Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: review of the literature and personalized risk-based prevention strategy

In the paper

“Based on these data and by analogy with the treatment of classical ADs, patients with active ADs could be considered candidates for ICIs, even in the context of active immunosuppressive therapy.”

In the paper

“This issue represents a knowledge gap and limits the use of ICI therapy that could be considered in the estimated 20e50 million patients in the USA with ADs. 5”

What the sources say

• Not checked yetcites [5]

In the paper

“It appears that the effectiveness of ICIs is not lowered in this special population.”

In the paper

“At the time of treatment initiation, 82% of patients in these studies had no active symptoms of AD, and only 15%e20% were receiving immunosuppressive treatment of such conditions.”

In the paper

“At present, there are no consensus guidelines to treat this specific patient population, nor are there means to determine the riskebenefit ratio for individual patients.”

In the paper

“In these studies, investigators reported that only a minority of patients (20%e40%) experienced exacerbation of their ADs, 11e15 which were manageable.”

What the sources say

• Not checked yetcites 11e15

In the paper

“The immunopathology underlying irAEs has not been fully described; based on accumulating evidence, the development and resolution of ICI-related colitis is significantly associated with serum IL-17 fluctuations in ipilimumab-treated patients, suggesting a main role for Th17 cells.”

In the paper

“Furthermore, it was demonstrated that TCZ may be used as a second-line therapy for irAEs and for steroid-refractory irAEs; clinical improvement was observed in 79.4% of patients, with 52.9% of patients requiring only a single dose for a symptomatic response.59”

What the sources say

• Not checked yetcites [59] Stroud, 2019, Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade, J Oncol Pharm Pract source

In the paper

“Prospective studies are lacking to determine the best strategy to deliver ICIs to patients with cancer and active or symptomatic AD.”

In the paper

“Overall, low-grade AD flares seem to occur more frequently and are manageable with standard treatment algorithms.”

In the paper

“Summarizing the existing data on PD-1/PD-L-1 and ADs, we can conclude that (i) irAEs occur at an increased rate compared with patients in clinical trials without AD, and the excess morbidity appears largely confined to mild-moderate flares of ADs”

In the paper

“Furthermore, permanent discontinuation of ICIs was rare and tumor responses were seen.”

In the paper

“Based on two retrospective series, VDZ is an effective and well-tolerated therapeutic for steroid-dependent or refractory ICI-induced enterocolitis.69,70”

What the sources say

• Not checked yetcites [69] Bergqvist, 2017, Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis, Cancer Immunol Immunother source
• Not checked yetcites [70] Abu-Sbeih, 2018, Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor-induced colitis: a multi-center study, J Immunother Cancer source

In the paper

“Importantly, baseline CS !10 mg of prednisone or equivalent dose was associated with poor outcome in patients with NSCLC treated with PD-1 axis inhibition (odds ratio 0.42, P ¼ 0.053), progression-free survival (PFS) and overall survival (hazard ratio ¼ 1.31 and 1.66, P ¼ 0.03 and <0.001, respectively).20,21”

What the sources say

• Not checked yetcites [20] Arbour, 2018, Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer, J Clin Oncol source
• Not checked yetcites [21] Hughes, 2019, Colitis after checkpoint blockade: a retrospective cohort study of melanoma patients requiring admission for symptom control, Cancer Med source

In the paper

“Contrarily, other published reports showed evidence in mouse models that anti-TNF-a enhances the antitumor activity of combined anti-PD-1 and anti-CTLA-4 immunotherapy, 61 reinforces both CD8 T-cell-dependent immunity and anti-PD-1 therapy, by preventing anti-PD-1-induced cell death of tumor infiltrating lymphocytes as well as PD-L1 and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3)”

What the sources say

• Not checked yetcites [61] Perez-Ruiz, 2019, Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy, Nature source
• Not checked yetcites [62] Bertrand, 2017, TNFalpha blockade overcomes resistance to anti-PD-1 in experimental melanoma, Nat Commun source
• Not checked yetcites [63] Bertrand, 2015, Blocking tumor necrosis factor alpha enhances CD8 T-cell-dependent immunity in experimental melanoma, Cancer Res source

In the paper

“Intriguingly, blocking the IL-6 and PD-1/PD-L1 axes simultaneously provides synergistic antitumor effects on multiple levels, and the lack of IL-6 in the tumor microenvironment augments Th1 immunity and increases the efficacy of ICIs.51e53”

What the sources say

• Not checked yetcites 51e53

In the paper

“Overall, ICIs could be considered reasonable to use in patients with advanced cancer and preexisting minimally active or asymptomatic ADs.”

In the paper

“Interestingly, IL-6 is a major acute inflammatory phase mediator with pro-tumorigenic properties.49,50”

What the sources say

• Not checked yetcites [49] Horisberger, 2018, A severe case of refractory esophageal stenosis induced by nivolumab and responding to tocilizumab therapy, J Immunother Cancer source
• Not checked yetcites [50] Fisher, 2014, The two faces of IL-6 in the tumor microenvironment, Semin Immunol source

In the paper

“CS, the most widely used immunosuppressants, promote M2 macrophage polarization, 36 induce T regulatory cells recruitment and expansions, 37 Th1 to Th2 phenotype skewing, 38 and apoptosis in lymphocytes, 39 thereby blunting a proliferative burst of CD8-positive T cells needed in cancer response to PD-1/PD-L-1 blockade.40”

What the sources say

• Not checked yetcites [36] Sica, 2012, Macrophage plasticity and polarization: in vivo veritas, J Clin Invest source
• Not checked yetcites [37] Edward, 2017, Selective expansion of human regulatory T cells in nasal polyps, and not adjacent tissue microenvironments, in individual patients exposed to steroids, Clin Immunol source
• Not checked yetcites [38] Libert, 2014, How steroids steer T cells, Cell Rep source

In the paper

“(ii) flares often do not require therapy discontinuation and are manageable with standard treatment algorithms”

In the paper

“In order to limit the risk of severe immune-related adverse events (irAEs) or exacerbation of underlying autoimmune or inflammatory disease, patients with preexisting autoimmune disorders (ADs) or those receiving systemic immunosuppression for organ transplantation have been universally excluded from clinical trials.3,4”

What the sources say

• Not checked yetcites [3] Hodi, 2010, Improved survival with ipilimumab in patients with metastatic melanoma, N Engl J Med source
• Not checked yetcites [4] Robert, 2015, Pembrolizumab versus Ipilimumab in Advanced Melanoma, N Engl J Med source

In the paper

“Similarly, many studies reported that patients receiving immunosuppressive therapy at ICI initiation had worse clinical outcomes and shorter PFS, which was confirmed in multivariable analysis.23e25”

What the sources say

• Not checked yetcites 23e25

In the paper

“Unfortunately, immunosuppressive treatment options for ASS-ILD are limited with low efficacy, even in highly immunosuppressed patients with nSI, and the specific use of additional immunosuppressive agents is empirical.117”

What the sources say

• Not checked yetcites [117] Wilkes, 2005, Treatment of antisynthetase-associated interstitial lung disease with tacrolimus, Arthritis Rheum source

In the paper

“Moreover, infliximab treatment is associated with more colitis recurrence than VDZ, with the confounding factor of overall less infusion doses compared with VDZ.71”

What the sources say

• Not checked yetcites [71] Abu-Sbeih, 2019, Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor-induced colitis, J Immunother Cancer source

In the paper

“TNF antagonists allow CS tapering and are highly efficacious in patients with severe/refractory SX with success rates in skin (80%), neurologic (95%), hepatic (50%), cardiac (88%), bone (67%), and ocular SX (86%).103,104”

What the sources say

• Not checked yetcites [103] Jamilloux, 2017, Efficacy and safety of tumor necrosis factor antagonists in refractory sarcoidosis: A multicenter study of 132 patients, Semin Arthritis Rheum source
• Not checked yetcites [104] Maneiro, 2012, Efficacy and safety of TNF antagonists in sarcoidosis: data from the Spanish registry of biologics BIOBADASER and a systematic review, Semin Arthritis Rheum source

In the paper

“IL-6 plays a key role in the immune-pathogenesis of GCA and was identified as a potential target for the treatment of GCA.95”

What the sources say

• Not checked yetcites [95] Dasgupta, 1990, Interleukin-6 in serum of patients with polymyalgia rheumatica and giant cell arteritis, Br J Rheumatol source

In the paper

“ILD is often severe and rapidly progressive and is the major determinant of morbidity and mortality, which occurs in >70% of patients.117”

What the sources say

• Not checked yetcites [117] Wilkes, 2005, Treatment of antisynthetase-associated interstitial lung disease with tacrolimus, Arthritis Rheum source

In the paper

“Intravenous and s.c.TCZ have been approved for the treatment of adults with moderate to severe active RA.111,112”

What the sources say

• Not checked yetcites [111] Gabay, 2013, Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial, Lancet source
• Not checked yetcites [112] Burmester, 2016, Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial, Ann Rheum Dis source

In the paper

“TCZ, a humanized mAb, binds to both soluble and membrane-bound IL-6R and inhibits IL-6R-mediated signaling.96”

What the sources say

• Not checked yetcites [96] Scheinecker, 2009, Tocilizumab, Nat Rev Drug Discov source

In the paper

“TCZ is also effective and safe for PMR treatment.114,115”

What the sources say

• Not checked yetcites [114] Izumi, 2015, Tocilizumab is effective against polymyalgia rheumatica: experience in 13 intractable cases, RMD Open source
• Not checked yetcites [115] Devauchelle-Pensec, 2016, Efficacy of first-line tocilizumab therapy in early polymyalgia rheumatica: a prospective longitudinal study, Ann Rheum Dis source

In the paper

“ICI-related eosinophilia was described initially with ipilimumab 120 and later with PD-1/PD-L1 inhibitors; additionally, it was frequently associated with a favorable response to ICIs.121e123”

What the sources say

• Not checked yetcites [120] Moreira, 2017, Eosinophilic count as a biomarker for prognosis of melanoma patients and its importance in the response to immunotherapy, Immunotherapy source
• Not checked yetcites 121e123

In the paper

“ICI-related eosinophilia is a rare irAE (estimated frequency of approximately 2%e3%).”

In the paper

“Patients with persistent disease may benefit from BLM; more likely to respond are patients with high disease activity (e.g.SLE disease activity index >10), prednisone dose >7.5 mg/day, and serological activity (low C3/C4, high anti-dsDNA titers), with cutaneous, musculoskeletal, and serological manifestations responding the most.73e77”

What the sources say

• Not checked yetcites 73e77

In the paper

“CD20 is also aberrantly expressed in subsets of melanoma cells with stem-cell properties.87”

What the sources say

• Not checked yetcites [87] Fang, 2005, A tumorigenic subpopulation with stem cell properties in melanomas, Cancer Res source

In the paper

“Patients appear to remain asymptomatic, and none have developed any organ damage secondary to this ICI-related eosinophilia.121”

What the sources say

• Not checked yetcites [121] Bernard-Tessier, 2017, Immune-related eosinophilia induced by anti-programmed death 1 or death-ligand 1 antibodies, Eur J Cancer source

In the paper

“Consequently, IL-5 is one of the main pathogenesis players of hypereosinophilic syndrome (HES).125”

What the sources say

• Not checked yetcites [125] Sutton, 2005, Anti-IL-5 and hypereosinophilic syndromes, Clin Immunol source

In the paper

“Moreover, tumor-associated B cells in melanoma are involved in drug resistance and retain a pro-tumorigenic property in part through insulin-like growth factor-I secretion.86”

What the sources say

• Not checked yetcites [86] Somasundaram, 2017, Tumor-associated B-cells induce tumor heterogeneity and therapy resistance, Nat Commun source

In the paper

“One RCT 132 reported a significant reduction in reported extraglandular manifestations and improvement of musculoskeletal features at weeks 12 and 36 (P ¼ 0.029) and vasculitis at week 24 (P ¼ 0.03).”

What the sources say

• Not checked yetcites [132] Meijer, 2010, Effectiveness of rituximab treatment in primary Sjogren's syndrome: a randomized, double-blind, placebo-controlled trial, Arthritis Rheum source

In the paper

“Immunosuppressive agents should be mainly used as CSsparing agents, with no evidence supporting the choice of one agent over another and that B-cell targeted therapies (with BLM or RTX) may be considered in patients with severe, refractory systemic disease (ESSDAI score >14, or high activity in any of the ESSDAI domains).”

What the sources say

• Not checked yetcites [142] Ramos-Casals, 2020, EULAR recommendations for the management of Sjogren's syndrome with topical and systemic therapies, Ann Rheum Dis source

In the paper

“Most deaths are related to pulmonary fibrosis, pulmonary arterial hypertension, or cardiac causes.143”

What the sources say

• Not checked yetcites [143] Allanore, 2016, Treatment of systemic sclerosis: is there any hope for the future?, RMD Open source

In the paper

“The new 2019 EULAR recommendations 142 propose that the treatment of systemic disease should be tailored to organ-specific severity using the ESSDAI definitions.”

What the sources say

• Not checked yetcites [142] Ramos-Casals, 2020, EULAR recommendations for the management of Sjogren's syndrome with topical and systemic therapies, Ann Rheum Dis source

In the paper

“Immunosuppressive agents should be mainly used as CSsparing agents, with no evidence supporting the choice of one agent over another and that B-cell targeted therapies (with BLM or RTX) may be considered in patients with severe, refractory systemic disease (ESSDAI score >14, or high activity in any of the ESSDAI domains).”

What the sources say

• Not checked yetcites [142] Ramos-Casals, 2020, EULAR recommendations for the management of Sjogren's syndrome with topical and systemic therapies, Ann Rheum Dis source

In the paper

“An open-label trial showed a reduction in the mean ESSDAI score from 8.7 to 5.7 at week 28 (P < 0.0001), with a decrease of at least four points in 40% of cases and improvements in parotid swelling in 77% of cases, in patients with pSS treated by BLM.140”

What the sources say

• Not checked yetcites [140] Mariette, 2015, Efficacy and safety of belimumab in primary Sjogren's syndrome: results of the BELISS open-label phase II study, Ann Rheum Dis source

In the paper

“Thus, the safety and effectiveness of ICI therapy in this special population are unknown.34”

What the sources say

• Not checked yetcites [34] Johnson, 2017, Immune checkpoint inhibitors in challenging populations, Cancer source

In the paper

“Moreover, one RCT 138 reported statistically significant placebo differences at week 36 (P ¼ 0.03) and a statistically significant trend at week 48 (P ¼ 0.07) in the logtransformed ESSDAI score.”

What the sources say

• Not checked yetcites [138] Bowman, 2017, Randomized controlled trial of rituximab and cost-effectiveness analysis in treating fatigue and oral dryness in primary Sjogren's syndrome, Arthritis Rheumatol source

In the paper

“Several published studies reported efficacy of RTX in pSS.”

What the sources say

• Not checked yetcites [132] Meijer, 2010, Effectiveness of rituximab treatment in primary Sjogren's syndrome: a randomized, double-blind, placebo-controlled trial, Arthritis Rheum source
• Not checked yetcites 133e135
• Not checked yetcites 134e137

In the paper

“Noteworthy, in this report tumor response was documented 40% of patients who experienced allograft rejection and 52% of those who did not.155,156”

What the sources say

• Not checked yetcites [155] Abdel-Wahab, 2019, Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature, J Immunother Cancer source
• Not checked yetcites [156] Shirali AC. Minimizing the impact of imAEs and maximizing efficacy: renal toxicities. Medscape 2019.

In the paper

“According to EULAR recommendations, 145 in view of the results from two high-quality RCTs 146,147 and despite its known toxicity, CYC should be considered for treatment of SSc-ILD, in particular for patients with SSc with progressive ILD.”

What the sources say

• Not checked yetcites [145] Kowal-Bielecka, 2017, Update of EULAR recommendations for the treatment of systemic sclerosis, Ann Rheum Dis source
• Not checked yetcites [146] Tashkin, 2006, Cyclophosphamide versus placebo in scleroderma lung disease, N Engl J Med source
• Not checked yetcites [147] Hoyles, 2006, A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma, Arthritis Rheum source

In the paper

“Otherwise, the use of antimalarial drug (HCQ) should be restricted to patients with active systemic disease (clinic ESSDAI score !1).”

What the sources say

• Not checked yetcites [142] Ramos-Casals, 2020, EULAR recommendations for the management of Sjogren's syndrome with topical and systemic therapies, Ann Rheum Dis source

In the paper

“The involvement of B cells as a central pathophysiologic role for B cells is illustrated by the presence of autoantibodies against SS-A/Ro and/or SS-B/La, elevated levels of rheumatoid factor (RF), hypergammaglobulinemia, and elevated levels of circulating and salivary gland tissue levels of BAFF.131”

What the sources say

• Not checked yetcites [131] Jonsson, 2005, Association between circulating levels of the novel TNF family members APRIL and BAFF and lymphoid organization in primary Sjogren's syndrome, J Clin Immunol source

In the paper

“Importantly, SSc is frequently associated with malignancy.144”

What the sources say

• Not checked yetcites [144] Tyndall, 2010, Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database, Ann Rheum Dis source

In the paper

“Interestingly, a recent systematic review and institutional experience report 155 that included 39 ICI-treated transplant recipients (23 renal, 11 hepatic, 5 cardiac) reported allograft rejection in 41% of patients [11 renal (48%), 4 hepatic (36%), 1 cardiac (20%)] with very similar rates between anti-PD-1 versus anti-CTLA-4 agents (40% versus 36%).”

What the sources say

• Not checked yetcites [155] Abdel-Wahab, 2019, Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature, J Immunother Cancer source

In the paper

“there is still much to learn about how to treat this special population with the best selective immunosuppressive therapy without compromising ICI effectiveness and without exposing patients to a life-threatening risk from AD exacerbations or from graft rejection.”

In the paper

“So far, they consider whether the risk in transplant recipients may be due to alloimmunity and acute rejection of the allograft, rather than an ICI-induced imAE.155”

What the sources say

• Not checked yetcites [155] Abdel-Wahab, 2019, Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature, J Immunother Cancer source

In the paper

“We are still in the learning phase regarding the best use of ICIs in patients with cancer and preexisting active ADs.”

In the paper

“Another monocentric study reported a rate of graft rejection of 28.6%, which is very similar to the 33.3% graft rejection rate reported in previous case reports that received PD-1 inhibitors.158”

What the sources say

• Not checked yetcites [158] DeLeon, 2018, Pilot evaluation of PD-1 inhibition in metastatic cancer patients with a history of liver transplantation: the Mayo Clinic experience, J Gastrointest Oncol source

In the paper

“We searched PubMed for papers published in English between 1 January 2008, and 30 December 2019, using the terms 'checkpoint inhibitor ICI', 'immune-related adverse event', 'CTLA4', 'PD-1', 'PD-L1', preexisting autoimmune diseases, Antisynthethase syndrome, Azathioprine, Connective tissue disease, Cyclophosphamide, Cyclosporine, Inflammatory bowel disease, ICI-related diarrhea and colitis, Interst”

In the paper

“In general, allograft preservation strategies in these special patients follow general acute rejection guidelines, with i.v.solumedrol 250e500 mg daily for 3 days being the most common first-line strategy.156,174”

What the sources say

• Not checked yetcites [156] Shirali AC. Minimizing the impact of imAEs and maximizing efficacy: renal toxicities. Medscape 2019.
• Not checked yetcites [174] 2009, KDIGO clinical practice guideline for the care of kidney transplant recipients, Am J Transplant

In the paper

“Concomitant treatment with ICI and calcineurin inhibitor (CNI), which is an anti-T-cell-specific drug, used widely for maintenance graft regimen, was unfortunately associated with a lower antitumor response; in a recent review of nine patients who were left on full dose of CNI during ICI therapy, rejection was not observed but objective tumor response was seen in only one of nine patients.165,166”

What the sources say

• Not checked yetcites [165] Kittai, 2017, Immune checkpoint inhibitors in organ transplant patients, J Immunother
• Not checked yetcites [166] Grant, 2018, Checkpoint inhibitor use in two heart transplant patients with metastatic melanoma and review of high-risk populations, Melanoma Manag source

In the paper

“Recently, it was reported that the addition of sirolimus resulted in ongoing antitumor efficacy while promoting allograft tolerance in melanoma patients with organ rejection and colitis induced by anti-PD-1 therapy.”

What the sources say

• Not checked yetcites [168] Esfahani, 2019, Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation, Nat Commun source

In the paper

“Authors also suggest a possible difference in immune mechanisms mediating the occurrence of irAEs and allotransplantation immunity because they observed an irAEs rate similar to the cohort exempt from rejection and to the classical rate obtained in non-SOT recipients.”

What the sources say

• Not checked yetcites [155] Abdel-Wahab, 2019, Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature, J Immunother Cancer source

In the paper

“The median time to rejection reported in previous case reports is 8 days with a range of 5e63 days.27,159e164”

What the sources say

• Not checked yetcites 27,159e164

In the paper

“Concerning antibody-mediated rejections, many possible therapies have been reported in patients without cancer including plasma exchange, IVIG, anti-CD20 antibodies, and anti-T-cell antibodies.156,174”

What the sources say

• Not checked yetcites [156] Shirali AC. Minimizing the impact of imAEs and maximizing efficacy: renal toxicities. Medscape 2019.
• Not checked yetcites [174] 2009, KDIGO clinical practice guideline for the care of kidney transplant recipients, Am J Transplant

In the paper

“Globally, graft rejection appears to be an early PD-1 inhibitor adverse event and occurs earlier than most other irAEs.”

In the paper

“It is likewise not well defined the most important risk factors leading to graft rejection.156”

What the sources say

• Not checked yetcites [156] Shirali AC. Minimizing the impact of imAEs and maximizing efficacy: renal toxicities. Medscape 2019.

In the paper

“It stays unknown whether ICI treatment directly prompts allograft reflection or whether it is the consequence of diminished immunosuppression or some other factor.”

In the paper

“and because ICIs could be beneficial in such patients”

In the paper

“Because SOT patients or patients with active preexisting ADs have been universally excluded from clinical trials with ICIs”

In the paper

“Cotreatment with sirolimus abated cytotoxic T cell numbers and eosinophilia, while elevated Treg cell numbers in the peripheral blood were maintained.”

What the sources say

• Not checked yetcites [168] Esfahani, 2019, Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation, Nat Commun source

In the paper

“Although most transplant recipients without cancer respond to the highdose CS approach, 174 it is unclear whether the same is true in the ICI-rejected SOT population.156”

What the sources say

• Not checked yetcites [174] 2009, KDIGO clinical practice guideline for the care of kidney transplant recipients, Am J Transplant
• Not checked yetcites [156] Shirali AC. Minimizing the impact of imAEs and maximizing efficacy: renal toxicities. Medscape 2019.

In the paper

“Interestingly, numbers of IFN-gþ CD4þ T cells and serum IFN-g levels increased, with the addition of sirolimus treatment likely promoting ongoing anti-PD-1 efficacy.168”

What the sources say

• Not checked yetcites [168] Esfahani, 2019, Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation, Nat Commun source

In the paper

“It remains unclear which immunosuppression regimen is most efficacious at reducing the risk of graft rejection without completely compromising ICI efficiency.156”

What the sources say

• Not checked yetcites [156] Shirali AC. Minimizing the impact of imAEs and maximizing efficacy: renal toxicities. Medscape 2019.