treatment of chemotherapy refractory human epidermalgrowth factor receptor-2( her-2) positive advanced solid tumors

Conditions: Advanced HER-2 Positive Solid Tumors; Chemotherapy Refactory; HER-2 Antibody Inhibitor Therapy Refactory

Summary: ratinale: placing a tumor antigen chimeric receptor that has been created in the laboratory into patient autologous t cells may make the body build immune response to kill cancer cells. purpose: this clinical trial is to study genetically engineered lymphocyte therapy in treating patients with her-2 positive advanced solid tumors,such as breast cancer, gastric cancer, hepatic carcinoma, endometrial cancer and ovary cancer.

primary objectives: i.determine the safety and feasibility of the chimeric antigen receptor t cells transduced with anti-her-2 vector(referred to as cart-her-2 cells). ii.determine duration of in vivo survival of cart-her-2 cells. rt-pcr(reverse transcription polymerase chain reaction)analysis of whole blood will be used to detect and quantify survival of cart-her-2 tcr zeta:cd137 and tcr(t-cell receptor) zeta cells over time. secondary objectives: i.for patients with detectable diseases, measure anti-tumor response due to cart-her-2 cell infusions. ii.estimate relative trafficking of cart-her-2 cells in tumor bed. iii.determine if cellular or humoral host immunity develops against the murine anti-her-2, and assess correlation with loss of detectable cart-her-2(loss of engraftment). iv.determine the relative subsets of cart-her-2 t cells (tcm,tem,and treg). outline: patients are assigned to 1 group according to order of enrollment. patients receive anti-her-2-car (coupled with cd137 and cd3 zeta signalling domains)vector-transduced autologous t cells on days 0,1, and 2 in the absence of unacceptable toxicity. after completion of study treatment, patients are followed intensively for 6 months, every 3 months for 2 years, and annually thereafter for 13 years. estimate relative trafficking of cart-her-2 cells in peripheral blood.

Eligibility criteria:
inclusion criteria: * chemotherapy refractory her-2-positive breast cancer, gastric cancer, non-small cell lung cancer, and chemotherapy resistant or relapsed ovary cancer. * relapsed patients after anti-her-2 using antibody or kinase inhibitor therapy. * patients must be 18 years of age or older. * patients must have an ecog (eastern cooperative oncology group )performance status of 0-2. * patients must have evidence of adequate bone marrow reserve, hepatic and renal function as evidenced by the following laboratory parameters: absolute neutrophil count greater than 1500/mm3. platelet count greater than 100,000/mm3. hemoglobin greater than 10g/dl (patients may receive transfusions to meet this parameter). total bilirubin \< 1.5 times upper limits of normal. serum creatinine less than or equal to 1.6 mg/ml or the creatinine clearance must be greater than 70 ml/min/1.73m(2). * seronegative for hiv antibody. * seronegative for active hepatitis b, and seronegative for hepatitis c antibody. * patients must be willing to practice birth control during and for four months following treatment.note:women of child-bearing age must have evidence of negative pregnancy test. * patients must be willing to sign an informed consent. exclusion criteria: * patients with life expectancy less than 12 months will be excluded. * patients with uncontrolled hypertension (\> 160/95), unstable coronary disease evidenced by uncontrolled arrhythmias, unstable angina, decompensated congestive heart failure (\> new york heart association class ii), or myocardial infarction within 6 months of study will be excluded. * patients with any of the following pulmonary function abnormalities will be excluded: fev(forced expiratory volume), \< 30% predicted; dlco (diffusing capacity of lung for carbon monoxide) \< 30% predicted (post-bronchodilator); oxygen saturation less than 90% on room air. * patients with severe liver and kidney dysfunction or consciousness disorders will be excluded. * pregnant and/or lactating women will be excluded. * patients with active infections, including hiv, will be excluded, due to unknown effects of the vaccine on lymphoid precursors. * patients with any type of primary immunodeficiencies will be excluded from the study. * patients requiring corticosteroids (other than inhaled) will be excluded. * patients with history of t cell tumors will be excluded. * patients who are participating or participated any other clinical trials in latest 30 days will be excluded.

Keywords: cart-her-2 her-2 positive advanced refactory solid tumors