Dual-targeting HER2 and PD-L1 CAR-T for Solid Tumors

Phase I Study of Specific CAR-T Dual-targeting HER2 and PD-L1 for HER2-positive Solid Tumors

CAR-T therapy has achieved unprecedented success in hematological tumors in recent years, but the progress of CAR-T cells in the treatment of solid tumors is facing difficulties. HER-2 is frequently expressed in breast cancer, ovarian cancer, lung cancer, gastric cancer and other malignant tumors. In this study, the PD-L1 inhibitory signal was transformed into an activation signal in the tumor microenvironment, and enhanced the killing activity and survival ability of CAR-T cells. The HER-2/PD-L1 dual-targeting CAR-T will be investigated in patients with HER2-positive solid tumors, and all enrolled subjects will receive HER2/PD-L1 CAR T cells via intravenous or thoracic/peritoneal cavity infusion.

Study Overview

• Status: Recruiting
• Conditions: Pleural Effusion, Malignant; Peritoneal Carcinoma Metastatic; HER2 Positive Malignancies
• Intervention / Treatment: Biological: Dual-targeting HER2 and PD-L1 CAR-T cells

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Qizhi Ma, Dr; Phone Number: +8602885421139; Email: maqzh95@163.com

Study Locations

• China
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Recruiting
      • West China Hospital, Sichuan University
      • Contact: Qizhi Ma; Phone Number: 02885422707; Email: maqzh95@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female, Age 18-75 years old; If the subjects are over 75 years old, the researchers will determine whether to enroll according to the basic health conditions of the subjects, regardless of gender. No upper age limit was set for chest/abdominal reinfusion CAR-T subjects.
2. Estimated life expectancy ≥ 3 months (according to investigator's judgement);
3. The Eastern Cooperative Oncology Group (ECOG) performance status score is 0-2;
4. Patients diagnosed as ovarian cancer, non-small cell lung cancer, breast cancer, gastric cancer, head and neck cancer, pancreatic cancer, colorectal cancer, transitional cell carcinoma, endometrial carcinoma, sarcoma, glioblastoma, cholangiocarcinoma, etc. have received standard systemic treatment, have systemic metastasis/serosal cavity metastasis or are not tolerated;
5. Expressing HER2 >20% of primary tumors or metastatic cells in the serous cavity by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH);
6. Absolute neutrophil count ≥ 1×10^9/L, platelet count ≥ 75×10^9/L, absolute lymphocyte count ≥0.5×10^8/L, hemoglobin ≥ 8.0 g/dl;
7. Creatinine clearance rate ≥60ml/min, Serum ALT/AST≤2.5 times of the normal level, and total bilirubin≤1.5 times of the normal level;
8. Cardiac ejection fraction ≥50%, no pericardial effusion;
9. No other serious diseases (autoimmune diseases or any immune deficiency disease or other disease in need of immunosuppressive therapy);
10. Patients must stop chemotherapy and targeted therapy for at least 3 weeks before starting treatment;
11. Patients must take reliable contraceptive measures before entering the trial, during the research process until 1 year after CAR-T infusion; reliable contraceptive measures will be determined by the main investigator or designated personnel;
12. Voluntarily participate in the research, understand and sign the informed consent;
13. The side effect of the last anti-tumor treatment was reduced to ≤1 grade, except for hair loss.

Exclusion Criteria:

1. Allergic to cytokines;
2. Uncontrolled activity infection;
3. Acute or chronic (graft-versus-host disease) GVHD;
4. Accompanied by other uncontrolled malignant tumors;
5. Patient with hepatitis B or C active period, HIV infection ≥ the upper limit of the normal level;
6. Suffer from serious diseases such as coronary heart disease, angina pectoris, myocardial infarction, arrhythmia, cerebral thrombosis, cerebral hemorrhage, etc.;
7. Patients with grade 2-3 hypertension or poorly controlled;
8. History of mental illness that is difficult to control;
9. Patients have used immunosuppressive agents for a long time after organ transplantation, except for recent or current inhaled corticosteroid therapy;
10. The existing medical history or mental state history or laboratory abnormalities may increase the risk associated with participating in the study or the administration of the study drug;
11. Unstable pulmonary embolism, deep venous embolism or other major arterial/venous thromboembolic events occurred within 6 months before enrollment. If receiving anticoagulant therapy;
12. Pregnant or nursing women, or plan to become pregnant during the treatment period or within 1 year after the treatment ends;
13. Patient suffering from diseases that have signed written informed consent or comply with research procedures; or are unwilling or unable to comply with research requirements.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CAR-T cell therapy; Dual-targeting HER2 and PD-L1 CAR-T cell therapy	Biological: Dual-targeting HER2 and PD-L1 CAR-T cells; HER2-positive solid tumor serosal cavity infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Related Adverse Events	AE during the first 28 days after CAR-T cell administration	12 months
Dose-limiting toxicity (DLT)	Baseline up to 28 days after CAR-T cells infusion	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR（objective response rate）	Include CR（complete response）and PR（partial response）	Month 1，month 3, month 6
DOR (duration of response)	The time from achievement of disease control	12 months

Collaborators and Investigators

• Sponsor: Sichuan University

Publications and helpful links

General Publications

• Ma Q, He X, Zhang B, Guo F, Ou X, Yang Q, Shu P, Chen Y, Li K, Gao G, Zhu Y, Qin D, Tang J, Li X, Jing M, Zhao J, Mo Z, Liu N, Zeng Y, Zhou K, Feng M, Liao W, Lei W, Li Q, Li D, Wang Y. A PD-L1-targeting chimeric switch receptor enhances efficacy of CAR-T cell for pleural and peritoneal metastasis. Signal Transduct Target Ther. 2022 Nov 19;7(1):380. doi: 10.1038/s41392-022-01198-2.

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2021
• Primary Completion (Estimated): December 30, 2025
• Study Completion (Estimated): December 30, 2025

Study Registration Dates

• First Submitted: December 21, 2020
• First Submitted That Met QC Criteria: December 23, 2020
• First Posted (Actual): December 24, 2020

Study Record Updates

• Last Update Posted (Actual): October 30, 2024
• Last Update Submitted That Met QC Criteria: October 27, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Pleural Neoplasms; Pleural Diseases; Pleural Effusion, Malignant; Pleural Effusion
• Other Study ID Numbers: MCART-002

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No