Study On Treatment Of Mutant Neoantigen Specific T Cells

[Objective]Cancer has become one of the major diseases that affect public health.Tumor immunotherapy is an ancient and emerging therapy,especially the development and application of checkpoint inhibitors is the milestone in human anti-tumor history.However,the essence of checkpoint inhibitors is still nonspecific,and its efficiency is not very satisfactory.The treatament of mutant neoantigen specific T cells developed in this study is an adoptive cell treatment for each individual tumor,and it is specific immunotherapy.The aim of this study is to explore the difference in efficacy and safety between mutant neoantigen specific T cells therapy and PD1 monoclonal antibody therapy,and to evaluate the effect of mutant neoantigen specific T cells therapy on immune function via immune repertoire and immune factors.[Method]a total number of 11 patients with advanced solid tumors who failed after multiline treatments were enrolled in the study.They were treated with mutant neoantigen T cells and PD1 monoclonal antibody,and the other 11 patients with the similar basic conditions were treated with PD1 monoclonal antibody as control.Peripheral blood was collected at baseline and per cycle respectively.Multiple PCR and the next generation high throughput sequencing platform IR-Seq and Elisa were used to detect the immune repertoire and immune factors respectively to evaluate immunity.[Results]the PFS of the two groups was analyzed by Kaplan-Meier method.The statistical results showed that PFS of two groups had statistical significance(P<0.05);the HR point estimated value was 0.21,and the 95%confidence interval was(0.043-0.981),which was also statistically significant(P<0.05).It is suggested that the mutant neoantigen specific T cells therapy may prolong patients' PFS.COX of single factor analysis showed that 9 indexes of test group,percentage of neutrophils and lymphocytes,hemoglobin,red blood cells,platelets,aspartate aminotransferase,total protein and albumin values have statistical significance(P<0.05),indicating that the above 9 indicators may be related with PFS.There was no statistical significance in multifactor analysis.The safety of the two groups was analyzed from 7 indexes,including body temperature,blood routine,urine routine,stool routine,blood coagulation function,liver function and kidney function.Statistical results showed that there was no significant difference in baseline level between the two groups(P>0.05).The total protein,albumin and urea levels decreased and creatinine level increased in both of the groups in different follow-up periods(P<0.05).Compared with the control group,the level of total protein and albumin in the treatment group had a transient decrease in the 3rd and 4th,5th follow-up,respectively,with a statistically significant difference(P<0.05);and has a self recovery in the 6th follow-up.According to PFS,patients in treatment group were divided into responder and non-responder.V-J pairing frequency of the two groups had no significant difference in baseline and the 1st cycle(P>0.05),the dynamic changes between baseline and the 1st cycle was statistically significant with Shannon Index,Clonality Index and Evenness Index(P<0.05).Changes of immune factors of Non-responder:IL-lr alpha and GM-CSF decreased,IP-10 first increased and then decreased,IL-6 and G-CSF increased.Changes of immune factors in Responder:IL-12,G-CSF,VEGF decreased,IL-1 beta,IL-9 and PDGF-BB increased.Compared with non-responder,the level of IL-1 beta and PDGF-bb increased,G-CSF decreased.[Conclusion]the combined immunotherapy of mutant neoantigen specific T cells and PD1 monoclonal antibody is more effective than PD1 monoclonal antibody alone in prolonging the PFS of patients with advanced solid tumors after multiline treatments failure,and has a good safety.Immune repertoire may be a potential index for evaluating the effect of immunotherapy.