A Clinical Study And Mechanism Analysis On T-cell Receptor-Engineered T Cells(TCR-T) In Treating 2 Patients With Advanced Pancreatic Cancer

Background and objectives:Pancreatic cancer is always occult and rapid in development.It is also difficult to be diagnosed in advance.Because of this,it is usually of poor prognosis and brings serious burden and great pain to patients and their families.T cell receptor-engineered T cell(TCR-T)is a kind of engineered T cell with its receptors modified genetically for specific tumor killing effect.As a new means of tumor immunotherapy,TCR-T has great potentiality in killing tumors at molecular and cellular levels.This paper discusses the clinical efficacy and side effects of utilizing HLA-A*11:01 restricted KRAS G12V mutation TCR-T in patients with pancreatic cancer,and explores the factors concerning their efficacy and safety from its molecular mechanism.Methods:Two patients have been enrolled in this study by now.Their peripheral blood mononuclear cells were collected for TCR-T cell construction after testing of its quality.Fludarabine and cyclophosphamide(FC regimen)were used to clear their lymphocytes one week before the TCR-T cell reinfusion,the doses of which for the patients were 2.63×10~9 and 7.2×10~9 respectively.Then,the changes of vital signs and laboratory indexes were closely observed,and the efficacy and safety indexes of the treatments were tested in the 1st and the 4th week after the infusion.The duration of following-up observations was extended according to the status of the patients.Results:In terms of tumor indexes,CA199 in one patient decreased significantly after the treatment,while no significant change was achieved in the other.From imaging aspect,patients’abdominal MR showed that the abdominal lymph node metastasis of one patient shrank by about55%,while the other patient had new liver lesions after the treatment,which then disappeared in the follow-up observations.Their percentage of CD8~+T in lymphocyte subsets increased,and their cytokines also increased to a certain extent and fluctuated after the treatment.One patient had fever,both patients had diarrhea during their hospitalization.Both of them had no serious adverse reactions.Conclusion:This study preliminarily evaluates the efficacy and safety of autologous KRAS G12V mutation antigen specific TCR-T in treating pancreatic cancer.Based on the available clinical medical records and the mechanism of TCR-T in killing pancreatic cancer,it is believed that this treatment has a solid theoretical foundation and a good initial clinical evaluation in terms of effectiveness.Although we have observed no serious adverse reactions in both patients,this paper has also discussed the mechanism of TCR-T adverse reactions.