Human HER2-targeted Macrophages Therapy for HER2-positive Advanced Gastric Cancer With Peritoneal Metastases

NCT ID: NCT06224738

Last Updated: 2024-01-25

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 9 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-03-01
• Study Completion Date: 2026-03-01

Brief Summary

The goal of this exploratory clinical trial is to evaluate the safety and efficacy of human anti-human epidermal growth factor receptor 2(HER2) Chimeric antigen receptor macrophage cells (CAR-M) in advanced HER2+ gastric cancer. Participants will mobilize bone marrow stem cells and engineer autologous macrophages to express Chimeric antigen receptor (CAR), and CAR-M will be infused intraperitoneally back into the patient for systemic anti-tumor effects.

Detailed Description

The standard approach for managing advanced peritoneal metastatic gastric cancer typically involves systemic administration of antitumor drugs. In the case of HER2-positive gastric cancer patients, a combination of trastuzumab, platinum, and fluorouracil chemotherapeutic agents is commonly employed. Nevertheless, conventional therapy encounters obstacles stemming from tumor heterogeneity and the intricate microenvironment. The self-developed humanized anti-HER2 chimeric antigen receptor macrophage (human anti-HER2 CAR-M) uses an adenoviral vector system to genetically engineer autologous macrophages to express CAR molecules containing single-chain antibodies, which specifically bind to human HER2 antigens to recognize and kill tumor cells. Cell and animal experiments as well as preclinical trials showed that anti-human HER2 CAR M cells have significant anti-tumor efficacy and good safety. This study can provide abundant clinical data for the safety and feasibility of CAR macrophage therapy for solid tumors, and promote the progress of CAR macrophage therapy for solid tumors.

Conditions

Gastric Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

human HER2-targeted CAR-M cell

Recombinant human granulocyte stimulating factor treatment mobilized bone marrow stem cells, when the mononuclear cells rose to more than 8×10\^8/L, the collection of peripheral blood single nuclei cells, the total number of mononuclear cells collected 1.5×10\^9-1.8×10\^9. Intraperitoneal infusion of anti-human HER2 CAR-M cells 3×10\^8 cells/person, in a single administration.According to the principle of "3+3 dose increment", enter dose 2 and dose 3. Dose2: the monocyte rises to more than 9.5×10\^8/L and collect peripheral blood single nucleus cells. Reinfuse anti-human HER2 CAR-M cells 5×10\^8 cells/person, 1 person/bag/dose, 100 ml/bag. Dose3: the mononuclear cell rises to more than 1.3×10\^9/L and collect peripheral blood single nucleus cells. Reinfuse anti-human HER2 CAR-M cells 1×10\^9 cells/person, 1 person/bag/dose, 200 ml/bag.

Group Type: EXPERIMENTAL

human HER2-targeted CAR-M cells

Intervention Type: BIOLOGICAL

The human anti-HER2 chimeric antigen receptor macrophages (anti-HER2 CAR-M cells) independently developed use adenoviral vector system to genetically engineer autologous macrophages to express CAR molecules containing single-chain antibodies, which specifically bind to the human HER2 antigen to recognize and kill tumor cells.

Interventions

human HER2-targeted CAR-M cells

The human anti-HER2 chimeric antigen receptor macrophages (anti-HER2 CAR-M cells) independently developed use adenoviral vector system to genetically engineer autologous macrophages to express CAR molecules containing single-chain antibodies, which specifically bind to the human HER2 antigen to recognize and kill tumor cells.

Intervention Type: BIOLOGICAL

Other Intervention Names

anti-HER2 CAR-M cells

Eligibility Criteria

Inclusion Criteria

1. age between 18 and 75 years (including borderline values), male or female.

2. expected survival of more than 12 weeks.

3. histologically confirmed HER2-positive gastric cancer; HER2-positive is defined as immunohistochemistry (IHC) 3+ or (IHC) 2+ with in situ hybridization (ISH) +.

4. confirmation of peritoneal metastasis by imaging or cytologic testing of peritoneal fluid.

5. presence of measurable lesions.

6. patients with peritoneal metastases of gastric cancer who had previously failed second-line or higher therapy. Treatment failure is defined as an intolerable toxic reaction or disease progression during treatment or tumor recurrence or metastasis after completion of treatment. Prior therapy of targeted agents, immunosuppressants, or radiotherapy is permitted; prior systemic therapy with at least 1-2 chemotherapeutic agents of fluorouracil, platinum, and paclitaxel in combination with targeted agents.

7. have an Eastern Cooperative Oncology Group (ECOG) activity status score of 0-2

8. at least 2 weeks have elapsed since receiving the most recent drug therapy to the time of single nucleated cell collection.

9. patients of childbearing age are required to use appropriate contraception (protection or other birth control) prior to enrollment and during the study.

10. the patient is willing to accept intraperitoneal administration of the drug.

11. the patient understands the trial and has signed an informed consent form.

12. the patient is able to follow the study protocol and follow-up procedures.

Exclusion Criteria

1. previous or current other types of malignant tumors, except for the following: completely resected or eradicated basal and squamous cell carcinoma of the skin, and carcinoma in situ of the cervix.

2. patients requiring immunosuppressive drugs (except physiologic replacement doses).

3. history of central nervous system (CNS) disorders such as seizures, paralysis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, psychosis; untreated or symptomatic CNS metastases or cytologically confirmed carcinomatous meningitis (asymptomatic CNS metastases that do not require treatment may be enrolled).

4. left ventricular ejection fraction <50%.

5. White blood cell count <3×10^9/L and platelet count <80×10^9/L.

6. AST and ALT > 3 × upper limit of normal (ULN)

7. Total bilirubin > 1.5 × ULN.

8. creatinine clearance <60 ml/min.

9. Abnormal coagulation function (activated partial thromboplastin time (APTT) > 1.5 × ULN, international normalized ratio (INR) > 1.5 × ULN).

10. patients with intestinal obstruction (gastrointestinal obstruction within 30 days prior to administration).

11. patients with infectious diseases including, but not limited to: 1) known human immunodeficiency virus infection or acquired immunodeficiency syndrome-related disease; 2) known active liver disease, including hepatitis B and hepatitis C; 3) active tuberculosis infection, who are on anti-tuberculosis treatment or who have received anti-tuberculosis treatment within 1 year prior to the first dose of the study drug; 4) known syphilis infections requiring treatment; and 5) Other infectious diseases that, in the judgment of the investigator, make participation in this study unsuitable.

12. Diseases that, in the judgment of the investigator, preclude enrollment: including, but not limited to, severe hepatic, renal, or metabolic disease requiring drug therapy, uncontrolled coronary artery disease or asthma, and uncontrolled cerebrovascular disease.

13. pregnant or breastfeeding females; females or males of childbearing age with a pregnancy plan during the study.

14. psychotropic substance abuse, clinical or psychological or social factors that would compromise informed consent or study conduct (at the discretion of the investigator).

15. individuals who may be allergic to the study medication.

16. is participating in another clinical trial.

17. patients with inaccessible peripheral or deep venous access.

18. any uncertainty that has an impact on patient safety or compliance.

19. any other condition that the investigator considers inappropriate for enrollment.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Macera therapeutics

UNKNOWN

Sponsor Role: collaborator

First People's Hospital of Hangzhou

OTHER

Sponsor Role: lead

Responsible Party

Bing Xia

chief physician

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Bing Xia

Role: PRINCIPAL_INVESTIGATOR

First People's Hospital of Hangzhou

Locations

Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine

Hangzhou, Zhejiang, China

Countries

China

Central Contacts

Bing Xia, Doctor

Role: CONTACT

bxia_hzch@hotmail.com

(+86)18857210928

Song Zheng, Doctor

Role: CONTACT

tztree@126.com

References

Zhang W, Liu L, Su H, Liu Q, Shen J, Dai H, Zheng W, Lu Y, Zhang W, Bei Y, Shen P. Chimeric antigen receptor macrophage therapy for breast tumours mediated by targeting the tumour extracellular matrix. Br J Cancer. 2019 Nov;121(10):837-845. doi: 10.1038/s41416-019-0578-3. Epub 2019 Oct 1.

Reference Type: BACKGROUND

PMID: 31570753 (View on PubMed)

Dong X, Fan J, Xie W, Wu X, Wei J, He Z, Wang W, Wang X, Shen P, Bei Y. Efficacy evaluation of chimeric antigen receptor-modified human peritoneal macrophages in the treatment of gastric cancer. Br J Cancer. 2023 Aug;129(3):551-562. doi: 10.1038/s41416-023-02319-6. Epub 2023 Jun 29.

Reference Type: BACKGROUND

PMID: 37386139 (View on PubMed)

Other Identifiers

ITT-20231107-0257-02

Identifier Type: -

Identifier Source: org_study_id