Efficacy And Safety Of Cellular Immunotherapy Combined With Chemotherapy Versus Chemotherapy In The Treatment Of Colorectal Cancer

Objective:To evaluate the efficacy and safety of cellular immunotherapy combined with chemotherapy versus chemotherapy in patients with colorectal cancer,screen out the benefit groups of cellular immunotherapy,and provide evidence-based medical evidence for the application of cellular immunotherapy in patients with colorectal cancer.Method:A retrospective analysis of 377 patients with colorectal adenocarcinoma and chemotherapy received from the first hospital of Jilin University from December 2010 to December 2015 was performed.There were 97 patients in the CIT+chemotherapy group and 280 in the chemotherapy group.The chemotherapy regimen was the standard protocol recommended by the National Comprehensive Cancer Network(NCCN)guidelines at the time.Peripheral blood mononuclear cells were collected from patients receiving cellular immunotherapy in vitro,and the number of cells reached 1.2～2.0×109 for autoimmune cell reinfiision.The primaJy endpoints were progression free survival(PFS)and overall survival(OS).Secondary endpoints were objective response rate(ORR),disease control rate(DCR),adverse reactions,changes in immune indicators and treatment tolerance.The disease stage is based on the TNM staging of the American Joint Committee on Cancer(AJCC),and the adverse drug reaction is based on the NCI CTCAE 5.0(National Cancer Institute Common Terminology Criteria for Adverse Events 5.0)standard.Results:(1)The PFS and OS in the CIT+chemotherapy group were longer than those in the chemotherapy group.The 3-year PFS rate was 67.2%in the CIT+chemotherapy group and 53.9%in the chemotherapy group(P<0.01).The 3-year and 5-year OS rates in the CIT+chemotherapy group and the chemotherapy group were 81.3%vs 67%(P<0.001),74.1%vs 50.8%(P<0.001),respectively.Multivariate results showed that CIT+ chemotherapy was an independent factor affecting PFS(HR:0.446,95%CI:0.272-0.733)and OS(HR:0.259,95%CI:0.139-0.481).(2)Subgroup analysis results:①Disease staging:Patients with adjuvant therapy:In patients with stageⅡ:CIT+chemotherapy have longer PFS and OS than chemotherapy group.The 3-year and 5-year PFS rates in the CIT+chemotherapy group and the chemotherapy group were 100%vs78%(P<0.01)and 100%vs 68.7%(P<0.01).The 5-year OS rate was 100%vs 81.7%(P<0.01).In patients with stage III:CIT+chemotherapy have longer PFS and OS than chemotherapy group.The 3-year and 5-year PFS rates in the CIT+chemotherapy group and the chemotherapy group were 78%vs 61.7%(P<0.001)and 70.9%vs 50.6%(P=0.002).The 5-year OS rate was 85.8%vs 60.7%(P<0.01).In patients with stage IV:CIT+chemotherapy have longer PFS and OS than chemotherapy group.The median PFS was 19.8 months vs 10.1 months(P=0.038)in the CIT+chemotherapy and chemotherapy groups,respectively,the 1-year PFS rate was 64.4%vs 36.2%(P<0.001).and the 3-year OS rate were 54.9%vs 26.9%(P<0.001).②Primary tumor lymph node metastasis:In patients with no lymph node metastasis:The 2-year PFS rate was 87.5%vs 77%(P=0.06),and the 5-year OS rate was 88.4%vs 73.5%(P=0.03).In patients with lymph node metastasis:The 2-year PFS rate was 68.2%vs 54.7%(P<0.001)in the CIT+chemotherapy group and the chemotherapy group,respectively,and the 5-year OS rate was 68.3%vs 45.3%(P<0.001).③Primary tumor tissue differentiation:In patients with undifferentiated or poorly differentiated:The 2-year PFS rate in the CIT+chemotherapy group and the chemotherapy group was 64.3%vs 41.8%(P=0.026),respectively.The 5-year OS rate was 47.6%vs 40%(P=0.267).In patients with moderately or medium differentiated:The 2-year progression-free survival rate was 75.9%vs 65.6%(P=0.018)in the CIT+chemotherapy group and the chemotherapy group respectively.The 5-year OS rate was 79.5%vs 56.1%(P<0.01).④In rectal cancer patients combined radiotherapy:The PFS and OS in the CIT+chemotherapy group were longer than those in the chemotherapy group.The median PFS and median OS were not reached in the two groups.The PFS and OS in the CIT+chemotherapy group were longer than in the chemotherapy group,but the difference was not statistically significant(P=0.261;P=0.113).⑤The PFS in male,left half CRC patients was longer in CIT+chemotherapy group than chemotherapy group(P<0.05).In patients with left half CRC had longer OS in CIT+chemotherapy than chemotherapy group(P<0.05).(3)Immune function evaluation:The percentage of total T cells(CD3+)in peripheral blood immune cells before and after treatment in CIT+chemotherapy group were 70.11%(63.35,78.43)vs 75.87%(68.29,80.34)(P=0.00),respectively.The ratio of Th cells(CD3+CD4+)was 42.53%(35.97,55.13)vs 44.39%(37.81,58.53)(P=0.02),respectively.(4)Safety evaluation:①The incidence of adverse reactions:The overall incidence of adverse reactions in the CIT+chemotherapy group and the chemotherapy group were 75.3%and 75.4%(P=0.98),respectively,and the incidence of Ⅲ-Ⅳ grade adverse reactions were 13.4%and 17.5%(P:=0.35),respectively.Only 2 patients in the CIT+chemotherapy group developed transient fever,and the remaining patients had no obvious discomfort.②Drug tolerance:The number of median chemotherapy courses and the dose of chemotherapy drugs in the CIT+chemotherapy group were higher than those in the chemotherapy group.The median chemotherapy course in the CIT+chemotherapy group was 7,and the chemotherapy group was 6(P=0.006).The median dose of capecitabine in the CIT+chemotherapy and chemotherapy groups was 308 g vs 224 g(P=0.01),respectively.Conclusion:(1)Cellular immunotherapy combined with chemotherapy can further improve the therapeutic effect of patients with colorectal cancer,reduce tumor recurrence rate and prolong survival.(2)Combined cellular immunotherapy is an independent factor to improve the prognosis of patients with colorectal cancer.(3)The safety of cellular immunotherapy is good.The combination with chemotherapy does not increase the toxicity,but improves the patient’s tolerance to chemotherapy,so that patients have the opportunity to receive adequate dose and course to ensure the quality of treatment.(4)Cellular immunotherapy can improve the immune status of patients with colorectal cancer,and may provide ideas for combining application with immunological checkpoint inhibitors.(5)This study suggests that adjuvant therapy,first-line therapy,colorectal cancer patients with age<65 years,left colon,primary tumor tissue type is better,and primary tumor tissue differentiation is better may be suitable for combined CIT,maybe they are the potential advantage groups.(6)High-quality and standardized CIT is a prerequisite for exerting anti-tumor effects.