Inflammatory disease in people with multiple sclerosis treated with immune checkpoint inhibitors

Abstract

This study evaluated disease activity in people with Multiple Sclerosis (PwMS) who received immune checkpoint inhibitors (ICIs) compared to PwMS not treated with ICIs. There were 108 PwMS included (27 PwMS+ICIs and 81 PwMS controls), matched on age, sex, disease duration, DMTs, and MS disease course. Of 27 PwMS+ICIs, one (4%) had a relapse and four (15%) developed new MRI lesions without clinical symptoms. Time to relapse and MRI activity were compared using Kaplan–Meier curves and Cox regression models. There was no significant difference for either time to relapse (p = 0.34) or MRI activity (p = 0.15) in PwMS+ICIs compared to controls.

Introduction

Immune checkpoint inhibitors (ICIs) have improved cancer survival by targeting immune checkpoints that augment the antitumor response.¹ The use of ICIs has expanded to include early-stage cancers resulting in increasing number of patients eligible for ICIs, from 1.54% in 2011 to 43.63% in 2018.^2,3 Despite their efficacy, ICIs can provoke immune-related adverse events (irAEs), affecting approximately 60%–70% of treated patients.^4,5

This raises questions regarding whether ICIs can trigger inflammatory activity among people with multiple sclerosis (PwMS). In a report of one patient with MS treated with ipilimumab who developed inflammatory brain lesions, the functional profiles of myelin-reactive T cells had greater proliferation rates as well as greater proinflammatory cytokine production compared to age and sex matched PwMS and healthy controls, suggesting ICIs may induce or worsen inflammation in PwMS.⁶ However, other case series of PwMS receiving ICIs (PwMS+ICIs) have shown minimal clinical and MRI activity in PwMS+ICIs.^7–10 Limitations of studies to date include sample size, lack of radiological follow-up, and lack of comparison to matched PwMS controls to determine if PwMS+ICIs have an increased risk of inflammatory events.

This study aims to address this gap by matching PwMS demographic and clinical parameters, including age, sex, disease duration, disease-modifying therapy (DMTs), and MS disease course to examine if ICI use is associated with MS disease activity.

Methods

In this retrospective multicenter cohort study, we identified adult PwMS from the Cleveland Clinic Mellen Center registry (n = 9158) and cases exposed to ICIs (CTLA4, PD1 or PDL1 inhibitors) at Cleveland Clinic (Ohio, Florida, Nevada) between 2017 and 2023. This study was approved by the Cleveland Clinic institutional review board. Clinical data were extracted from the medical records. Outcomes included clinical relapse (new neurological symptoms for ≥24 h) or MRI lesion activity (new T2 or contrast-enhancing lesions).

Statistical analysis

PwMS+ICIs (cases) and PwMS controls were matched on age, sex, MS disease course, and DMT class (1:3). Patient characteristics were summarized using median with interquartile range for continuous variables and frequency with percentage for categorical variables. For PwMS+ICIs, the start date of ICI treatment was defined as the baseline. For PwMS controls, the first clinical assessment 1 year after diagnosis was defined as baseline. DMTs were matched on drug type/class for sphingosine-1-phosphate receptor modulators (fingolimod), anti-CD20 (rituximab, ocrelizumab), fumaric acid esters (dimethyl fumarate), natalizumab, pooled low efficacy DMTs (interferon beta, glatiramer acetate, teriflunomide), and no DMT. All DMTs were administered for at least 1 year duration prior to ICI start.

In the matched sample, the balance of covariates between cases and controls was assessed using standardized mean difference (SMD). Time to clinical relapse and time to subclinical relapse (MRI activity only) were compared between the two groups using Kaplan–Meier curves and Cox regression models. Clinical and MRI activity in the control group was evaluated for 2 years from the time point of matching. All statistical analyses were conducted using SAS Enterprise Guide version 8.2 (SAS Institute Inc, Cary NC). p-values <0.05 were considered statistically significant.

Results

Study population

From our registry of 9158 PwMS, we identified 27 PwMS cases with cancer who received ICIs. The median age was 64 years (range = 41–79), and 67% were female. MS disease course included relapsing–remitting (n = 19, 73%), primary progressive (n = 2, 9%), secondary progressive (n = 1, 4%), clinically isolated syndrome (n = 1, 4%), and missing (n = 4, 14%). Indications for ICIs included lung cancer 12 (44%), melanoma 5 (18%), genitourinary cancer 5 (18%), squamous cell carcinoma (maxillary, tongue, anus) 3 (11%), and gynecologic cancer (ovarian and endometrial) 2 (8%). The most common ICIs administered were pembrolizumab 15 (55%), nivolumab 10 (37%), and durvalumab 2 (7%).

There were 81 PwMS controls without cancer matched on age, sex, disease course, and duration (Table 1). DMTs for both groups included natalizumab (7.4%), ocrelizumab or rituximab (11%), fingolimod (7.4%), dimethyl fumarate (3.7%), low efficacy therapies (11.1%), and patients with no DMTs (59.2%) (Table 1). Of the PwMS+ICIs, four (36%) had their DMT stopped at ICI commencement (fingolimod [2], ocrelizumab [1], natalizumab [1]). DMT was maintained in the whole period of ICI use for rest of patients (ICI duration range 1–520 days). Seventeen PwMS+ICIs (63%) also received concurrent/prior chemotherapy.

Table 1 Demographics and clinical characteristics in PwMS who received ICIs and matched PwMS controls.

	PwMS+ICIs (N = 27)	PwMS controls (N = 81)	Standardized mean difference
Age	59.4 ± 10.6	59.2 ± 10.6	0.017
Female	18 (66.7)	54 (66.7)	0.000
Disease duration at baseline (years since diagnosis)	16.0 ± 9.8	15.3 ± 13.8	0.058
Number of cycles of ICIs	12 ± 15
Moderate and high efficacy DMTs	8 (29.6)	24 (29.6)
Fingolimod	2 (7.4)	6 (7.4)
Ocrelizumab or rituximab	3 (11.1)	9 (11.1)
Dimethyl fumarate	1 (3.7)	3 (3.7)
Natalizumab	2 (7.4)	6 (7.4)
Low efficacy DMTs	3 (11.1)	9 (11.1)
Teriflunomide	0 (0.00)	1 (1.2)
Interferon beta	0 (0.00)	9 (11.0)
Glatiramer acetate	3 (11.1)	3 (3.7)
No DMT	16 (59.2)	48 (59.2)
MS disease course			0.000
Relapsing	20 (74.1)	60 (74.1)
Progressive	3 (11.1)	9 (11.1)
Missing	4 (14.8)	12 (14.8)

Inflammatory clinical and radiological activity in PwMS ICI

Of 27 PwMS+ICIs, the median clinical follow-up time post-ICI treatment was 1.2 years (IQR = 0.26–3.5). One patient (4%) exhibited relapse with new brain MRI T2 and contrast-enhancing lesions, 37 weeks after fingolimod discontinuation. (Table 2). Among those with MRI follow-up (n = 18) after ICIs initiation at a median radiological follow-up duration of 1 year (IQR = 0.22–1.8), five PwMS+ICIs (27%) had new brain MRI activity including four that were asymptomatic. The treatment history for these patients with MRI activity only (no clinical symptoms of attack) included natalizumab paused 10 weeks after ICI start (1), fingolimod paused 24 weeks after ICI start (1), ocrelizumab continued (1), and dimethyl fumarate continued (1) (Table 2). Among five patients with relapse or new MRI activity, three received corticosteroids. Three PwMS+ICIs who had their DMTs held were restarted on DMTs (natalizumab, diroximel fumarate, and ofatumamab). Two patients went to hospice, and ICIs were stopped in all five. One patient was subsequently rechallenged with ICI and continued the therapy for 14 months, with no further relapses reported.

Table 2 Details of PwMS who received ICI and developed clinical or radiological activity.

Clinical activity	Age	Sex	MS disease course	History of relapse in last 5 years	Current MS DMTa	DMT paused during ICI	Time between last MRI and disease activity	Time between last DMT dose and disease activity	Time between ICI start and disease activity	Prior chemotherapy	New disease activity treated with steroids
Clinical relapse with new MRI lesions	58	Female	SPMS	No	Fingolimod	Yes	9 mo	37 weeks	35 weeks	No	Yesc
MRI new lesions	50	Male	RRMS	No	Fingolimod	Yes	2 mo	24 weeks	20 weeks	Yes	Noc
47	Female	RRMS	No	Dimethyl fumarate	No	12 mo	5 weeks	2 weeks	Yes	Yes
44	Male	RRMS	Yes	Natalizumab	Yes	3 mo	10 weeks	7 weeks	No	Noc
65	Female	N/A	No	Ocrelizumab	No	3 mo	N/Ab	11 weeks	Yes	No

Comparison of inflammatory clinical and radiological activity to PwMS controls

In the matched PwMS control group, 3 (4%) had clinical relapse and 7 (10%) had new MRI activity during the follow-up time period (Table 2). Comparison between PwMS+ICIs and PwMS controls revealed no statistically significant difference in time to clinical relapse (Hazard ratio (HR) = 3, 95% CI [0.31, 28.84], p = 0.34) or new MRI activity (HR = 2.55, 95% CI [0.72, 9.06], p = 0.15) (Fig. 1A,B). In a sensitivity analysis of patients on moderate (fingolimod, dimethyl fumarate) and high efficacy therapy (antiCD20 and natalizumab), we observed an increased relapse rate among PwMS+ICIs, p = 0.023 (Table S1). We did not observe an increase in inflammatory disease activity in patients aged <55 years between PwMS+ICIs and PwMS controls, p = 0.43 (Table S2).

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Clinical outcomes: survival and systemic irAE

Of 27 PwMS+ICIs, 63% were alive at last follow-up and 23% were still receiving ICI. Seven patients experienced other irAE including; grade 4 myasthenia gravis (1), grade 3 pneumonitis and colitis (2) and grade 2 adverse events including peripheral neuropathy (1), pneumonitis (1), colitis (1), and rash (1).

Discussion

The potential impact of age, DMTs, disease course, and disease duration upon clinical activity in MS necessitates comparative analyses that match PwMS by these factors to determine whether disease activity is beyond what is observed with exposure to ICIs. In this study, matched PwMS+ICIs were compared to PwMS controls unexposed to ICIs and there was no difference in clinical or radiological activity. These findings align with prior case series that have reported minimal clinical and radiological activity.^8–11 Overall, these findings are reassuring for oncologists and MS neurologists caring for PwMS. However, there are a few observations from this case control study that deserve some nuanced discussion.

In our cohort, among the five PwMS+ICIs who experienced clinical or radiological disease activity, four were aged <60, similar to another study.¹⁰ As MS disease activity is typically greater in younger patients and decreases in sixth decade,^12,13 there might be a potential gradient of risk. However, we did not observe an increase in inflammatory activity among patients under 55 when comparing PwMS+ICIs with PwMS controls. Further studies with a greater proportion of younger PwMS are needed.

There are limited data available regarding the impact of DMTs and risk of disease activity in patients receiving ICIs. In our cohort, all five PwMS+ICIs with disease activity were on moderate or high efficacy DMTs before ICIs treatment. Among these patients, two discontinued fingolimod and one discontinued natalizumab at the commencement of ICIs therapy. Discontinuation of these two therapies have been associated with “rebound activity.”^14,15 Similar to prior study, these cases highlights potential risk of disease reactivation in patients treated with S1P receptor modulators and natalizumab.¹⁰ However, we are unable to make causal inferences regarding whether this inflammatory activity is an adverse event of ICIs treatment, or due to rebound activity. Furthermore, a sensitivity analysis comparing just patients treated with moderate and high efficacy therapies, found a greater risk of relapse in PwMS+ICIs than those without. Therefore, further studies examining cohorts on moderate-high efficacy therapies treated with ICIs are needed.

Limitations of our study include its retrospective design, sample size, and the short follow-up, which may have influenced the detection of long-term effects of ICIs therapy on MS disease activity. No patients received CTLA4 inhibitors (e.g., ipilimumab) which may be associated with greater risk of inflammatory events.¹⁶ However, one prior study comparing CTLA-4 and PD-1/PD-L1 inhibitors outcomes in PwMS did not show any significant difference.⁷

In conclusion, this study suggests that ICIs therapy in PwMS does not significantly increase the risk of new disease activity compared to matched PwMS controls. However, further studies are needed to examine younger patients and prognosticate whether discontinuation of some therapies (e.g., sphingosine 1-phosphate receptor modulators or natalizumab) have a higher risk of subsequent inflammatory activity.

Author Contributions

Conception and design of the study: S.A., A.K.; Acquisition and analysis of data: S.A., Y.L., B.L., R.F., L.H.H., L.B.K., M.M., W.W.M., J.C., A.K.; Drafting a significant portion of the manuscript or figures: S.A., Y.L., B.L., L.H.H., L.B.K., M.M., W.W.M., J.C., A.K.

Acknowledgements

None.

Conflicts of Interest

Dr. Saira Afzal reports no disclosures. Yadi Li reports no disclosures. Brittany Lapin reports no disclosures. Dr. Le H Hua serves as consultant to Genentech, Novartis, EMD Serono, TG therapeutics, Horizon, and Alexion; on scientific advisory boards for Genentech, EMD Serono, and Novartis and has received nonpromotional speaker honoraria for Genzyme and TG therapeutics. She received research funding from Biogen and Genentech. Dr. Lucy B. Kennedy receives research funding to the institute from Regeneron, Ideaya, and EpicentRx. Dr. Wen Ma reports no disclosures. Dr. Marisa McGinley receives research support from the National Institutes of Health (NIH), Agency for Healthcare Research and Quality (AHRQ), Genentech, and Biogen. Consulting fees from Genentech and EMD Serono. Dr. Jeffrey Cohen has received personal compensation for consulting for Astoria, Atara, Biogen, Bristol-Myers Squibb, Conevlo, and Viatris. Dr. Amy Kunchok has received compensation for consulting for Genentech, Horizon, Alexion, and EMD Serono.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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