TCR-T Cell Therapy on Advanced Pancreatic Cancer and Other Solid Tumors

Lead Sponsor: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

The primary aim of this study is to evaluate the safety and tolerability of TCR-T therapy . The secondary aim is to assess the effectiveness and the pharmacokinetics / pharmacodynamics（PK/PD） characteristics of the TCR-T treatment and TCR-T cells combined with tumor antigen specific dendritic cells(DC cells)treatment. The investigators will explore the changes of tumor microenvironment after treatment and evaluate the association of cytokines with neurotoxicity.

1.This study is a single-arm, open-label, single-infusion clinical study. In this trial, 11 subjects with KRAS G12V or G12D mutations and matching HLA-A*11:01 subtypes are recruited for autologous Tumor-T Cell Receptor (TCR) -Mediated T Cells therapy(TCR-T) therapy.Within 3 - 5 days after pretreatment, subjects will receive a single TCR-T infusion with an infusion dose of about 1 × 10⁹～1 × 10¹¹.Once every 12 hours within 24 hours after TCR-T cell infusion, recombinant human interleukin-2 will be injected intravenously for 14 days .The safety and tolerability of TCR-T therapy is assessed by observing adverse events after cell therapy.The effectiveness of the TCR-T treatment is assessed by comparing to the results or historical data from the subjects' own past standard treatment regimens. 2.6-8 weeks after the first TCR-T treatment, if the disease progress is evaluated, the second TCR-T treatment will be given, followed by DC vaccine injection . The day of second TCR-T treatment is marked as Day0. The administration scheme of TCR-T cells is the same as that described above. Day1 received the first intradermal DC vaccine . Before DC vaccine injection, patients will receive intradermal test dose (DC of 10³). After half an hour of observation of possible allergic reactions, the full dose will be injected intradermal in the lower abdominal area above the groin (1 × 10⁷dc 0.2ml) DC vaccine. After the first DC vaccine injection, the patient will receive another two doses of DC vaccine every two weeks, a total of three doses.

• Pancreatic Cancer

Intervention Type: Biological

Intervention Name: TCR-T therapy

Description: 1.Preprocessing strategy： Cyclophosphamide: 500mg/m², dissolved in 100ml 0.9% sodium chloride saline, intravenous drip for 60minutes, and 0.4g Mesna injected at 0hour, 4hours and 8 hours after cyclophosphamide,4days and 5 days before TCR-T cell infusion. Fludarabine: 30mg/m² , dissolved in 100ml 0.9% sodium chloride saline, intravenous drip for 30minutes before 3 to 5days before TCR-T cell infusion. 2.Within 3 - 5 days after pretreatment, subjects will receive a single TCR-T reinfusion with an infusion dose of about 1 × 10⁹～1 × 10¹¹. 3.Once every 12 hours within 24 hours after TCR-T cell infusion, recombinant human interleukin-2 (injection unit: 500000 units /m², once every 12 hours, subcutaneous injection) will be injected intravenously for 14 days (24 times in total). 4.6-8 weeks later, if the disease progressed, the second TCR-T treatment will be given(the same as above). This time will combine the DCvaccine injection.

Arm Group Label: TCR-T treatment group

Criteria:

Inclusion Criteria： 1. Age greater than 18 years old； 2. Pathological diagnosis of recurrent/metastatic pancreatic cancer and other solid tumors (except intracranial metastasis). Patients who have had prior therapy with at least one standard treatment regimen remain in stable or progressive disease states and refuse subsequent chemotherapy; 3. Mutations in KRAS G12V or G12D and expression of matched HLA -A*11:01 subtypes are confirmed in previous tumor or biopsy tissues； 4. Expected survival duration of more than 3 months； 5. Eastern Cooperative Oncology Group( ECOG )score ≤2； 6. All participants voluntarily participate in this study and sign an informed consent. And the subjects have good compliance and can cooperate with investigators follow-up study. 7. Patients at least have had at least one measurable lesion as defined by RECIST v1.1 criteria； 8. Female participants can not be pregnant or lactating and their serum or urine human chorionic gonadotropin tests must be negative within 72 hours prior to study enrollment；All subjects must be using a medically accepted means of contraception ( (e.g., oral contraceptives, intrauterine device) during the course of this study and for at least 3 months after completion of study therapy. 9. Organ function and bone marrow reserve are in good condition, and the following requirements must be met: 1)Absolute neutrophil count≥1.5×10⁹/L；2)Platelet count≥50×10⁹/L；3)Hemoglobin≥90g/L；4)Bilirubin < 1.5 times upper limit of normal（Bile duct obstruction due to tumor compression were excluded)；5)Serum creatinine ≤ 1.5 times the upper limit of normal range or creatinine clearance ≥ 60 mL/min.6)Serum alanine aminotransferase or aspartate aminotransferase is < 2.5 times the upper limit of the normal value (ULN) (if patients with liver metastasis, ≤5 times the ULN).7)Coagulation function normalised：INR≤1.5，PTT<1.2 times the upper limit of normal（Tumor - related anticoagulant therapy was excluded). Exclusion Criteria: 1. Use of immunosuppressants or glucocorticoids within 1 week before enrollment; 2. Patients with moderate or severe hydrothorax need drain placement to relieve symptoms. 3. Human immunodeficiency virus (HIV) positive； 4. Active Hepatitis B or Hepatitis C infection； 5. Pregnant women and lactating females； 6. Previous or concurrent history of other malignant tumors. Exceptions include curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy; 7. Patients with central nervous metastases； 8. Serious, uncontrolled comorbidities that may affect protocol compliance or interfere with interpretation of results，or any serious medical condition that may affect the safety of the subjects ; 9. History of clinically significant respiratory diseases or other respiratory diseases that seriously affect Pulmonary function; 10. Any active autoimmune disease,any condition requiring steroid hormones or immunosuppressive therapy( including but not limited to systemic lupus erythematosus, sjogren's syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, etc., require > 10 mg/D of prednisone or equivalent hormone） 11. A history of organ transplantation； 12. A history of myocardial infarction and severe arrhythmia within six months；Ineligible also includes uncontrolled hypertension, coronary heart disease, stroke, liver cirrhosis, nephritis and other serious complications; 13. Those who have a history of psychotropic drug abuse and cannot quit or have a history of psychiatric impairment； 14. Participants with an allergic constitution, known sensitivity to human serum albumin, cyclophosphamide, fludarabine and interleukin 2; 15. Those with bleeding or thromboembolic tendency：bleeding symptoms of clinical significance or a clear tendency to bleeding within 2 weeks prior to entering the study. And those with hereditary or acquired bleeding and thrombotic tendencies； serious arterial/venous thromboembolic events occurred in the previous 6 months; 16. Other severe, acute or chronic medical or mental illnesses that in the investigator's judgement will might be increase the risk associated with the patient's participation in the study or interfere with interpretation of research results.

Gender:

All

Minimum Age:

18 Years

Maximum Age:

N/A

Healthy Volunteers:

No

Last Name: Meng Zhang, MD

Phone: +86 13926178231

Email: [email protected]

China

2022-06-01

Type: Sponsor

• Pancreatic Cancer
• Solid tumor
• PK/PD
• TCR-T
• Safety
• Efficiency

• Pancreatic Neoplasms

Label: TCR-T treatment group

Type: Experimental

Description: Within 3 ~ 5 days after pretreatment, subjects will receive a single TCR-T infusion with an infusion dose of about 1 × 10⁹～1 × 10¹¹.6-8 weeks after the first TCR-T treatment, if the disease progress is evaluated, the second TCR-T treatment will be given(marked Day0). The administration scheme of TCR-T cells is the same as that described above.Day1 received the first intradermal DC vaccine in the morning. Before DC vaccine injection, patients will receive intradermal test dose (DC of 10³). After half an hour of observation of possible allergic reactions, the full dose will be injected intradermal in the lower abdominal area above the groin (1 × 10⁷dc 0.2ml) DC vaccine. After the first DC vaccine injection, the patient will receive another two doses of DC vaccine every two weeks, a total of three doses.

Allocation: N/A

Intervention Model: Single Group Assignment

Primary Purpose: Treatment

Masking: None (Open Label)