TAEST16001 in the Treatment of Soft Tissue Sarcoma

This study is an open, single arm, dose increasing early clinical study, which is divided into two parts: "3 + 3" designed dose escalation study and extended group study. The purpose of this study is to evaluate the safety, tolerance, PK, PD characteristics, and preliminary efficacy of TAEST16001 immunotherapy in the treatment of patients with solid tumor maily containing soft tissue sarcoma whose tumor antigen NY-ESO-1 expression is positive (HLA-A \* 02:01).

Immunotherapy is one of the most promising and effective methods to cure tumor besides operation, chemotherapy and radiotherapy. T cell therapy, which belongs to immunotherapy, mainly includes CAR-T (Chimeric Antigen Receptor, CAR) and TCR-T (T cell Receptor-T). The existing CAR-T treatment can only kill blood tumor cells, the effect on solid tumor treatment was not well. Therefore, people need a better method than CAR-T, which can kill tumor cell internal antigen and has better curative effect on solid tumor treatment, and has less side effect. This is the TCR-T cell treatment developed by the applicant now.

In view of the cross reaction between tumor antigen and normal cell antigen, which is easy to cause adverse reactions, this mainly focuses on a kind of antigen that is not expressed in normal cells, but expressed in testis, and is defined as cancer testis antigen. The applicant preferred NY-ESO-1 antigen, which was first found in esophageal cancer, then 10-50% in melanoma, non-small cell lung cancer (NSCLC), liver cancer, breast cancer, prostate cancer, bladder cancer, thyroid cancer and ovarian cancer, 60% in multiple myeloma, 70-80% in synovial cell sarcoma and 22.5% in osteosarcoma.

In 2015, the University of Pennsylvania, the University of Maryland and Adaptimmune in the United Kingdom reported the breakthrough progress of TCR-T cells in the world-class Journal of natural medicine. This clinical trial showed that high affinity anti-NYESO-1 and LAGE-1 specific TCR-T were effective in 16 (80%) of 20 patients with multiple myeloma, with an average progression free survival of 19.1 months, and the side effects were mild, without serious side effects of CAR-T.

Another clinical trial of NY-ESO-1-specific TCR-T in the treatment of synovial cell sarcoma (synovial cell sarcoma) and melanoma by a team of Dr. Rosenberg from the National Cancer Research Institute of the United States showed that 61% of synovial cell sarcomas and 55% of melanoma had clinical effects. Due to the good clinical results of anti-NY-ESO-1-specific TCR-T of adaptimmune company in the treatment of synovial sarcoma, the US FDA approved this TCR-T cell treatment of synovial sarcoma to enter the breakthrough treatment

These clinical data indicate that TCR-T cell therapy can be applied to a variety of tumors, including soft tissue sarcoma.

Eligibility Criteria:
Inclusion Criteria:

1. The informed consent form (ICF) (genotype and tumor antigen screening and primary screening) should be signed before any research related operation;
2. Age ≥ 18 years and ≤ 70 years;
3. Advanced solid tumor with definite pathological diagnosis;
4. Unresectable advanced solid tumor that fails to undergo standard treatment (disease progression or recurrence or intolerable, such as chemotherapy, radiotherapy, targeted treatment, etc.) or lacks effective treatment:

1) Soft tissue sarcoma: a) Soft tissue sarcoma failed to be treated by chemotherapy containing doxorubicin and ifosfamide; 2) Primary liver cancer: a) Child Pugh liver function score A within 7 days before cell reinfusion; 3) Ovarian cancer: a) Platinum based chemotherapy (such as paclitaxel combined with carboplatin) failed. 4) Non small cell lung cancer (NSCLC): a) failure (disease progression or toxicity intolerance) or lack of effective treatment method of previous standard treatment (including platinum chemotherapy scheme or driven gene targeted treatment); 5) Breast cancer: a) patients who have received standard treatment failure or not applicable standard treatment.

5、At least 1 measurable lesion (according to recist1.1 standard） 6、Genotype and tumor antigen screening must meet the following two criteria: 1) HLA-A \* 02:01 positive; 2) NY-ESO-1 positive: immunohistochemistry positive cells ≥ 20%; 7、ECOG score 0-1 and expected survival time \> 3 months; 8. Color Doppler echocardiography indicates left ventricular ejection fraction ≥ 50%; 9. Laboratory test results should at least meet the following criteria:

* White blood cell count ≥ 3.0 × 109 / L
* Absolute neutrophil count (ANC) ≥ 1.5 × 109 / L (without the support of G-CSF and GM-CSF, at least 14 days before CLT);
* Absolute lymphocyte count (ALC) ≥ 0.7 × 109 / L;
* Platelet (PLT) ≥ 75 × 109 / L (no transfusion treatment 14 days before CLT);
* Hemoglobin ≥ 10g / dl (no transfusion treatment 14 days before CLT);
* Prothrombin time international INR ≤ 1.5 × ULN, unless anticoagulant therapy is used;
* APTT ≤ 1.5 × ULN, unless anticoagulant therapy is used;
* Serum creatinine ≤ 1.5mg/dl (or 132.6 μ mol / L)
* Creatinine clearance ≥ 60ml / min;
* AST / SGOT ≤ 2.5 × ULN; - ALT / SGPT ≤ 2.5 × ULN; - TBIL ）≤1.5×ULN； 10、Women of childbearing age who have not undergone sterilization before menopause must agree to use effective contraceptive measures within one year from the beginning of study treatment (chemotherapy for clearing lymph nodes) to the end of cell transfusion, and the serum pregnancy test is negative within 14 days before the first cell transfusion.

  11、Men who have not undergone sterilization must agree to use effective contraceptive measures from the beginning of the study treatment (chemotherapy) until one year after the last cell transfusion.

Exclusion Criteria:

1. The last dose of anti-tumor therapy (chemotherapy, endocrine therapy, targeted therapy, immunotherapy, tumor embolization or traditional Chinese medicine / Chinese herbal medicine with anti-tumor indications) was received within 4 weeks before cell reinfusion;
2. The live attenuated vaccine had been inoculated within 4 weeks before cell reinfusion;
3. The patients with bone metastasis in the whole body;
4. It is known that any component used in the treatment of this study will produce allergy Response;
5. Not recovered from previous operation or treatment-related adverse reactions to \< 2-level CTCAEv5.0;
6. Patients with a history of meningeal or central nervous system metastasis, or patients with clear basic diseases of central nervous system and left significant symptoms within 6 months before cell transfusion;
7. Patients with poor drug control hypertension (systolic blood pressure \> 160mmhg and / or diastolic blood pressure \> 90mmHg) or with clinical significance Cardiovascular and cerebrovascular diseases, such as cerebrovascular accident (within 6 months prior to signing the master informed consent), myocardial infarction (within 6 months prior to signing the master informed consent), unstable angina pectoris, congestive heart failure with NYHA grade II or above, or serious arrhythmia that cannot be controlled by drugs or has potential impact on research and treatment Results of ECG showed clinically significant abnormality or average QTCF ≥ 450ms;
8. Combined with other serious organic or mental diseases;
9. Suffering from systemic active infection requiring treatment, including but not limited to active tuberculosis, known HIV positive patients or clinical active hepatitis A, B and C Patients with inflammation, including virus carriers, should be excluded;
10. Patients with autoimmune diseases: those with inflammatory bowel disease history and those with autoimmune disease history determined by the researchers as unsuitable for this study, such as systemic lupus erythematosus, vasculitis, and invasive lung disease, should be excluded (except vitiligo subjects);
11. Those with cell transfusion within 4 weeks before and during the study should be used (if there is a long-term plan) Use) systemic sterols, hydroxyurea, immunomodulators (e.g., interferon α or γ, GM-CSF, mTOR inhibitors, cyclosporin, thymosin, etc.);
12. History of organ transplantation, allogeneic stem cell transplantation, and renal replacement therapy;
13. Diabetes, pulmonary fibrosis, interstitial lung disease, acute lung disease, or liver failure that are not known to be controlled;
14. Alcohol and / or drug abusers;
15. Pregnant or lactating women;
16. Subjects with any coexisting medical conditions or diseases that may affect the development of this study determined by the investigator;
17. Subjects without legal capacity / limited capacity of behavior;
18. Patients who have received similar gene therapy products within 4 weeks before cell reinfusion and are not suitable for inclusion by evaluation;
19. Patients judged by the investigator are difficult to complete all visits or procedures required by the protocol (including the follow-up period), or insufficient compliance to participate in the study, or the patients considered unsuitable by the investigator.