitors and targeted therapy in the treatment of melanoma: A systematic scoping review. Crit. Rev. Oncol. Hematol. 2023; 183, 103919. . Rates of irAEs are similar for patients with auto-immune conditions but the majority of patients included in these studies did not have active or uncontrolled autoimmune disease symptoms [11]Meserve J, Facciorusso A, Holmer AK, Annese V, Sandborn WJ, Singh S. Safety and Tolerability of Immune Checkpoint Inhibitors in Patients with Pre-existing Inflammatory Bowel Diseases: A Systematic Review and Meta-analysis. Aliment Pharmacol. Ther. 2023; 53(3), 374. [12]Menzies AM, Johnson DB, Ramanujam S, et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2017; 28(2), 368–376. [13]Calvo V, Fernández MA, Collazo-Lorduy A, Franco F, Núñez B, Provencio M. Use of immune checkpoint inhibitors in patients with solid tumors and pre-existing autoimmune or inflammatory disease: real-world data. Lung Cancer Manag. 2021; 10(4), LMT51. [14]Johnson DB, Sullivan RJ, Ott PA, et al. Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders. JAMA Oncol. 2016; 2(2), 234–240.. For safety reasons, it has been suggested that autoimmune conditions be effectively treated before commencing treatment [15]Tang H, Zhou J, Bai C. The Efficacy and Safety of Immune Checkpoint Inhibitors in Patients With Cancer and Preexisting Autoimmune Disease. Front. Oncol. 2021; 11, 625872..

The severity of irAEs is evaluated using Common Terminology Criteria for Adverse Events with grade 1 representing mild, grade 2 moderate, and grades 3 and 4 severe events. ICI treatment normally continues following grade 1 irAEs, is interrupted for grade 2 until resolution to grade 1 or below and discontinued for grade 3 or higher. Systemic oral and intravenous high-dose steroids or immuno-modulatory agents are often required for grade 2 or higher irAE [16]Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J. Clin. Oncol. 2018; 36(17), 1714. [17]Ascierto PA, Simeone E, Sileni VC, et al. Clinical experience with ipilimumab 3 mg/kg: real-world efficacy and safety data from an expanded access programme cohort. J. Transl. Med. 2014; 12(1), 116.. The toxicity-induced fatality rates for ICIs have been estimated at 0.36–1.23% [18]Teraoka S, Fujimoto D, Morimoto T, et al. Early Immune-Related Adverse Events and Association with Outcome in Advanced Non-Small Cell Lung Cancer Patients Treated with Nivolumab: A Prospective Cohort Study. J. Thorac. Oncol. 2017; 12(12), 1798–1805.. Certain immune-related endocrinopathies can also result in chronic morbidity and the requirement for long-term hormone replacement therapies [19]Ghisoni E, Wicky A, Bouchaab H, et al. Late-onset and long-lasting immune-related adverse events from immune checkpoint-inhibitors: An overlooked aspect in immunotherapy. Eur J. Cancer 2021; 149, 153–164. [20]Okura N, Asano M, Uchino J, et al. Endocrinopathies Associated with Immune Checkpoint Inhibitor Cancer Treatment: A Review. J. Clin. Med. 2020; 9(7), 1–12.. Despite this, no biomarkers are currently in use clinically to predict the patients at risk of these severe events. The ICI regimes currently in use are often combined with other anti-cancer therapies including chemotherapy or targeted therapies. Predictive biomarkers of risk of toxicity will need to be tested for their clinical utility in patients being considered for increasingly complex regimens. There is also a growing need for clinically useful biomarkers of treatment response and resistance.

Limited tumor biomarkers such as microsatellite stability status and PD-L1 expression are used to select patients for treatment with ICIs [21]Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/ mismatch repair–deficient cancer: Results from the phase II KEYNOTE-158 study. J. Clin. Oncol. 2020; 38(1), 1–10. [22]Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer. N. Engl. J. Med. 2016; 375(19), 1823–1833.. High tumor expression of PD-L1 and high tumor mutation load have both been shown to be associated with favorable responses in multiple settings, but efficacy has also been seen in patients whose tumors do not display these features [23]Daud AI, Wolchok JD, Robert C, et al. Programmed Death-Ligand 1 Expression and Response to the Anti-Programmed Death 1 Antibody Pembrolizumab in Melanoma. J. Clin. Oncol. 2016; 34(34), 4102–4109. [24]Cristescu R, Mogg R, Ayers M, et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 2018; 362(6411), eaar3593. [25]Goodman AM, Kato S, Bazhenova L, et al. Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers. Mol. Cancer. Ther. 2017; 16(11), 2598–2608. [26]Negrao M V, Skoulidis F, Montesion M, et al. Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer. J. Immunother. Cancer 2021; 9(8), e002891.. Despite only using ICI in tumor types where a response is predicted e.g., due to the presentation of a large number of neo-epitopes on the surface of tumor cells, only 20–30% of patients experience a durable response to treatment [27]Ott PA, Bang YJ, Piha-Paul SA, et al. T-cell–inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J. Clin. Oncol.. 2019; 37(4), 318–327.  [28]Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer. N. Engl. J. Med 2015; 21, 2018–2046. . Biomarkers are urgently required to identify this subset of patients. A potential challenge to overcome before implementing biomarkers is the potential overlap between markers that predict tumors of toxicity and markers of durable response. As shown in Figure 1 multiple tumor and host factors are likely to be important in explaining the risk of irAEs and the likelihood of efficacy in response to ICIs.

What evidence is there for a link between survival and toxicity?

It has been suggested that skin toxicities such as hand-foot syndrome are associated with an improved response in patients treated with conventional chemotherapies [30]Stintzing S, Fischer Von Weikersthal L, Vehling-Kaiser U, et al. Correlation of capecitabine-induced skin toxicity with treatment efficacy in patients with metastatic colorectal cancer: results from the German AIO KRK-0104 trial. Br. J. Cancer 2011; 105(2), 206. [31]Jandu H, Church D, Paul J, et al. Hand-foot syndrome is a biomarker of improved survival following treatment with capecitabine. Ann. Oncol. 2019; 30, 117–118.. There is now a considerable body of work suggesting that irAEs are a biomarker of response and survival [17]Ascierto PA, Simeone E, Sileni VC, et al. Clinical experience with ipilimumab 3 mg/kg: real-world efficacy and safety data from an expanded access programme cohort. J. Transl. Med. 2014; 12(1), 116. [18]Teraoka S, Fujimoto D, Morimoto T, et al. Early Immune-Related Adverse Events and Association with Outcome in Advanced Non-Small Cell Lung Cancer Patients Treated with Nivolumab: A Prospective Cohort Study. J. Thorac. Oncol. 2017; 12(12), 1798–1805. [40]Masuda K, Shoji H, Nagashima K, et al. Correlation between immune-related adverse events and prognosis in patients with gastric cancer treated with nivolumab. BMC Cancer 2019; 19(1), 974. [41]Watson AS, Goutam S, Stukalin I, et al. Association of Immune-Related Adverse Events, Hospitalization, and Therapy Resumption With Survival Among Patients With Metastatic Melanoma Receiving Single-Agent or Combination Immunotherapy. JAMA Netw. Open 2022; 5(12), E2245596. [32]Cortellini A, Chiari R, Ricciuti B, et al. Correlations Between the Immune-related Adverse Events Spectrum and Efficacy of Anti-PD1 Immunotherapy in NSCLC Patients. Clin. Lung Cancer 2019; 20(4), 237–247. [33]Eggermont AMM, Kicinski M, Blank CU, et al. Association Between Immune-Related Adverse Events and Recurrence-Free Survival Among Patients With Stage III Melanoma Randomized to Receive Pembrolizumab or Placebo: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol. 2020; 6(4), 519. [34]Elias R, Yan F, Singla N, et al. Immune-related adverse events are associated with improved outcomes in ICI-treated renal cell carcinoma patients. World J. Clin. Oncol. 2019; 37, 645–645.  [35]Freeman-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS. Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes. Clin. Cancer Res. 2016; 22(4), 886–894. [36]Grangeon M, Tomasini P, Chaleat S, et al. Association Between Immune-related Adverse Events and Efficacy of Immune Checkpoint Inhibitors in Non-small-cell Lung Cancer. Clin. Lung Cancer 2019; 20(3), 201–207. [37]Haratani K, Hayashi H, Chiba Y, et al. Association of Immune-Related Adverse Events With Nivolumab Efficacy in Non-Small-Cell Lung Cancer. JAMA Oncol. 2018; 4(3), 374–378. [38]Indini A, Di Guardo L, Cimminiello C, et al. Immune-related adverse events correlate with improved survival in patients undergoing anti-PD1 immunotherapy for metastatic melanoma. J. Cancer Res. Clin. Oncol. 2019; 145(2), 511–521. [39]Kawai T, Sato Y, Makino K, et al. Immune-related adverse events predict the therapeutic efficacy of pembrolizumab in urothelial cancer patients. Eur. J. Cancer 2019; 116, 114–115. in patients treated with ICIs. Most of the studies investigating this coded the presence of irAEs as a binary explanatory stratification variable and did not account for the timing/onset of the irAE. In addition, the majority of studies analyzed the relationship between any grade irAE and outcome rather than investigating how this association changes with increasing grade of irAE. This may be due to the small number of high-grade irAEs observed in modestly sized studies [18]Teraoka S, Fujimoto D, Morimoto T, et al. Early Immune-Related Adverse Events and Association with Outcome in Advanced Non-Small Cell Lung Cancer Patients Treated with Nivolumab: A Prospective Cohort Study. J. Thorac. Oncol. 2017; 12(12), 1798–1805. [34]Elias R, Yan F, Singla N, et al. Immune-related adverse events are associated with improved outcomes in ICI-treated renal cell carcinoma patients. World J. Clin. Oncol. 2019; 37, 645–645.  [35]Freeman-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS. Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes. Clin. Cancer Res. 2016; 22(4), 886–894. [37]Haratani K, Hayashi H, Chiba Y, et al. Association of Immune-Related Adverse Events With Nivolumab Efficacy in Non-Small-Cell Lung Cancer. JAMA Oncol. 2018; 4(3), 374–378. [38]Indini A, Di Guardo L, Cimminiello C, et al. Immune-related adverse events correlate with improved survival in patients undergoing anti-PD1 immunotherapy for metastatic melanoma. J. Cancer Res. Clin. Oncol. 2019; 145(2), 511–521. [40]Masuda K, Shoji H, Nagashima K, et al. Correlation between immune-related adverse events and prognosis in patients with gastric cancer treated with nivolumab. BMC Cancer 2019; 19(1), 974..

In 2021, two meta-analyses were published which examined the relationship between irAEs and treatment efficacy [42]Zhong L, Wu Q, Chen F, Liu J, Xie X. Immune-related adverse events: promising predictors for efficacy of immune checkpoint inhibitors. Cancer Immunol. Immunother. 2021; 70(9), 2559–2576. [43]Hussaini S, Chehade R, Boldt RG, et al. Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors–A systematic review and meta-analysis. Cancer Treat. Rev. 2021; 92, 102134. Hussaini S, Chehade R, Boldt RG, et al. Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors–A systematic review and meta-analysis. Cancer Treat. Rev. 2021; 92, 102134. Hussaini S, Chehade R, Boldt RG, et al. Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors–A systematic review and meta-analysis. Cancer Treat. Rev. 2021; 92, 102134. . Both studies stratified analyses by the outcome and methodology used in the source papers and the meta-analysis by Hussani et al [43]Hussaini S, Chehade R, Boldt RG, et al. Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors–A systematic review and meta-analysis. Cancer Treat. Rev. 2021; 92, 102134. Hussaini S, Chehade R, Boldt RG, et al. Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors–A systematic review and meta-analysis. Cancer Treat. Rev. 2021; 92, 102134.  was also stratified by cancer type. Hussani et al included patients on single-agent Nivolumab (anti- PD-1), Pembrolizumab (anti-PD-1) or Ipilimumab (anti-CTLA4) or combination ICI therapies (anti-PD1 and anti-CTLA4) and reported significant increases in progression free survival (PFS), objective response rate (ORR) and overall survival (OS) in the group of patients who experienced any grade irAEs [43]Hussaini S, Chehade R, Boldt RG, et al. Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors–A systematic review and meta-analysis. Cancer Treat. Rev. 2021; 92, 102134. Hussaini S, Chehade R, Boldt RG, et al. Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors–A systematic review and meta-analysis. Cancer Treat. Rev. 2021; 92, 102134. . This effect was seen in both melanoma and NSCLC patients. The second meta-analysis, by Zhong et al, combined data from patients with multiple cancer types, stratifying by the outcome measure analyzed. The authors reported results from a random-effects meta-analysis of ORR, OS, and PFS because of the significant heterogeneity in effects seen across the included studies in each analysis (I2=55–73%, P=<0.0003). ORR, OS, and PFS were statistically significantly improved in patients who experienced any grade irAEs, however, in the sub-analyses restricted by the type of ICI agent used, the presence of irAE was only significantly associated with OS and PFS in the anti PD-1/PD-L1 group and not in the anti-CTLA4 group. This must be caveated by highlighting that the CTLA-4 evidence was from a small number of studies, consistent with the fact that single-agent Ipilimumab is not so commonly used.

Zhong et al were also able to perform meta-analyses to investigate which of the common irAEs were associated with OS and PFS (three to seven studies included in each analysis). Skin, endocrine, and gastrointestinal irAEs were associated with significantly increased OS and PFS but pneumonitis and hepatobiliary irAEs were not. Zhong et al also identified 3 studies where the grade of irAE had been investigated in relation to OS. No significant association between grade of event and OS was observed. Das et al [44]Das S, Johnson DB. Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J. Immunother. Cancer 2019; 7(1), 306. discussed in their review of ICI-induced irAE and efficacy that it is possible that patients experiencing high-grade events might not experience a survival benefit due to the immune suppression associated with treatment for irAEs.

There is a complex relationship between irAE onset and outcome measures which may not be fully captured in simple Cox regression models. Some of the patients who experience irAEs are likely to be those that stay on treatment longer and we know that despite treatment discontinuing following a grade 3+ irAE, the effects of ICIs can be long-lasting and durable. To assess if the occurrence of irAEs serves as a biomarker for PFS, Eggermont et al [33]Eggermont AMM, Kicinski M, Blank CU, et al. Association Between Immune-Related Adverse Events and Recurrence-Free Survival Among Patients With Stage III Melanoma Randomized to Receive Pembrolizumab or Placebo: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol. 2020; 6(4), 519. incorporated irAE as a time-varying covariate. In their model, the irAE variable was coded as 0 until the time of onset of the irAE and then 1 thereafter, while also accounting for the time to irAE. 1019 patients with stage III melanoma, treated with pembrolizumab, were included in this study, and consistent with studies not considering the time dependency of both irAEs and PFS, the authors reported improved PFS (hazard ratio [HR] 0.61) in the group of patients who experienced irAEs. Another approach that tries to control for the time patients were at risk of experiencing irAEs, is to perform a landmark analysis. This involves defining a time point at which to perform an analysis of outcome e.g., once all patients have received the same number of cycles of treatment or at a timepoint where 90% irAEs seen across a cohort have already occurred [45]Kim S, Logan B, Riches M, Chen M, Ahn KW. Statistical methods for time-dependent variables in hematopoietic cell transplantation studies. Transplant Cell Ther. 2021; 27(2), 125.. Authors reporting the results of landmark analyses also identified associations between irAEs (either skin or any irAE) and improved measures of survival and response (PFS, ORR, or OS) [32]Cortellini A, Chiari R, Ricciuti B, et al. Correlations Between the Immune-related Adverse Events Spectrum and Efficacy of Anti-PD1 Immunotherapy in NSCLC Patients. Clin. Lung Cancer 2019; 20(4), 237–247. [35]Freeman-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS. Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes. Clin. Cancer Res. 2016; 22(4), 886–894. [37]Haratani K, Hayashi H, Chiba Y, et al. Association of Immune-Related Adverse Events With Nivolumab Efficacy in Non-Small-Cell Lung Cancer. JAMA Oncol. 2018; 4(3), 374–378. [46]Khan Z, Di Nucci F, Kwan A, et al. Polygenic risk for skin autoimmunity impacts immune checkpoint blockade in bladder cancer. Proc. Natl. Acad. Sci. USA 2020; 117(22), 12288–12294.. Despite the different methods used for analysis, there is strong evidence that irAEs are truly biomarkers of PFS and OS, accepting that the magnitude of the association reported may have been mis-estimated in some studies due to the failure to consider competing risks. PFS is considered to be a good surrogate endpoint for OS in studies investigating evaluating the effectiveness of ICI therapy [47]Ritchie G, Gasper H, Man J, et al. Defining the Most Appropriate Primary End Point in Phase 2 Trials of Immune Checkpoint Inhibitors for Advanced Solid Cancers: A Systematic Review and Meta-analysis. JAMA Oncol. 2018; 4(4), 522–528. [48]Kok PS, Cho D, Yoon WH, et al. Validation of Progression-Free Survival Rate at 6 Months and Objective Response for Estimating Overall Survival in Immune Checkpoint Inhibitor Trials: A Systematic Review and Meta-analysis. JAMA Netw. Open 2020; 3(9), E2011809. [49]Zhu AX, Lin Y, Ferry D, Widau RC, Saha A. Surrogate end points for survival in patients with advanced hepatocellular carcinoma treated with immune checkpoint inhibitors. Immunotherapy 2022; 14(16), 1341–1351.. However, as the indications for ICI therapies move earlier in the treatment pathway such as in the peri-operative setting, OS may be a more appropriate endpoint to establish the efficacy of treatment used for curative intent.

Role of genetic biomarkers

As reviewed by us and others [50]Chin IS, Khan A, Olsson-Brown A, Papa S, Middleton G, Palles C. Germline genetic variation and predicting immune checkpoint inhibitor induced toxicity. Genom. Med. 2022; 7(1), 73. [51]Khan Z, Hammer C, Guardino E, Chandler GS, Albert ML. Mechanisms of immune-related adverse events associated with immune checkpoint blockade: using germline genetics to develop a personalized approach. Genome Med. 2019; 11(1), 39. [52]Kirchhoff T, Ferguson R. Germline Genetics in Immuno-oncology: From Genome-Wide to Targeted Biomarker Strategies. Methods Mol. Biol. 2020; 2055, 93–117., germline genetic variation may explain the variable outcomes from ICI in terms of both toxicity and response to treatment. Genetic variation is likely to contribute to cellular responses which have been shown to differ between those that experience irAEs and those that do not, such as the ability of suppressive B cells to be induced and limit the self-reactive response of T cells [53]Patel AJ, Willsmore ZN, Khan N, et al. Regulatory B cell repertoire defects predispose lung cancer patients to immune-related toxicity following checkpoint blockade. Nat. Commun. 2022; 13(1), 3148.. Hundreds of genetic regions have also been found to explain risk of multiple autoimmune diseases and some of these have been shown to also be associated with response to ICIs [54]Chat V, Ferguson R, Kirchhoff T. Germline genetic host factors as predictive biomarkers in immuno-oncology. Immuno-oncology Technol. 2019; 2, 14–21.. Polygenic risk scores (PRS) can be calculated by summing the effects of multiple genetic markers to generate a per-person score. Scores can then be compared between groups such as those that experience irAEs and those that do not. PRS for autoimmune disorders have been shown to be associated with increased risk (odds) of irAEs. Khan et al reported a significant association between a PRS for psoriasis and increased risk of skin irAEs in patients treated with anti-PD-L1 inhibitor Atezolizumab [46]Khan Z, Di Nucci F, Kwan A, et al. Polygenic risk for skin autoimmunity impacts immune checkpoint blockade in bladder cancer. Proc. Natl. Acad. Sci. USA 2020; 117(22), 12288–12294.. The same group also showed significant associations between PRS for psoriasis, atopic dermatitis, and vitiligo, and OS in patients treated with Atezolizumab. Increased risk scores for psoriasis and vitiligo were associated with longer OS whereas decreased risk scores for atopic dermatitis were associated with longer OS. A PRS for hypothyroidism developed using UK Biobank data consisting of 1,502 single nucleic polymorphisms were also found to predict thyroid irAEs in non-small cell lung cancer patients [55]Luo J, Martucci VL, Quandt Z, et al. Immunotherapy-Mediated Thyroid Dysfunction: Genetic Risk and Impact on Outcomes with PD-1 Blockade in Non-Small Cell Lung Cancer. Clin. Cancer. Res. 2021; 27(18), 5131–5140..

Rarely, heterozygous (monoallelic) germline loss of function mutations in CTLA-4, leading to loss of protein expression, have been identified [56]Kuehn HS, Ouyang W, Lo B, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 2014; 345(6204), 1623–1627.. Patients present with autoantibody-mediated cytopenia, lymphadenopathy/splenomegaly, hypogammaglobulinemia, organ-specific autoimmunity, and lymphocytic infiltration of nonlymphoid organs in late childhood or early adulthood [57]Lo B, Fritz JM, Su HC, Uzel G, Jordan MB, Lenardo MJ. Blood Spotlight CHAI and LATAIE: new genetic diseases of CTLA-4 checkpoint insufficiency. Blood 2016; 128(8), 1037–1042.. The penetrance of these mutations is incomplete, with 40% of carriers having no clinical signs of disease [58]Schubert D, Bode C, Kenefeck R, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat. Med. 2014; 20(12), 1410–1416.. Screening for rare variants in genes like CTLA-4 and 54 other genes implicated in inborn errors of immunity [59]Tangye SG, Al-Herz W, Bousfiha A, et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J. Clin. Immunol. 2022; 42(7), 1473–1507. are likely to also be important to avoid severe reactions to ICIs.

Progress so far in identifying genetic biomarkers of irAEs

The first genome-wide association study of immune checkpoint blockade-induced irAEs was published last year [60]Groha S, Alaiwi SA, Xu W, et al. Germline variants associated with toxicity to immune checkpoint blockade. Nat. Med. 2022; 28(12), 2584–2591.Groha S, Alaiwi SA, Xu W, et al. Germline variants associated with toxicity to immune checkpoint blockade. Nat. Med. 2022; 28(12), 2584–2591. which identified a marker, rs16906115, associated with any grade irAEs (P<5 × 10–8). The discovery phase of the study was conducted in 339 cases and 1,412 controls. Patients were diagnosed with one of 12 different cancer types and predominantly received single agent therapy. Cases were defined as those who experienced an irAE as deduced from autoimmune-like electronic health record diagnoses codes. Importantly the marker, rs16906115, was also associated with irAEs in three independent cohorts (two multi-cancer cohorts and one melanoma cohort). The HR in the combined analysis was 2.1, p-value of 3.6 × 10−11, with stronger effects seen in the discovery Dana Faber Cancer Institute dataset (HR 2) and Massachusetts General Hospital validation cohort (HR 2.5) and a weaker effect in the meta-analysis of 12 clinical trials (validation cohort 2) (HR 1.2). It was not clear which type of irAEs was driving the observed association as nominal significance was observed across multiple irAE subtypes, but it was noted that this single nucleic polymorphism has not previously been implicated in predisposition to autoimmune diseases and it is not part of existing PRS for autoimmune diseases. A second independent study of 214 melanoma patients receiving ICI [61]Taylor CA, Watson RA, Tong O, et al. IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma. Nat. Med. 2022; 28(12), 2592. also found that rs16906115 was associated with an odds ratio (OR) of 2.24, p-value 0.046, and as also described in [60]Groha S, Alaiwi SA, Xu W, et al. Germline variants associated with toxicity to immune checkpoint blockade. Nat. Med. 2022; 28(12), 2584–2591.Groha S, Alaiwi SA, Xu W, et al. Germline variants associated with toxicity to immune checkpoint blockade. Nat. Med. 2022; 28(12), 2584–2591., the marker was associated with a much stronger effect in patients receiving single-agent ICI (OR = 6.0 [95% confidence interval: 1.5–23.0, P = 0.0084]).

Groha et al [60]Groha S, Alaiwi SA, Xu W, et al. Germline variants associated with toxicity to immune checkpoint blockade. Nat. Med. 2022; 28(12), 2584–2591. investigated whether rs16906115 is associated with survival in patients treated with ICI and did not find a significant association with either PFS or OS across the cohorts studied. Interestingly they did find a significant association between the irAE risk allele and improved survival in 433 primary and metastatic melanoma patients from the The Cancer Genome Atlas cohort. These patients received chemotherapy rather than immunotherapy suggesting that the irAE-associated allele exerts an anti-tumor effect independent of the presence of an ICI agent and that carriers of rs16906115, who are at increased risk of irAEs, may respond well to conventional chemotherapy.

Potential for implementation of biomarker testing

Globally many groups are collecting samples; irAE and survival data from patients treated with ICIs and as this data is combined, it is likely that additional markers of ICI-induced irAEs will be identified. As more markers are identified that are associated with irAEs but not with survival, these could be combined into PRS to predict risk of irAEs. Similarly, if markers of survival and efficacy are identified PRS predicting likelihood of efficacy following treatment can also be generated.

The clinical utility of rs16906115 remains to be determined, particularly in patients receiving combination immunotherapy or chemo-immunotherapy regimens, which are increasingly being used, but, for the first time, we have a robustly identified biomarker of ICI-induced irAEs that deserves clinical evaluation. Determining the correct strategy for testing clinical benefit is challenging, as is implementing routine clinical testing of pharmacogenetic markers [62]Pirmohamed M. Pharmacogenomics: current status and future perspectives. Nat. Rev. Genet. 2023; 24(6), 350–362. [63]Taylor C, Crosby I, Yip V, Maguire P, Pirmohamed M, Turner RM. A Review of the Important Role of CYP2D6 in Pharmacogenomics. Genes (Basel) 2020; 11(11), 1–23.. Possible study designs for the evaluation of predictive markers of irAEs include randomized controlled trials and comparison of incidence of irAEs before and after implementing testing and enhanced management of marker-positive patients. The lack of association between rs16906115 and PFS and OS in patients treated with ICIs demonstrates the possibility of identifying genetic variants associated with increased irAE risk but not improved ICI treatment efficacy. Careful evaluation of this variant and those that follow will be essential in informing how genetic biomarkers enhance clinical practice. Being able to predict both the risk of toxicity and the likelihood of favorable response prior to ICI treatment will enable clinicians to deliver personalized safer treatments and allow patients to make informed decisions.

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Affiliations

Claire Palles
Institute of Cancer and Genomic Sciences,
College of Medical and Dental Sciences,
University of Birmingham,
and
National Institute for Health and Care Research (NIHR),
Birmingham Biomedical Research Centre,
Birmingham, UK

Ik Shin Chin
Institute of Cancer and Genomic Sciences,
College of Medical and Dental Sciences,
University of Birmingham

Authorship & Conflict of Interest

Contributions: The named author takes responsibility for the integrity of the work as a whole, and has given their approval for this version to be published.

Acknowledgements: This research is funded by the National Institute for Health and Care Research (NIHR), Birmingham Biomedical Research Centre (BRC). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

Disclosure and potential conflicts of interest: Palles C is a member of the Oncology Translational Research Collaboration, and
the Birmingham Centre Academic lead, and co-leads the toxicity work conducted by the Immunotherapy workstream. Chin IS received grant funding from Cancer Research UK Birmingham Centre for a clinical PhD fellowship.

Funding declaration: The author received no financial support for the research, authorship and/or publication of this article.

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Attribution: Copyright © 2024 Palles C, Chin IS. Published by Immuno-Oncology Insights under Creative Commons License Deed CC BY NC ND 4.0.

Article source: Invited.

Revised manuscript received: Jan 4, 2024; Publication date: Jan 17, 2024.