Immunocheckpoint Inhibitors Research Articles

Clinical Diagnosis and Treatment Recommendations for Ocular Toxicities of Target Therapy and Immune Checkpoint Inhibitor Therapy

靶向治疗和免疫治疗给晚期肿瘤患者带来了希望。但是治疗过程中的药物毒副作用也随着药物的普及而逐渐展现出来。其中眼部的毒副反应常被患者和医生忽视。眼部的不良反应包括从眼睑、睫毛、结膜、角膜、葡萄膜、视网膜、视神经和眼眶等，可累及眼部的所有组织。本文就靶向治疗和免疫治疗相关的眼部毒副作用的诊断和治疗给予相应的描述和建议。

Clinical Diagnosis and Treatment Recommendations for Adverse Reaction in the Nervous System Related to Immunocheckpoint Inhibitor

免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）可引起神经系统的不良反应，发生率在0.1%-12%，80%发生在应用前4个月内。可以引起神经系统各部位的病变，包括无菌性脑膜炎，脑膜脑炎，坏死性脑炎，脑干脑炎，横贯性脊髓炎等中枢神经系统病变，也可引起颅神经周围神经病、多灶性神经根神经病、格林巴利综合征、脊神经根神经病、重症肌无力、肌病等周围神经病变。对于神经系统的这些并发症，均需要症状体征，并结合影像学、脑脊液细胞学、脑电图或肌电图等检查，除外感染或恶性肿瘤后获得诊断。治疗中，在严重病例需停用ICIs，并用大剂量糖皮质激素或丙种球蛋白治疗和对症支持治疗。在出现神经系统不良反应后，严重病例预后较差。

Diagnosis and Treatment Recommendation and Exploration for Critical and Refractory Adverse Effects Related to Immunocheckpoint Inhibitors

免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）的应用改写了很多恶性肿瘤的治疗策略，成为肿瘤治疗的又一个里程碑。ICIs作用原理可以理解为“刹车理论”，在“松开刹车”后会带来一系列的全身性毒副反应，其中部分可能为危重和难治性，甚至具有潜在致死性。本文对免疫相关不良事件（immune-related adverse effects, irAEs）相关的最新国内外指南及共识中关于3度-4度irAEs的诊治建议进行了汇总，包括欧洲肿瘤内科学会年会（European Society for Medical Oncology, ESMO）、美国国立综合癌症网络（National Comprehensive Cancer Network, NCCN）/美国临床肿瘤学会（American Society of Clinical Oncology, ASCO）、肿瘤免疫治疗学会（Society for Immunotherapy of Cancer, SITC）和中国临床肿瘤学会（Chinese Society of Clinical Oncology, CSCO）指南，并复习了2019年5月20日前公开发表的关于irAEs的个案报告和相关的综述文献后，对以上指南和共识中尚未纳入的3级-4级irAEs的诊治建议进行补充，重点介绍了特异性免疫抑制药物在不同的irAEs中成功应用的情况，包括抗白介素6（interleukin 6, IL-6）阻断、抗CD20单抗、抗肿瘤坏死因子α（tumor necrosis factor-α, TNFα）单抗、抗整合素4单抗、Janus激酶抑制剂、血小板生成素受体激动剂和抗胸腺细胞球蛋白（antithymocyte globulin, ATG）。本文对于类固醇激素在irAEs中超大剂量使用和升级使用及反复使用提出质疑，并强调应同时关注激素继发的感染、肿瘤进展和无法满足ICIs再挑战的等问题。本文提出对于危重和难治性irAEs的“降阶梯治疗”原则，建议应尽早使用细胞因子靶向药物这些特异性免疫抑制药物。免疫治疗时代诸多的irAEs是传统化疗及小分子靶向治疗时代不曾有过的，不断地挑战肿瘤科大夫的知识储备和临床基本技能。因此，建立肿瘤多学科讨论体系对于肿瘤患者的治疗管理极为重要。

The role of immuno-checkpoint inhibitors in Hodgkin lymphoma

Abstract Although Hodgkin lymphoma has become one of the most curable lymphomas, 20-30% of patients still relapse after first-line treatment. In relapsed patients, high dose chemotherapy followed by autologous stem cell transplantation (HDC/ASCT) is a standard treatment approach, however transplant-ineligible patients or patients who relapse after HDC/ASCT still have a rather poor prognosis. Immuno-checkpoint inhibitors are one of the most promising cancer immunotherapies in various advanced cancers including hematologic malignancies. PD-1-blocking antibodies have been used to enhance immunity in several malignancies and obtain durable responses, especially in the patients with heavily treated relapsed/refractory Hodgkin lymphoma. Nowadays, several clinical trials including single agent or combination therapies for Hodgkin lymphoma have been developed or are currently under investigation. The results of ongoing and future clinical trials may establish new treatment paradigm in Hodgkin lymphoma.

Randomized phase II study of CDDP+S-1 vs CDDP+PEM combined with thoracic RT for locally advanced non-squamous NSCLC

Abstract Background We previously reported that toxicities were tolerable and manageable in both arms; however, febrile neutropenia was more frequently observed in the CDDP+S-1 arm. Response rate was 60%/64%. Here, we present primary analysis of 2-year survival data. Methods Patients were randomly assigned to receive CDDP+S-1 (CDDP 60mg/m2, d1, and S-1 80mg/m2, d1-14, q4w, up to 4 cycles) or CDDP+PEM (CDDP 75mg/m2, d1, and PEM 500mg/m2, d1, q3w, up to 4 cycles) combined with TRT 60Gy in 30 fractions. The primary endpoint was 2-year progression-free survival (PFS) rate. The sample size was set at 100 patients. Results Between Jan 2013 and Oct 2016, 102 patients were enrolled in this study from 9 institutions in Japan. All 102 patients were eligible and assessable, of whom 52 were assigned to CDDP+S-1 and 50 to CDDP+PEM. Baseline characteristics were similar (CDDP+S-1/CDDP+PEM): median age (range) 64.5 (39-73)/63.5 (32-74) years; women, n = 17 (33%)/n=17 (34%); stage IIIB, n = 21 (40%)/n=20 (40%); ECOG PS of 1, n = 14 (27%)/n=14 (28%); never smoker, n = 12 (23%)/n=12 (24%); and adenocarcinoma, n = 47(90%)/n=45(90%); activating EGFR mutation, n = 9 (17%)/n=4 (8%); ALK fusion, n = 2 (4%)/n=3 (6%). A total of 72 PFS events were observed at the data cut-off (28 November 2018). After a median follow-up of 32.1 months, median PFS was 12.7/13.8 months (HR = 1.16, 95% CI, 0.73-1.84, p = 0.538), and 2-year PFS rate was 36.5% (95% CI, 23.5-49.6)/32.1% (95%CI, 18.9-45.4). After a median follow-up of 34.6 months, 44 OS events were observed. Median OS was 48.3/59.1 months (HR = 1.05, 95%CI, 0.58-1.90, p = 0.883), and 2-year OS rate was 69.2% (95%CI, 56.7-81.8)/66.4% (95%CI, 53.0-79.9). 27 patients in each arm received post-study chemotherapy including EGFR-TKIs (n = 7/n=5), ALK-TKIs (n = 0/n=3), and immunocheckpoint inhibitors (n = 6/n=10). Conclusions 2-year PFS rate in the CDDP+S-1 arm was better than that in the CDDP+PEM arm. We will select the CDDP+S-1 arm as the investigational arm in a future phase III study.

The therapeutic effect and immune-related adverse event of nivolmab in Anjo Kosei Hospital

Abstract Background Nivolmab is approved as a novel immunocheckpoint inhibitor and peculiar immune-related adverse events (irAE) including interstitial lung disease (ILD), endocrinological disorder, and immunological colitis are reported. The rapid diagnosis and treatment are indispensable for the irAE of nivolmab. Cases and Methods We examined the therapeutic effect and irAE of the 116 cases administrated nivolmab from February 2016 to January 2019 in Anjo Kosei Hospital. Result The cases included 52 cases of non-squamous cell lung carcinoma (NSCLC), 20 cases of squamous cell lung carcinoma (SCLC), 12 cases of renal cell carcinoma (RCC) and adenocarcinoma of stomach, 5 cases of squamous carcinoma of head and neck region, and 3 cases of malignant melanoma and hodgkin lymphoma. The median observation period was 9.53 months in total. The median overall survival period was 26.8 months in the cases of NSCLC, 27.2 months in SCLC, 14.2 months in RCC, 11.0 months in adenocarcinoma of stomach, respectively. The 12 cases of hyper and hypothyroidism, 7 cases of colitis, 5 cases of ILD and endocrinological disorder, and other 15 cases of irAE were diagnosed. No case of novel diabetes mellitus was developed. The cumulative incidence rate of irAE reached 69.3% through all over the cases. The Brinkman Index over 700 was recognized as clinical factor for development of total irAE with significant p-value 0.039. No clinical factor for specific irAE including ILD, thyroid disorder, endocrinological disorder, colitis and diabetes mellitus respectively. Conclusion We examined 116 cases administrated nivolmab and recognized equivalent effect with clinical trial and significant relation of Brinkman Index to development of irAE.

Efficacy of chemotherapy following nivolumab in metastatic gastric cancer

Abstract Background Immuno-checkpoint inhibitors, nivolumab targeting programmed cell death 1 (PD-1) can result in significant benefit to gastric cancer. Some recent data about non-small cell lung cancer suggest anti-PD-1 therapy may enhance sensitivity to subsequent chemotherapy. To date, there are no reports on treatment efficacy after failure of PD-1 blockade in advanced gastric cancer. Therefore, we aimed to report the efficacy of chemotherapy after progressive disease on nivolumab. Methods We have retrospectively reviewed data of all patients in metastatic gastric cancer who received chemotherapy in our hospital and investigated the efficacy and adverse events of chemotherapy after progression on nivolumab. Results Between September 2017 and January 2019, 29 patients received nivolumab for metastatic gastric cancer. 11 patients received subsequent treatment following nivolumab. The median age was 70. Performance status (0/1/2); 2/8/1. Previous treatment regimens (2/3/4/5); 4/3/2/1. Chemotherapy regimen (irinotecan / nab-paclitaxel±ramcirumab / CAPOX±trastuzumab / SOX+trastuzumab); 3/5/2/1. Overall Response rate was 27%. 2 patients for nab-PTX+ramcirumab and 1patient of CAPOX+trastuzumab had a PR, 1patient for nab-PTX+ramcirumab had a SD, 5 patients had a PD and 1 patient had a NE. Median PFS was 3.3 (95% CI. 0.8-5.5) months. Median OS was 8.0 (95%CI. 2.3-11.6) months. One patient developed Gr3 dysfunction of liver maybe due to nivolumab. Other adverse events were mild. Conclusions We evaluated the efficacy of chemotherapy after progression on nivolumab. Further investigation is warranted to reveal an immunotherapy-induced chemosensitization effect.

Immunocheckpoint inhibition in head and neck squamous cell carcinoma: the current status and progress

Over the past decades, although the clinical efficacy of advanced head and neck squamous cell carcinoma (HNSCC) has been moderately improved by the combination of cetuximab and chemotherapy, no remarkable treatment has emerged. The prognosis of HNSCC is still unsatisfied. With the deeper exploration of tumor immunological therapy, immunocheckpoint inhibitors such as monoclonal antibodies targeting on programmed cell death protein 1 (PD-1)/ cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have shown appreciable anti-tumor effect on cancers such as melanoma and non-small cell lung cancer. Some successful clinical studies on HNSCC have also been reported, which provide a new opportunity for the improvement of HNSCC prognosis.Here we systemically review the progress of checkpoint inhibitors and its combination therapy in HNSCC, some immunotherapy efficacy-related biomarkers are also discussed.

Abstract 582: Tumor immunoediting in a lung cancer mouse model harboring EGFR mutations

Abstract Background: Anti-Programed cell death 1 (PD-1) antibodies such as nivolumab or pembrolizumab show promising treatment effects in smoking-related lung cancer. However, anti-PD-1 antibodies have very little effect on epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). EGFR mutations are the most frequent oncogenic drivers in non-smoking related NSCLC. Therefore, we aimed to explore the mechanism underlying tumor immunoediting in a lung cancer mouse model harboring EGFR mutations. Methods: We previously established two strains of transgenic lung cancer mouse (C57BL/6) harboring a mouse Egfr exon 19-deletion (mDEL) or a human EGFR L858R (hLR) mutation, driven by a surfactant protein (SP)-C promoter (Ohashi, Cancer Sci. 2008; Ohashi, Cancer Res. 2009). These mice developed EGFR-dependent multifocal lung adenocarcinomas from type II pneumocytes. We modified the two models by transplanting lung tumors subcutaneously into C57BL/6 (Ohashi, AACR. 2018). Evaluation of mice tumor lymphocyte profile was done through flow cytometry or immunohistochemistry (IHC). Effects of T cell depletion or anti-mouse PD-1 antibody (4H2) in vivo were also assessed. Comprehensive analysis of mRNA expression of immuno-checkpoint molecules in the tumors was performed using PanCancer Immune Profiling Panel (NanoString Technologies). Results: CD4+ T cells and/or CD8+ T cells were depleted in the subcutaneously transplanted tumor model followed by treatment with gefitinib (50 mg/kg/day, 5 days/week) for 2 weeks. As a result, after gefitinib discontinuation, rapid regrowth was seen in the tumors from groups with depletion of CD8+ T cells; depletion of CD4+ T cells had little effect on tumor regrowth, and tumor inhibition continued for 2 weeks after cessation of gefitinib. IHC showed relatively increased numbers of CD4+ T cells in the mice tumors whereas a decrease in the number of CD8+ T cells or Foxp3 positive cells was noted. PD-L1 expression was not observed in the tumors. Consistently, 4H2 showed little effect on tumor growth in vivo. The cancer immune panel showed increased expression of immune mediators such as Ccl6, Clec4n, and Lcn2. Conclusions: Our results suggest that CD8+ T cells can recognize mice tumors in vivo. New immuno-checkpoint molecules regulating CD8+ T cells from PanCancer Immune Profiling Panel were evaluated. Further, we plan to evaluate the efficacy of various immuno-checkpoint inhibitors in vivo. Citation Format: Kazuya Nishii, Kadoaki Ohashi, Kiichiro Ninomiya, Go Makimoto, Hiromi Watanabe, Hirohisa Kano, Naofumi Hara, Heiichiro Udono, Katsuyuki Kiura. Tumor immunoediting in a lung cancer mouse model harboring EGFR mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 582.

Poor prognosis of hypermutant colorectal cancer with KRAS mutations: A retrospective analysis of 1,052 Japanese colorectal cancer patients without treatment of immuno-checkpoint inhibitors

Poor prognosis of hypermutant colorectal cancer with KRAS mutations: A retrospective analysis of 1,052 Japanese colorectal cancer patients without treatment of immuno-checkpoint inhibitors

Combinations of immuno-checkpoint inhibitors predictive biomarkers only marginally improve their individual accuracy

BackgroundThere are no accepted universal biomarkers capable to accurately predict response to immuno-checkpoint inhibitors (ICI). Although recent literature has been flooded with studies on ICI predictive biomarkers, available data show that currently approved companion diagnostics either leave out many possible responders, as in the case of PD-L1 testing for first-line metastatic lung cancer, or apply to a small subset of patients, such as the recently approved treatment for microsatellite instability-high or mismatch repair deficiency tumors. In this study, we conducted a survey of the available data on ICI trials with matched genomic or transcriptomic datasets in order to cross-validate the proposed biomarkers, to assess whether their prediction power was confirmed and, mainly, to investigate if their combination was able to generate a better predictive tool.MethodsWe extracted clinical information and sequencing data details from publicly available datasets, along with a list of possible biomarkers obtained from the recent literature. After an operation of data harmonization, we validated the performance of all the biomarkers taken individually. Furthermore, we tested two strategies to combine the best performing biomarkers in order to improve their predictive value.ResultsWhen considered individually, some of the biomarkers, such as the ImmunoPhenoScore, and the IFN-γ signature, did not confirm their originally proposed predictive power. The best absolute scoring biomarkers are TIDE, one of the ICB resistance signatures and CTLA4 with a mean AUC > 0.66. Among the combinations tested, generalized linear models showed the best performance with an AUC of 0.78.ConclusionsWe confirmed that the available biomarkers, taken individually, fail to provide a satisfactory predictive value. Unfortunately, also combination of some of them only provides marginal improvements. Hence, in order to generate a more robust way to predict ICI efficacy it is necessary to analyze and combine additional biomarkers and interrogate a wider set of clinical data.

免疫チェックポイント阻害薬の効果を左右する腫瘍微小環境

免疫チェックポイント阻害薬の効果を左右する腫瘍微小環境

Advances in Research on Immunological Checkpoint Inhibitors in Immunotherapy of Liver Cancer

The current treatments of liver cancer in China are mainly comprehensive treatment and systematic treatment, with poor therapeutic effect and high recurrence rate and metastasis rate. The existence of immunosuppressive microenvironment is an important reason for liver tumor cells to escape from the host immune system, and also an important basis for the occurrence and development of liver cancer. With the recent transformation of the target of tumor therapy from tumor cells to tumor cell immune microenvironment, immunotherapy has emerged quietly. It is a new strategy for the treatment of hepatocellular carcinoma to improve the immune attack on tumor cells by changing the immunosuppressive environment of hepatocellular carcinoma cells. Immune checkpoint is the main mechanism by which liver cancer cells escape the host immune system. PD-1/PDL-1 and CTLA-4 are targeted immunocheckpoint inhibitors, which have shown good therapeutic effects and application prospects in the clinical treatment of HCC. This article reviews the latest advances in immunocheckpoint inhibitors in the immunotherapy of hepatocellular carcinoma.

Clinical Development of Immunotherapy for Small Cell Lung Cancer

小细胞肺癌（small cell lung cancer, SCLC）约占肺癌的15%，恶性程度高，侵袭性强，尽管其对放化疗比较敏感，但极易发生耐药，复发率高，后期治疗效果欠佳。近年来，免疫抑制剂展现了良好的抗肿瘤活性，特别是程序性死亡受体-1/配体-L1（programmed death receptor-1/ligand-L1, PD-1/L1）和细胞毒性T淋巴细胞相关抗原-4（cytotoxic T-lymphocyte-associated antigen 4, CTLA-4）检查点抑制剂的问世改变了肿瘤治疗的格局，同时SCLC具有高免疫源性，高突变负荷等免疫利好因素，免疫检查点抑制剂有望成为该领域治疗的重要突破口，本文将对SCLC免疫治疗的临床研究进展做简要综述。

1211P - Hyperprogression during immuno-checkpoint inhibitors (ICIs): A clinically significant problem?

1211P - Hyperprogression during immuno-checkpoint inhibitors (ICIs): A clinically significant problem?

Pembrolizumab and salvage chemotherapy in EGFR T790M-positive non-small-cell lung cancer with high PD-L1 expression

Immuno-checkpoint inhibitors (ICI) have become an effective treatment option for non-small-cell lung cancer patients. However, ICI therapy was reported to be less effective in patients with epidermal growth factor receptor (EGFR) mutations than in those with wild-type EGFR. We report here that an non-small-cell lung cancer patient with the EGFR mutant T790M showed a programmed cell death ligand 1 (PD-L1) expression level that increased from <25% to >90% after eighth-line osimertinib therapy. He was treated with pembrolizumab as a ninth-line treatment, and attained stable disease. After the pembrolizumab therapy, he was treated with gemcitabine, which produced a good response despite being the 10th-line treatment. We should consider administering ICI and chemotherapy even to EGFR mutant patients after failure of EGFR tyrosine kinase inhibitor, especially in cases with high PD-LI expression.

Impact of metastatic local treatment in the strategy of metastatic renal cell carinoma including sterotactic radiotherapy, surgery, and radiofrequency in an expert center.

596 Background: Standard treatment of metastatic renal clear cell carcinoma is based upon nephrectomy, and systemic treatment with targeted agents. These drugs induce frequent side effects that may compromise observance and quality of life. Considering a focal treatment of one or more metastases can lead to a drug-holidays, or allow to postpone systemic treatment start in oligometastatic disease. Such focal treatment techniques are surgery, radiofrequency ablation (RFA) or stereotactic radiotherapy (SRT). Methods: In this retrospective, monocentric and analytic study, we analyzed progression-free survival (PFS) and overall survival (OS) after a focal treatment in a cohort of patients from Bordeaux University Hospital, involving similar staff members along time. We have also reported local control, complications and potential predictive factors associated with a better outcome. Results: Seventy-one patients with 78 focal treatments (23 RFA, 47 metastasectomy and 8 SRT) have been included in our study. For 44 patients, the disease was oligometastatic, (1 to sites, less than 5 metastases) including 15 patients with a partial response to systemic treatment before the focal approach, and 12 patients with a dissociated response to systemic treatment. Progression post focal treatment occurred in 53 (74.6 %) of patients. Median PFS was 14 months (95 % confidence interval [CI], - 8-16 months); and median OS was 77 months (95 % CI, 41 months-not reach). Local control rate was 83.3 %, and complication rate was 36.3 % due to local treatments, without death related to iatrogenic events. A diagnosis of metachrone metastases and a disease-free interval between the first diagnosis and the occurrence of the metastases of at least one year seemed to be associated with better outcomes. Conclusions: Data observed in our study are consistent with those reported in literature. The prolonged OS and PFS post focal treatment should encourage clinical oncologists to discuss this multimodal approach (association of systemic and focal treatments). This approach should be also evaluated in the context of the immunocheckpoint inhibitor in the future.

P105 SHORT TERM ENDOSCOPIC FOLLOW UP ON IMMUNO-CHECKPOINT INHIBITOR INDUCED COLITIS POST TREATMENT

Immuno-checkpoint inhibitor induced colitis (ICI-C) is a serious adverse event (AE) and can persist months after stopping the triggering ICI. Clinical symptoms resolution does not always correlate with endoscopic/histological findings. We report a case series with discordance between symptom profile and endoscopic/histological findings of colitis. A 77 y/o male with prostate cancer, experienced 8–11 bloody stools 3 months after 2nd dose ipilimumab. Colonoscopy revealed multiple large ulcerations throughout, with biopsy showing chronic active colitis. Patient’s symptoms partially improved after treatment with high dose steroids for 2 months, and 2 doses of infliximab, resolved after adding 3 doses of vedolizumab. Colonoscopy after 5 months of treatment showed persistent ulcers. A 51 y/o male with bladder cancer treated with atezolizumab developed grade 2–3 diarrhea a week after the 2nd dose. Colonoscopy showed normal mucosa with biopsy revealing lymphocytic colitis. The patient failed mesalamine and high dose steroids, resolved with 2 doses of infliximab. Symptoms recurred 3 months later. Repeat biopsy of the colon showed persistent colitis. 2 more doses of infliximab was given with symptoms resolution. A 66 y/o male with metastatic melanoma treated with ipilimimab and pembrolizumab experienced grade 3 diarrhea after 2nd dose. A colonoscopy revealed mild patchy erythema in the colon. Biopsy revealed moderate active colitis. Symptoms improved to grade 1 after steroids and 4 doses of infliximab. Repeat colonoscopy showed normal mucosa, with biopsy showing persistent active colitis. The symptoms of ICI-C do not always correlate with endoscopic/histological findings. Persistent endoscopic/histological inflammation likely predict recurrent symptoms, despite short term clinical remission. Deeper level remission may be a better surrogate marker for good long term outcome.

Current status and perspectives in immunotherapy for metastatic melanoma.

Metastatic melanoma was the first malignancy in which immune checkpoint inhibitors demonstrated their successful efficacy. Currently, the knowledge on the interaction between the immune system and malignant disease is steadily increasing and new drugs and therapeutic strategies are overlooking in the clinical scenario. To provide a comprehensive overview of immune modulating drugs currently available in the treatment of melanoma as well as to discuss of possible future strategies in the metastatic melanoma setting, the present review aims at analyzing controversial aspects about the optimal immunomodulating treatment sequences, the search for biomarkers of efficacy of immunocheckpoint inhibitors, and innovative combinations of drugs currently under investigation.

P105 SHORT TERM ENDOSCOPIC FOLLOW UP ON IMMUNO-CHECKPOINT INHIBITOR INDUCED COLITIS POST TREATMENT

Immuno-checkpoint inhibitor induced colitis (ICI-C) is a serious adverse event (AE) and can persist months after stopping the triggering ICI. Clinical symptoms resolution does not always correlate with endoscopic/histological findings. We report a case series with discordance between symptom profile and endoscopic/histological findings of colitis. A 77 y/o male with prostate cancer, experienced 8-11 bloody stools 3 months after 2nd dose ipilimumab. Colonoscopy revealed multiple large ulcerations throughout, with biopsy showing chronic active colitis. Patient’s symptoms partially improved after treatment with high dose steroids for 2 months, and 2 doses of infliximab, resolved after adding 3 doses of vedolizumab. Colonoscopy after 5 months of treatment showed persistent ulcers. A 51 y/o male with bladder cancer treated with atezolizumab developed grade 2-3 diarrhea a week after the 2nd dose. Colonoscopy showed normal mucosa with biopsy revealing lymphocytic colitis. The patient failed mesalamine and high dose steroids, resolved with 2 doses of infliximab. Symptoms recurred 3 months later. Repeat biopsy of the colon showed persistent colitis. 2 more doses of infliximab was given with symptoms resolution. A 66 y/o male with metastatic melanoma treated with ipilimimab and pembrolizumab experienced grade 3 diarrhea after 2nd dose. A colonoscopy revealed mild patchy erythema in the colon. Biopsy revealed moderate active colitis. Symptoms improved to grade 1 after steroids and 4 doses of infliximab. Repeat colonoscopy showed normal mucosa, with biopsy showing persistent active colitis. The symptoms of ICI-C do not always correlate with endoscopic/histological findings. Persistent endoscopic/histological inflammation likely predict recurrent symptoms, despite short term clinical remission. Deeper level remission may be a better surrogate marker for good long term outcome.