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

Sponsor

Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University (Other)

Overall Status

Recruiting

CT.gov ID

NCT05438667

Collaborator

(none)

Enrollment

Location

Arm

36.8

Anticipated Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Cancer	Biological: TCR-T therapy	Early Phase 1

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

11 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Exploring Clinical Research on Evaluating the Safety, Efficiency and Pharmacokinetics / Pharmacodynamics of KRAS Mutated Antigen-specific TCR-T Cell Therapy for Advanced Pancreatic Cancer and Other Solid Tumors

Actual Study Start Date :

Jun 7, 2022

Anticipated Primary Completion Date :

May 30, 2025

Anticipated Study Completion Date :

Jun 30, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TCR-T treatment group 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.	Biological: TCR-T therapy 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

Intervention/Treatment

Experimental: TCR-T treatment group

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.

Biological: TCR-T therapy

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.

Outcome Measures

Primary Outcome Measures

Adverse events [12months after TCR-T(or combined DC vaccine) infusion]
The type, incidence and severity of adverse events include abnormal laboratory examination results with clinical significance after treatment, abnormal physical examination and blood examination results, bone marrow examination results, etc. Clinical and laboratory adverse events will be classified according to the National Cancer Institute general terminology standard for adverse events (NCI CTCAE) version 5.0.

Secondary Outcome Measures

The overall survival(OS) [At 12months after the TCR-T cell(or combined DC vaccine) infusion]
The overall survival period refers to the time of the TCR-T infusion to the death of the patient for any cause.
Progression free survival (PFS) [At 12months after the TCR-T cell(or combined DC vaccine) infusion]
Progression free survival refers to the time from TCR-T infusion to the first occurrence of disease or death from any cause.According to RECIST version 1.1, the tumor evaluation of all subjects will be evaluated within 12 months after TCR-T treatment.
Time to progression (TTP) [12months after the TCR-T cell(or combined DC vaccine) infusion]
Time to progression (TTP) refers to the time from TCR-T infusion to objective tumor progression.According to RECIST version 1.1, the tumor evaluation of all subjects will be evaluated within 12 months after TCR-T treatment.
Peak plasma concentration (Cmax) [12months after the TCR-T cell(or combined DC vaccine) infusion]
Peak plasma concentration (Cmax) refers to the maximum concentration of TCR-T cells in peripheral blood after the TCR-T cells infusion.
Area under the plasma concentration versus time curve (AUC) [12months after the TCR-T cell (or combined DC vaccine)infusion]
Area under the plasma concentration versus time curve (AUC) is used to access the absorbed TCR-T cells dose into human blood circulation after TCR-T cells injection.
Peak time (Tmax) [12months after the TCR-T cell(or combined DC vaccine) infusion]
Peak time (Tmax) refers to the time when the blood concentration reaches the peak after TCR-T cells injection.
Cell number of TCR-T cells in peripheral blood [12months after the TCR-T cell (or combined DC vaccine)infusion]
Cell numbers of TCR-T cells after the injection of TCR-T cells
Peak value of cytokines [1 month after TCR-T cell(or combined DC vaccine) infusion]
The peak value of cytokines within 1 month after TCR-T cell infusion .

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria：

Age greater than 18 years old；
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;
Mutations in KRAS G12V or G12D and expression of matched HLA -A*11:01 subtypes are confirmed in previous tumor or biopsy tissues；
Expected survival duration of more than 3 months；
Eastern Cooperative Oncology Group( ECOG )score ≤2；
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.
Patients at least have had at least one measurable lesion as defined by RECIST v1.1 criteria；
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.
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:

Use of immunosuppressants or glucocorticoids within 1 week before enrollment;
Patients with moderate or severe hydrothorax need drain placement to relieve symptoms.
Human immunodeficiency virus (HIV) positive；
Active Hepatitis B or Hepatitis C infection；
Pregnant women and lactating females；
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;
Patients with central nervous metastases；
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 ;
History of clinically significant respiratory diseases or other respiratory diseases that seriously affect Pulmonary function;
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）
A history of organ transplantation；
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;
Those who have a history of psychotropic drug abuse and cannot quit or have a history of psychiatric impairment；
Participants with an allergic constitution, known sensitivity to human serum albumin, cyclophosphamide, fludarabine and interleukin 2;
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;
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.