A Clinical Study Of Anti-PD-1 Antibody Combined With RCAT In Treatment Of Advanced Malignant Tumor

Background and objectiveAs the main cause of death in China,the morbidity and mortality of malignant tumors are increasing year by year.For a long time,the conventional treatment of tumor includes surgery,chemotherapy and radiotherapy.Among them,early tumor can be excised by surgical excision.However,many cancer patients have been found in the middle and late stage,lost the chance of operation.Other treatment methods are relatively inefficient,and drug resistance inevitably occurs during the treatment,which results in poor prognosis.Therefore,finding a safer and more effective way to treat malignant tumors is the focus of current research.In recent years,with the vigorous development of tumor biological immunotherapy,it has become the fourth treatment modality of cancer.Especially,the inhibitors of immune checkpoints represented by anti-PD-1 antibodies are the hot spot at present.In addition,the adoptive immunotherapy,represented by the CD3 RetroNectin Activated T cell(RCAT),has also shown good prospects in the treatment of malignant tumors.Due to the safe and efficient antitumor properties of RCAT,it has a potential complementation with other therapies,and in view of their T cell sources,the combination of anti-PD-1 and RCAT is reasonable and feasible.Based on this,the purpose of this study is to evaluate the clinical efficacy and safety of anti-PD-1antibody combined with RCAT in the treatment of advanced malignant tumors,and to detect the changes in the treatment process of peripheral blood related immune cells in patients with advanced renal cell carcinoma,and to further explore the prognostic indicators.Methods22 patients with advanced cancer(10 metastatic renal cell carcinoma,6non-small cell lung cancer,2 ureteral carcinoma,1renal pelvic carcinoma,1 breast cancer,1 osteosarcomaand 1 melanoma)who were hospitalized in Department of biotherapy,Affiliated Cancer Hospital of Zhengzhou University(Henan Cancer Hospital)and duringJune 2015 to February 2018 were recruited.All patients received at least 4 times of anti-PD-1 antibody combined with RCAT cell therapy,of which 15patients received Nivolumab(BMS-936558)3mg/Kg,1 times every 2 weeks,7patients received Keytruda(MK-3475)2mg/Kg,1 treatment every 3 weeks.The subgroup distribution of peripheral blood related immune cells was detected in 8advanced renal cell carcinomapatients before and after 2 cycles of treatment.All patients took CT and/or MRI examination to assess the short-term efficacy after each6 weeks.Our observed standards were disease control rate(DCR),objective response rate(ORR)and adverse effects.DCR included CR,PR and SD;ORR included CR and PR.ResultsThe efficacy of 22 patients could be evaluated,there were 6 case which achieved CR(27.27%),5 PR(22.73%),7 SD(31.82%),4 PD(18.18%),ORR(CR+PR)50.00%,DCR(CR+PR+SD)81.82%.Among the 10 patients with advanced renal cell carcinoma,5 CR(50%),2 PR(20%),3 SD(30%),ORR 70%and DCR 100%.5 cases of CR patients with a median CR time was 201 days(75-301 days),of which 3 cases stopped treatment at the time of the last follow-up is CR;in 3 SD patients,1 cases in the treatment of 142nd days of death,1 cases because of economic reasons in the treatment of 185th days after the cessation of treatment in 366th days PD was changed toAxitinib treatment,1months after the review of PR,is still in Axitinib taking treatment process,in addition to 1 cases of patients with SD is still in the course of treatment.There were no treatment-related deaths in 22 patients,5 patients had grade I/II hypothyroidism,4 patients had grade I/II transaminase rise,1patients had grade I fever,1 patients had grade II diarrhea,1 patients had grade II rash and immune associated pneumonia,and no grade III-IV adverse reactions occurred.The result of immune cells subsets in the peripheral blood:the PD-1~+/PBMC?PD-1~+CD3~+/CD3~+?PD-1~+CD4~+/CD4~+?PD-1~+CD8~+/CD8~+level of 8 patients is decreased significantly after two cycle therapy of anti-PD-1 antibody,the difference has statistical significance(p<0.05).The level of Treg and MDSCs has no obvious change after two cycle therapy of anti-PD-1 antibody.ConclusionsThe anti-PD-1 antibody(Nivolumab/Keytruda)combined with RCAT cells is safe and effective in the treatment of advanced malignant tumor,and it can improve the effective rate and tolerability of advanced renal cell carcinoma.The PD-1~+/PBMC?PD-1~+CD3~+/CD3~+?PD-1~+CD4~+/CD4~+?PD-1~+CD8~+/CD8~+level is decreased significantly after two cycle therapy of anti-PD-1 antibody.The level of Treg and MDSCs has no obvious change after two cycletherapy of anti-PD-1antibody.