A 42-year-old man has no clear incentive to present an eating obstruction in July 2020. Symptoms worsen when hard and dry foods are consumed, accompanied by paroxysms of dull pain in the upper left abdomen, no chest tightness or pain, no nausea and vomiting, no hematemesis and melena, no fever and chills, and other discomfort. No history of autoimmune disease, no pneumonia, interstitial lung disease, no chronic obstructive pulmonary disease (COPD), denial of hepatitis B virus (HBV) or hepatitis C virus (HCV), human immunodeficiency virus (HIV) carrier, no recent vaccinations. He visited a local hospital on 13 August 2020. Gastroscopy revealed the lower esophagus, cardia and cardia by lumen narrowing, allowing endoscopy to pass through. There is a huge ulcer in the cardia. The nodules at the bottom are uneven and covered with dirt moss ( Figures 1A, B ). Biopsy pathology: poorly differentiated adenocarcinoma ( Figure 1C ). The patient came to our hospital for further diagnosis and treatment 17 August 2020. Contrast-enhanced Computed tomography (CT) of the cervicothoracic abdomen and pelvis demonstrated: cardiac cancer involving the esophagus and lesser curvature of stomach, with multiple lymph node metastasis; superior lobe metastasis of the left lung; hepatic metastasis ( Figures 1D-F ). Eastern Oncology Collaborative Group (EOCG): 1, the patients had poor economic foundation, but as the breadwinner of the family, the patients and their families had a strong desire for therapy.
After communication with the patient and comprehensive consideration, the patient requested to be enrolled in the "open-label study of AK104 (PD-1/CTLA-4 bispecific antibody)". Patients with unknown HER-2 status or negative results could be included in the group. He did not undergo HER-2 and PD-L1 tests at enrollment. Six cycles of AK104 + mXELOX/q14d (AK104 6 mg/kg d1+ oxaliplatin 85 mg/m2 d1 + capecitabine 1,000 mg/m2 d1-10/Q14d) were initiated on 27 August 2020. A partial response (PR) was assessed by CT after three and six cycles of treatment (primary foci and hepatic and lung metastatic lesions were markedly decreased). After the sixth treatment cycle, the patient showed symptoms of fatigue, wheezing after activity, palpitation, cough, phlegm, dry mouth, and loss of appetite. On 15 November 2020, general bacterial sputum culture and identification were performed. No bacteria associated with inflammation were identified. Detection of 13 respiratory pathogens: hemophilus influenzae positive. PCT: 0.10 ng/ml. Chest CT: multiple floc and patchy high-density shadows in both lungs, appearance of interstitial pneumonia ( Figure 2A ). He had not caught a cold recently and had no symptoms of fever. In addition, symptoms and additional examinations were combined to rule out the virus/bacterial pneumonia, considering the possibility of immune pneumonia. Antitumor therapy was interrupted, methylprednisolone sodium succinate (MPSS) 80 mg iv drip for 5 days, oral prednisone acetate tablets (taper off), and the patient's symptoms were markedly improved. A CT scan performed on 28 December 2020 showed that the pneumonia was better than before, and the lung metastatic lesions continued PR ( Figure 2B ).
A cycle of oxaliplatin 85 mg/m2 d1 + capecitabine 1,000 mg/m2 d1-10/Q14d 1 cycle was initiated on 14 January 2021. AK104 6 mg/kg d1 + capecitabine 1,000 mg/m2 d1-10/Q14d regimen maintenance treatment commenced on 4 February 2021. During the CT evaluation, his condition was sustained at PR on 2 September 2021 monitoring of liver function: ALT 173.7 U/L and AST 148.4 U/L ( Figure 2C ). We delivered liver preservation therapy and, on 3 September 2021, retest liver function: ALT 189.0 U/L and AST 114.8 U/L. At this time, oxaliplatin had been discontinued for 7 months, so it was considered that liver damage was likely to be related to immunity. We gave MPSS 1 mg/kg combined with liver protection and gallbladder therapy to improve the liver function test on 14 September 2021: ALT 69.4 U/L and AST 26.5 U/L. Then the patient was treated at home with oral prednisone, and liver function returned to normal after regular review. 5 October 2021: ALT 650.4 U/L, AST 499.6 U/L, TBil 35 umol/L, DBil 23.1 umol/L, I-Bil 11.9 umol/L. Incorporating the patient's symptoms and hematologic findings, we diagnosed grade 3 immune-mediated hepatitis. MPSS 2 mg/kg combined with liver protection and gallbladder treatment was used to improve immune hepatitis. 14 October 2021: ALT 153.6 U/L, AST 35.2 U/L. 18 October 2021: ALT 171.3 U/L, AST 41.2 U/L. Considering corticosteroid resistance in patients, we treated them with the incorporation of mycophenolate mofetil. 25 October 2021: ALT 84.7 U/L , AST 18.2 U/L, TBil 17.3 umol/L , DBil 7.3 umol/L. The patient is getting better right now. Nevertheless, the patient was excluded from the clinical study due to the long-term absence of medication. Antitumor therapy was also discontinued in view of the adverse immune response of the patient. The patient did not receive subsequent immune antitumor therapy, and immune-related hepatitis still occurred intermittently, but the disease evaluation was maintained at PR. CR was confirmed by FDG-PET and the biopsy specimen from gastroscopy on 10 June 2020 ( Figures 3A-I ). Next-generation sequencing (NGS)-Geneseeq PRIME (425-Cancer Gene Panel) of first biopsy tissue to guide subsequent therapy at a recent follow-up visit. The results indicated that TP53, JAK3, JARID2, CDKN2C, GREM1, EMSY, ERBB2 mutations; copy number 58.4934 (ERBB2), 15.158 (CCNE1); structural variation (ERBB2, CDK12); tumor mutational burden (TMB) = 3.1, microsatellite stability (MSS) ( Figure 4A ,  Supplementary Figure S1 ). Immunohistochemistry (IHC): EBV (-), PD-L1 CPS = 3, HER-2 (3+) ( Figures 4B-D ).