neoantigen reactive t cells combined with shr-1210 for chinese patients with advanced refractory solid tumors

Conditions: Advanced Malignant Solid Tumor

Summary: the purpose of this study is to see the safety and efficient of neoantigen reactive t cells (nrts) combined with programmed cell death-1(pd-1) inhibitor（shr-1210）in the treatment of chinese patients with advanced refractory solid tumors.

the tumor-specific "none-self" immunogenic neoantigens encoded by either viral genes or somatic mutation genes, possess the potential to induce specific anti-cancer immunity, including cellular and humoral immune responses. today, numerous clinical trials demonstrate that although these "none-self" antigens initiate the antigen-specific immunoglobulin g antibodies and cluster of differentiation 4（cd4）+/cluster of differentiation 8（cd8）+t-cells response, not all of them show a clinical benefit in the response rate, progression-free survival or overall survival.immune tolerance induced by pd-1 or programmed cell death-ligand1（ pd-l1）maybe play a vital role for these negative outcomes.personalized cell therapy plus checkpoint inhibitors maybe own a breakthrough in the treatment of those malignant diseases without standard options.our center has successfully established a new method for preparing personalized neoantigen reactive t cells(nrts) for adoptive cell therapy(act). today, we will carry out a single center single arm clinical prospective study of nrts combined with pd-1 inhibitor(shr-1210) for the treatment of chinese patients with advanced refractory solid tumors. participants are assigned to receive 4 circles of cell therapy,and prior to each cycle's immunocytes treatment,preconditional chemotherapy and shr-1210 will be carried out, and il-2 continuous intravenous infusion（civ） will also be given for 5 consecutive days after each time's cell infusion. the safety and clinical response rate（rr） are evaluated. biomarkers and immunological markers are also monitored.

Eligibility criteria:
inclusion criteria: * adult patients aged 18 to 75 years old * histologic or cytologic confirmation of advanced refractory solid tumors with no available curative treatment options * at least one measurable disease: diameter ≥20mm or spiral computed tomography(ct)≥10mm; and can providing with tumor specimen (for testing the expression of pd -l1 and the infiltrating lymphocytes) * must be human leukocyte antigen (hla)-a2/a24/a11 positive * eastern cooperative oncology group(ecog)\<0-2 and expected survival time 3 months or more * at least one new antigen can induce t cell secrete interferon - gamma (ifn - gamma) twice as normal controls during the new antigens screening * without anticancer treatment more than one month * hematology index including: neutrophile granulocyte greater than 1.5×10\^9/l; hemoglobin greater than 10g/dl; platelet greater than 100×10\^9/l * biochemical index including: serum bilirubin not greater than 1.5x upper limit of reference range (uln); glutamic-pyruvic transaminase（alt） or glutamic-oxalacetic transaminase（ast） not greater than 2.5x uln; creatinine clearance no less than 60ml/min * peripheral venous channel open and no contraindications to separating lymphocytes * negative pregnancy test for women of childbearing potential, and patients must be willing to practice birth control during the regimen * provision of informed consent * be able to follow the research program and follow up process exclusion criteria: * those who now are undergoing other antitumor drug therapy (including chemotherapy, systemic steroids therapy, surgery, target therapy or immune therapy); * prior treatment with pd-1 monoclonal antibody(mab） or pd-l1 mab; * prior malignancy active within the previous 5 years except for locally curable cancers that have been apparently cured, such as basal cell skin cancer or carcinoma in situ of the cervix; * history with pulmonary tuberculosis, and positive tests for acquired immune deficiency syndrome(hiv),hepatitis c virus(hcv),hepatitis b virus(hbv); * patients with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, such as hypophysitis, pneumonia, colitis, hepatitis, nephritis, hyperthyroidism or hypothyroidism; severe, uncontrolled medical condition that would affect patients' compliance or obscure the interpretation of toxicity determination or adverse events, including active severe infection, uncontrolled diabetes, angiocardiopathy (heart failure \> class ii new york heart association(nyha), heart block \>ii grade, myocardial infarction, unstable arrhythmia or unstable angina within past 6 months, cerebral infarction within past 3 months) or pulmonary disease ( interstitial pneumonia, obstructive pulmonary disease or symptomatic bronchospasm). * evidence with central nervous system(cns) disease * pregnant or nursing * psychiatric medicines abuse without withdrawal, or history of psychiatric illness. * hypersensitivity to investigational drugs or its components.

Keywords: neoantigen neoantigen reactive t cells (nrts) pd-1 inhibitor advanced solid tumor adoptive cell therapy(act) pd-1 antibody shr1210