This is a single-center, single-arm, open-label, dose-escalation clinical study to evaluate the safety and preliminary efficacy of NKG2D CAR-NK cells followed by NKG2D CAR-T cells in patients with advanced solid tumors (e.g.,colorectal cancer) with liver metastases who have failed standard treatments. The study primarily focuses on determining the maximum tolerated dose and recommended phase II dose through sequential cohort dose escalation, while secondarily characterizing the pharmacokinetic parameters and collecting initial efficacy data regarding tumor response. This investigation comprehensively evaluates the pharmacodynamic and pharmacokinetic profile of NKG2D CAR cellular therapy through three primary objectives: (1) systematic monitoring of treatment-emergent adverse events and clinically significant laboratory parameter deviations; (2) assessment of antitumor activity with correlative biomarker analysis; and (3) characterization of cellular kinetics including biodistribution patterns, and mechanistic pathways of therapeutic activity. The protocol clarifies cellular persistence and functional regulation within the tumor microenvironment by longitudinal monitoring of cytokine release and using advanced molecular tracking methods.
This study plans to enroll 9-18 patients with advanced solid tumors (e.g.,colorectal cancer) with liver metastases who have failed standard treatments during a dose-finding phase (Phase IA ). CAR immune cell therapy will be administered primarily via hepatic artery infusion and intravenous infusion. Based on previous experience, hepatic artery infusion will deliver a fixed dose of 3×10\^9 NKG2D CAR-NK cells. After catheterization, the catheter will remain indwelling for two days to allow two NKG2D CAR-NK infusions: 1×10\^9 cells on Day 0 and 2×10\^9 cells on Day1. The preferred source for CAR-NK cells is umbilical cord blood. However, if post-treatment evaluation shows that a patient's results do not meet expected criteria, investigators will adjust the strategy based on clinical circumstances and switch to autologous peripheral blood as the source of CAR-NK cells to ensure optimal therapeutic efficacy. Investigators will determine whether to initiate autologous NKG2D CAR-T cell reinfusion 1-2 weeks post-intervention based on clinical response. The CAR-T cells will be administered via two consecutive intravenous infusions over two days, with dose escalation following the classical "3+3" schema. Based on prior experience, rapid titration dose escalation will initially proceed with 1 patient per cohort. The starting dose is set at 1.5×10\^7 cells/kg. If grade ≥2 CRS or related AEs occur, the study will switch to the 3+3 dose escalation mode. If no such events occur, escalation will follow 3×10\^7 cells /kg, 5×10\^7 cells /kg, and 7×10\^7 cells /kg doses using the 3+3 design, with 3 patients enrolled per dose level. Each CAR-T intravenous infusion involves two consecutive administrations over two days. Approximately two weeks after the first cycle of CAR-T infusions, a second cycle of two consecutive CAR-T infusions will be administered over two days using the same dose as the first cycle.The imaging re-examination will be performed approximately two weeks after completing one cycle of cell reinfusion (i.e., post-second CAR-T infusion), serving as the observation window for safety indicators such as dose-limiting toxicity (DLT) graded per NCI-CTCAE v5.0 criteria in the combined immunotherapy. Based on imaging findings, safety data, and investigator evaluation, subsequent indications for interventional therapy and continued autologous reinfusion will be determined. The trial progresses through sequential Phase IA (dose-finding) and Phase IB (dose-expansion) stages. Phase IA cessation triggers include either confirmation of Recommended Phase II Dose (RP2D) or investigator-verified favorable therapeutic index at any dose level. An interim analysis will be conducted upon Phase IA completion, followed by submission of an ethical amendment application prior to initiating Phase IB. The interim analysis incorporates exploratory subgroup analyses stratified by factors including tumor histology, NKG2D ligand expression levels, prior treatment regimens, baseline tumor burden, tumor markers, peripheral blood granulocyte-to-lymphocyte ratio, and metastatic sites during dose escalation. Following the completion of Phase IA, investigators may identify tumor types likely responsive to NKG2D CAR immune cell therapy based on preliminary data and existing literature, and select patients with potentially responsive tumor types for expanded cohort enrollment, treating advanced solid tumor patients with liver metastases who have failed standard treatments. In Phase IB, investigators will conduct multiple dose expansion cohorts , divided into colorectal cancer, gastric cancer, esophageal cancer, and other cohorts, with 9-18 cases each.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
12
* NKG2D CAR-NK cells (hepatic artery infusion, D0 dose: 1×10⁹ cells,D1 dose: 1×10⁹ cells) * NKG2D CAR-T cells (Over a two-day period, CAR-T cells are administered via intravenous infusion on two consecutive occasions.In the initial phase, rapid titration dose escalation was performed with 1 case per group.The initial dose is set at 1.5×10⁷/kg. If grade 2 or higher cytokine release syndrome (CRS) or related adverse events (AEs) occur, the 3+3 dose escalation protocol will be initiated. If not, the starting dose for escalation will be set at 3×10⁷/kg per administration of-T CAR cells, with subsequent escalations to 5×10⁷/kg per administration and 7×10⁷/kg per administration.) Chemotherapy: If you are treated with autologous CAR-NK cells, lymphodepleting chemotherapy with FC is usually not required. If you are treated with allogeneic NKG2D CAR-NK cells derived from umbilical cord blood of a healthy donor, the researchers will adjust the FC chemotherapy dosage or choose another appropriate
The First Affiliated Hospital Zhejiang University School of Medicine
Hangzhou, Zhejiang, China
RECRUITINGNumber of participants with treatment-related adverse events
Assessed by the investigator and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Treatment-related AEs are defined as events assessed by the investigator as having a reasonable possibility of being caused by the study treatment.
Time frame: 6 months
Number of participants with treatment-related serious adverse events
Assessed by the investigator and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Treatment-related SAEs are defined as SAEs assessed by the investigator as having a reasonable possibility of being caused by the study treatment.
Time frame: 6 months
Objective response rate (ORR) per RECIST 1.1
Defined as the proportion of participants achieving a best overall response of complete response (CR) or partial response (PR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Time frame: 1years
Disease control rate (DCR) per RECIST 1.1
Defined as the proportion of participants achieving a best overall response of complete response (CR), partial response (PR), or stable disease (SD) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Time frame: 1years
Duration of response (DOR) per RECIST 1.1
Defined as the time from the date of first documented response (CR or PR) to the date of first documented disease progression or death from any cause, whichever occurs first, as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Participants without progression or death will be censored at the date of their last evaluable tumor assessment.
Time frame: 1years
Progression-free survival (PFS) per RECIST 1.1
Defined as the time from the date of first infusion of NKG2D CAR-NK/CAR-T cells to the date of first documented disease progression or death from any cause, whichever occurs first, as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Participants without progression or death will be censored at the date of their last evaluable tumor assessment.
Time frame: 1years
Recommended Phase 2 Dose (RP2D)
The RP2D will be determined based on the evaluation of safety (including incidence and severity of adverse events and DLTs), efficacy signals (e.g., ORR, DCR), pharmacokinetic/pharmacodynamic (PK/PD) data, and biomarker data observed during the dose escalation phase.
Time frame: Up to 4 weeks after the last participant in the dose escalation cohort receives CAR-NK/CAR-T cell infusion
Maximum Tolerated Dose (MTD)
Defined as the highest dose level at which no more than 1 out of 6 evaluable participants experiences a dose-limiting toxicity (DLT) during the DLT evaluation period. DLTs are defined as protocol-specified adverse events occurring within 28 days after CAR-NK/CAR-T cell infusion and assessed as related to study treatment.
Time frame: 4 weeks after the CAR-NK/CAR-T cells infusion
Overall Survival (OS)
Defined as the time from the date of first infusion of NKG2D CAR-NK /CAR-T cells to the date of death from any cause. Participants without documented death will be censored at the last date they were known to be alive (last contact date) prior to the data cutoff date for analysis.
Time frame: 1years
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