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Selective immune suppression using interleukin-6 receptor inhibitors for management of immune-related adverse events

Fa'ak, Faisal; Buni, Maryam; Falohun, Adewunmi; Lu, Huifang; Song, Juhee; Johnson, Daniel H; Zobniw, Chrystia M; Trinh, Van A; Awiwi, Muhammad Osama; Tahon, Nourel Hoda; Elsayes, Khaled M; Ludford, Kaysia; Montazari, Emma J; Chernis, Julia; Dimitrova, Maya; Sandigursky, Sabina; Sparks, Jeffrey A; Abu-Shawer, Osama; Rahma, Osama; Thanarajasingam, Uma; Zeman, Ashley M; Talukder, Rafee; Singh, Namrata; Chung, Sarah H; Grivas, Petros; Daher, May; Abudayyeh, Ala; Osman, Iman; Weber, Jeffrey; Tayar, Jean H; Suarez-Almazor, Maria E; Abdel-Wahab, Noha; Diab, Adi
BACKGROUND:Management of immune-related adverse events (irAEs) is important as they cause treatment interruption or discontinuation, more often seen with combination immune checkpoint inhibitor (ICI) therapy. Here, we retrospectively evaluated the safety and effectiveness of anti-interleukin-6 receptor (anti-IL-6R) as therapy for irAEs. METHODS:We performed a retrospective multicenter study evaluating patients diagnosed with de novo irAEs or flare of pre-existing autoimmune disease following ICI and were treated with anti-IL-6R. Our objectives were to assess the improvement of irAEs as well as the overall tumor response rate (ORR) before and after anti-IL-6R treatment. RESULTS:We identified a total of 92 patients who received therapeutic anti-IL-6R antibodies (tocilizumab or sarilumab). Median age was 61 years, 63% were men, 69% received anti-programmed cell death protein-1 (PD-1) antibodies alone, and 26% patients were treated with the combination of anti-cytotoxic T lymphocyte antigen-4 and anti-PD-1 antibodies. Cancer types were primarily melanoma (46%), genitourinary cancer (35%), and lung cancer (8%). Indications for using anti-IL-6R antibodies included inflammatory arthritis (73%), hepatitis/cholangitis (7%), myositis/myocarditis/myasthenia gravis (5%), polymyalgia rheumatica (4%), and one patient each with autoimmune scleroderma, nephritis, colitis, pneumonitis and central nervous system vasculitis. Notably, 88% of patients had received corticosteroids, and 36% received other disease-modifying antirheumatic drugs (DMARDs) as first-line therapies, but without adequate improvement. After initiation of anti-IL-6R (as first-line or post-corticosteroids and DMARDs), 73% of patients showed resolution or change to ≤grade 1 of irAEs after a median of 2.0 months from initiation of anti-IL-6R therapy. Six patients (7%) stopped anti-IL-6R due to adverse events. Of 70 evaluable patients by RECIST (Response Evaluation Criteria in Solid Tumors) V.1.1 criteria; the ORR was 66% prior versus 66% after anti-IL-6R (95% CI, 54% to 77%), with 8% higher complete response rate. Of 34 evaluable patients with melanoma, the ORR was 56% prior and increased to 68% after anti-IL-6R (p=0.04). CONCLUSION/CONCLUSIONS:Targeting IL-6R could be an effective approach to treat several irAE types without hindering antitumor immunity. This study supports ongoing clinical trials evaluating the safety and efficacy of tocilizumab (anti-IL-6R antibody) in combination with ICIs (NCT04940299, NCT03999749).
PMID: 37328287
ISSN: 2051-1426
CID: 5538402

Safety and effectiveness of combination versus monotherapy with immune checkpoint inhibitors in patients with preexisting autoimmune diseases

Reid, Pankti; Sandigursky, Sabina; Song, Juhee; Lopez-Olivo, Maria A.; Safa, Houssein; Cytryn, Samuel; Efuni, Elizaveta; Buni, Maryam; Pavlick, Anna; Krogsgaard, Michelle; Abu-Shawer, Osama; Altan, Mehmet; Weber, Jeffrey S.; Rahma, Osama E.; Suarez-Almazor, Maria E.; Diab, Adi; Abdel-Wahab, Noha
Patients with preexisting autoimmune disease (pAID) are generally excluded from clinical trials for immune checkpoint inhibitors (ICIs) for cancer due to concern of flaring pAID. In this multi-center, retrospective observational study, we compared safety of ICI combination (two ICI agents) versus monotherapy in cancer patients with pAIDs. The primary outcome was time to AEs (immune-related adverse events (irAEs) and/or pAID flares), with progression-free survival (PFS) and overall survival as secondary outcomes. Sixty-four of 133 patients (48%) received ICI combination and 69 (52%) monotherapy. Most had melanoma (32%) and lung cancer (31%). Most common pAIDs were rheumatic (28%) and dermatologic (23%). Over a median follow-up of 15 months (95%CI, 11-18 mo), the cumulative incidence of any-grade irAEs was higher for combination compared to monotherapy (subdistribution hazard ratio (sHR) 2.27, 95%CI 1.35"“3.82). No statistically significant difference was observed in high-grade irAEs (sHR 2.31 (0.95"“5.66), P =.054) or the cumulative incidence of pAID flares. There was no statistically significant difference for melanoma PFS between combination versus monotherapy (23.2 vs. 17.1mo, P =.53). The combination group was more likely to discontinue or hold ICI, but > 50% of the combination group was still able to continue ICI therapy. No treatment-related deaths occurred. In our cohort with pAIDs, patients had a tolerable toxicity profile with ICI combination therapy. Our results support the use of ICI combination if deemed necessary for cancer therapy in patients with pAIDs, since the ICI toxicities were comparable to monotherapy, able to be effectively managed and mostly did not require ICI interruption.
SCOPUS:85175548637
ISSN: 2162-4011
CID: 5616442

Safety and effectiveness of combination versus monotherapy with immune checkpoint inhibitors in patients with preexisting autoimmune diseases

Reid, Pankti; Sandigursky, Sabina; Song, Juhee; Lopez-Olivo, Maria A; Safa, Houssein; Cytryn, Samuel; Efuni, Elizaveta; Buni, Maryam; Pavlick, Anna; Krogsgaard, Michelle; Abu-Shawer, Osama; Altan, Mehmet; Weber, Jeffrey S; Rahma, Osama E; Suarez-Almazor, Maria E; Diab, Adi; Abdel-Wahab, Noha
Patients with preexisting autoimmune disease (pAID) are generally excluded from clinical trials for immune checkpoint inhibitors (ICIs) for cancer due to concern of flaring pAID. In this multi-center, retrospective observational study, we compared safety of ICI combination (two ICI agents) versus monotherapy in cancer patients with pAIDs. The primary outcome was time to AEs (immune-related adverse events (irAEs) and/or pAID flares), with progression-free survival (PFS) and overall survival as secondary outcomes. Sixty-four of 133 patients (48%) received ICI combination and 69 (52%) monotherapy. Most had melanoma (32%) and lung cancer (31%). Most common pAIDs were rheumatic (28%) and dermatologic (23%). Over a median follow-up of 15 months (95%CI, 11-18 mo), the cumulative incidence of any-grade irAEs was higher for combination compared to monotherapy (subdistribution hazard ratio (sHR) 2.27, 95%CI 1.35-3.82). No statistically significant difference was observed in high-grade irAEs (sHR 2.31 (0.95-5.66), P = .054) or the cumulative incidence of pAID flares. There was no statistically significant difference for melanoma PFS between combination versus monotherapy (23.2 vs. 17.1mo, P = .53). The combination group was more likely to discontinue or hold ICI, but > 50% of the combination group was still able to continue ICI therapy. No treatment-related deaths occurred. In our cohort with pAIDs, patients had a tolerable toxicity profile with ICI combination therapy. Our results support the use of ICI combination if deemed necessary for cancer therapy in patients with pAIDs, since the ICI toxicities were comparable to monotherapy, able to be effectively managed and mostly did not require ICI interruption.
PMCID:10732692
PMID: 38126033
ISSN: 2162-402x
CID: 5626492

Safety and Effectiveness of Immune Checkpoint Inhibitors Combination versus Single Agent Therapy in Patients with Pre-existing Autoimmune Diseases [Meeting Abstract]

Reid, P; Sandigursky, S; Lopez-Olivo, M A; Song, J; Safa, H; Cytryn, S; Buni, M; Pavlick, A; Krogsgaard, M; Abu-Shawer, O; Altan, M; Weber, J; Suarez-Almazor, M; Diab, A; Abdel-Wahab, N
Background/Purpose: Treatment with a combination of immune checkpoint inhibitors (ICI) has promising outcomes in many tumor types but carries higher adverse event risk than ICI monotherapy. Also, patients with pre-existing autoimmune disease (AID) have largely been excluded from ICI clinical trials due to concern for pre-existing AID flare or immune-related adverse events (irAEs). This is the first study to analyze safety and effectiveness of ICI combination versus monotherapy for this at-risk population.
Method(s): We conducted a multi-center retrospective study in patients with pre-existing AIDs receiving ICIs (i.e., antiprogrammed cell death protein 1 (PD-1) single-agent (monotherapy) or ICI combination). Primary endpoints included the time to occurrence of any-type ICI AE (irAE or AID flare), time to irAEs and time to AID flares in the presence of the competing risk of death with progression free survival (PFS, time to progression or death) and overall survival (OS) as secondary endpoints. We used Fine-Gray models and Cox regression models to investigate the factors associated with these endpoints.
Result(s): 133 patients with pre-existing AID who received ICIs were identified: 69 (52%) monotherapy and 64 (48%) combination (Table 1). About half the patients had melanoma (44%) and 25% had lung cancer. Rheumatic (34%) or dermatologic (22%) pre-existing AIDs were the most common. Most patients (95%) had controlled autoimmune disease at ICI start. Six of 7 patients with active AID at baseline experienced some AE. Patients receiving baseline DMARD(s) were more likely to experience an AE (95%CI 1.079-2.996, p=0.024). The cumulative incidence of irAEs was higher for ICI combination compared to monotherapy (subdistribution hazard ratio (sHR) 2.28, 95%CI 1.36-3.84), adjusting for age at malignancy, but there was no significant difference between rate of high-grade toxicity for patients treated with ICI combination versus monotherapy (See Figure 1). On subgroup analysis for patients with melanoma or lung cancer, the cumulative incidence of irAEs or AID flares were not statistically different between treatment groups. PFS was longer (but not statistically significant) for combination therapy for any tumor type compared to single agent (median 12.3mo, 95%CI 5.0-23.2 versus 7.3mo, 95%CI 5.2-11.3, p=0.116). Similar trend was noted for PFS for melanoma (median 23.2mo combination vs. 14.0mo monotherapy, p=0.4237), while the opposite relation was noted for lung cancer subgroup (4.4mo combination vs. 7.1mo monotherapy, p=0.2933).
Conclusion(s): Efficacy of ICI combination versus monotherapy was not statistically significant and so still remains unclear in this patient population, but there was no significant difference in rates of high-grade toxicity between the two cohorts. Our data supports the notion that patients with pre-existing AIDs should not be indiscriminately precluded from getting ICI combination. Our results provide guidance for future prospective clinical trials studying combination therapy for subgroups of this at-risk population. No statistically significant difference appreciated in high grade adverse events between patients with pre-existing autoimmune disease treated with ICI combination versus monotherapy. Grading determined by the Common Terminology Criteria for Adverse Events rubric with grade 3 or higher considered "high grade."
EMBASE:639967125
ISSN: 2326-5205
CID: 5512972

Immune checkpoint inhibition in patients with inactive pre-existing neuromuscular autoimmune diseases

Snavely, Andrew; Pérez-Torres, Eduardo J; Weber, Jeffrey S; Sandigursky, Sabina; Thawani, Sujata P
OBJECTIVES/OBJECTIVE:To evaluate the safety of immune checkpoint inhibitor use in patients with pre-existing neurological autoimmune diseases. METHODS:In this retrospective case-series, we examined exacerbations of underlying disease and the occurrence of immune-related adverse events in 5 patients who had been diagnosed with a neurological autoimmune disease prior to receiving immune checkpoint inhibitor therapy for advanced malignancy. RESULTS:Two patients had a prior diagnosis of myasthenia gravis, two had Guillain-Barré syndrome, and one had chronic idiopathic demyelinating polyneuropathy. Only one patient experienced a flare of neurological autoimmune disease. Four of the five patients experienced immune-related adverse events unrelated to their neurological disease. CONCLUSIONS:In this case-series, exacerbations of neurological autoimmune disease were less common and less severe than expected. Further research is needed to determine which individuals are at greatest risk of neurological autoimmune disease complication while receiving immune checkpoint inhibitor therapy.
PMID: 35597082
ISSN: 1878-5883
CID: 5247742

Toxicity and cosmetic outcome of breast irradiation in women with breast cancer and autoimmune connective tissue disease: the role of fraction and field size

Purswani, Juhi M; Jaros, Brian; Oh, Cheongeun; Sandigursky, Sabina; Xiao, Julie; Gerber, Naamit K
BACKGROUND:Hypofractionation has historically been underutilized among breast cancer patients with connective tissue diseases given a theoretical risk for increased toxicity and their overall underrepresentation in clinical trials that established hypofractionation as standard of care. We aim to compare the rates of toxicity in patients with autoimmune connective tissue diseases treated with conventionally fractioned radiation therapy (CF-RT) and hypofractionated RT (HF-RT) including accelerated partial breast irradiation. MATERIALS AND METHODS/METHODS:1,983 patients treated with breast conservation between 2012 and 2016 were reviewed for diagnosis of autoimmune disease. Univariate analysis using binary logistic regression was performed to evaluate the effect of disease and treatment variables on acute and late toxicity. Multivariate analyses using Cox regression models were used to evaluate the independent associations between covariates and the primary endpoints. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated for reach risk group. RESULTS:92 patients with autoimmune disease were identified. Median follow-up was 59 months. 35% of patients received CF-RT and 65% of patients received hypofractionated RT (HF-RT), of which 70% received whole breast radiation (WBI) without regional nodal irradiation (RNI), 12% received WBI with RNI, and 18% received accelerated partial breast radiation. Patients who received CF-RT were significantly more likely to have AD symptoms (78% vs 37%, p<0.001), to be managed on DMARDs (41% vs 15%, p=0.013) and to have active autoimmune disease (84% vs 43%, p<0.001). On multivariate analysis, HF-RT was associated with a significantly decreased odds of acute and late grade 2/3 toxicity compared to CF-RT fractionation (acute: OR 0.200 95% CI 0.064-0.622, p=0.005; late: OR 0.127 95% CI 0.031 - 0.546, p=0.005). CONCLUSION/CONCLUSIONS:Hypofractionation including APBI is associated with less acute or late grade 2/3 toxicity in this population.
PMID: 34774868
ISSN: 1879-8519
CID: 5048852

Risk of Toxicity After Initiating Immune Checkpoint Inhibitor Treatment in Patients With Rheumatoid Arthritis

Efuni, Elizaveta; Cytryn, Samuel; Boland, Patrick; Niewold, Timothy B; Pavlick, Anna; Weber, Jeffrey; Sandigursky, Sabina
INTRODUCTION/BACKGROUND:Immune checkpoint inhibitors (ICIs) are increasingly used to treat advanced cancer. Rheumatoid arthritis (RA) is associated with an increased risk of malignancies; however, patients with RA have been excluded from ICI trials. In this study, we evaluated risk of toxicity after initiation of ICI treatment in RA patients. METHODS:We conducted a single-institution, medical records review analysis to assess the incidence of immune-related adverse events (irAEs) and autoimmune disease (AID) flares among patients with AIDs treated with ICIs from 2011 to 2018. A subgroup analysis for RA patients was performed with frequencies of irAEs and AID flares reported. RESULTS:Twenty-two patients with RA who were treated with ICI for malignancy were identified. At the time of ICI initiation, 86% had inactive RA disease activity. Immune-related adverse events occurred in 7 (32%) of patients, with 2 (9%) developing grade 3 (i.e., severe) irAEs. Immune checkpoint inhibitors were temporarily discontinued because of irAEs in 5 patients (23%), and permanently in 1 patient. Rheumatoid arthritis flares occurred in 12 patients (55%). Of those, 10 (83%) received oral corticosteroids with an adequate treatment response. CONCLUSIONS:Our analysis suggests that irAEs following ICI treatment are not increased among RA patients compared with other cancer patients. Heightened RA disease activity during ICI treatment is common, but most adverse events are manageable with oral corticosteroids, and few require permanent ICI discontinuation. A close collaboration between the oncologist and rheumatologist is advisable when considering ICIs in patients with RA.
PMID: 31977647
ISSN: 1536-7355
CID: 4273562

Role of IVIG in the Treatment of Autoimmune Conditions With Concurrent Immune Checkpoint Inhibitors for Metastatic Cancer

Punekar, Salman Rafi; Castillo, Rochelle; Sandigursky, Sabina; Cho, Daniel Chang
Immune checkpoint inhibitors (ICIs) are a class of medications targeting mostly the PD-1/PD-L1 and CTLA-4 immune pathways in the treatment of many cancers. Despite the encouraging success of ICIs, they are associated with immune-related adverse events as well as exacerbation of underlying autoimmune conditions. The treatment of these conditions often involves discontinuation of ICI in addition to the utilization of immunomodulatory agents. In this report, we discuss a case in which a patient with metastatic renal cell carcinoma experienced exacerbation of underlying paraneoplastic dermatomyositis after treatment with ICI. He was successfully continued on ICI with the use of intravenous immunoglobulin. The patient experienced adequate control of his myositis but also experienced deepening of his antitumor response.
PMID: 34166301
ISSN: 1537-4513
CID: 4918692

SHP2 Targets ITK Downstream of PD-1 to Inhibit T Cell Function

Strazza, Marianne; Adam, Kieran; Lerrer, Shalom; Straube, Johanna; Sandigursky, Sabina; Ueberheide, Beatrix; Mor, Adam
PD-1 is a critical therapeutic target in cancer immunotherapy and antibodies blocking PD-1 are approved for multiple types of malignancies. The phosphatase SHP2 is the main effector mediating PD-1 downstream signaling and accordingly attempts have been made to target this enzyme as an alternative approach to treat immunogenic tumors. Unfortunately, small molecule inhibitors of SHP2 do not work as expected, suggesting that the role of SHP2 in T cells is more complex than initially hypothesized. To better understand the perplexing role of SHP2 in T cells, we performed interactome mapping of SAP, an adapter protein that is associated with SHP2 downstream signaling. Using genetic and pharmacological approaches, we discovered that SHP2 dephosphorylates ITK specifically downstream of PD-1 and that this event was associated with PD-1 inhibitory cellular functions. This study suggests that ITK is a unique target in this pathway, and since ITK is a SHP2-dependent specific mediator of PD-1 signaling, the combination of ITK inhibitors with PD-1 blockade may improve upon PD-1 monotherapy in the treatment of cancer.
PMID: 33624224
ISSN: 1573-2576
CID: 4794612

Breast conservation in women with autoimmune disease: the role of active autoimmune disease and hypofractionation on acute and late toxicity in a case-controlled series

Purswani, Juhi M; Oh, Cheongeun; Jaros, Brian; Sandigursky, Sabina; Xiao, Julie; Gerber, Naamit K
PURPOSE/OBJECTIVE:Autoimmune connective tissue disease (CTD) has historically represented a relative contraindication to breast conservation (BC) among patients with early stage breast cancer. Controversy exists regarding hypofractionated radiotherapy (RT) among patients with CTDs. We evaluated acute and late toxicity in patients with breast cancer and CTD treated with BC. METHODS AND MATERIALS/METHODS:Of 1983 patients treated with BC from 2012 to 2016, we identified 91 patients with autoimmune disease (AD). Each patient was matched to a control without AD based on age, RT field and fractionation. RT toxicity and clinician-rated cosmesis were compared between cases and controls. Overall survival, disease-free survival, and local recurrence free survival were estimated using the Kaplan-Meier method. RESULTS:Median follow-up was 49.9 months for cases and 53.0 months for controls. 67% of cases and controls were treated with hypofractionated RT. There was no difference in grade 2/3 acute toxicity between cases and controls (26.4% vs. 16.5%, p=0.148, respectively). There was a significantly higher rate of grade 2/3 late toxicity among cases (25.8% vs 12.1%, p=0.049). Active AD at the time of RT increased the rate of grade 2/3 late toxicity compared to controls (41.7% vs. 11.4%, p=0.018). Among patients treated with hypofractionated RT, there was no difference in acute or late grade 2/3 toxicity between cases and controls (acute: 13.1% cases vs. 11.5% controls, p=1; late: 11.9% in cases vs 13.1% in controls, p=1). Rate of good/excellent clinician- rated cosmesis was similar between groups (92.9% vs 98.9%, p=0.142). CONCLUSIONS:In the largest matched case control study of patients with CTD treated with conventional and hypofractionated RT, we demonstrate low rates of radiation toxicity, with good to excellent clinician-rated cosmesis. There was increased late toxicity in cases, especially in patients with active AD at time of RT. There was no increase in acute or late toxicity in the patients treated with hypofractionation.
PMID: 33545303
ISSN: 1879-355x
CID: 4776772