In this single-center, single-arm,prospective, open-label, phase 1/2 study, the safety and efficacy of novel autologous hypoxia-activated CAR-T cell therapy targeting CD73 and AXL ( CD73/AXL.HypoSti.CAR-T) will be evaluated in patients with CD73/AXL antigen positive advanced/metastatic solid tumors. In this clinical trial, at least 12 eligible patients in dose escalation period will be enrolled to receive 3 doses Of CD73/AXL.HypoSti.CAR-T cell therapy according to the "3+3" principle. In dose expansion period, additional at most 21 eligible patients will be enrolled to receive CD73/AXL.HypoSti.CAR-T cell therapy at dose of recommended phase 2 dose(RP2D).
Currently, CAR T-cell therapy still faces significant challenges in its application to solid tumors due to multiple obstacles, including the lack of tumor-specific antigens, the complex immunosuppressive tumor microenvironment (TME), tumor heterogeneity, and on targeted/non-targeted (OTOT) toxicity. Previous studies have found that intratumoral hypoxic microenvironment facilitated the development and metastasis of tumor cells. Meanwhile, cytotoxic T cells, including CAR-T cells, struggle to survive and proliferate in this low-oxygen microenvironment. CD73 (also known as 5'-nucleotidase) and AXL (a receptor tyrosine kinase) are both overexpressed in multiple solid tumors, but less so in normal tissues. They are both involved in regulating tumorigenesis, development, metastasis processes, correlating with inferior prognosis.Dual targeting of CD73 and AXL can effectively address antigen escape and tumor heterogeneity, representing a promising novel immunotherapy strategy. In this study, combining hypoxia-activated precision with dual-targeting synergy,Investigators have developed a novel CD73/AXL.HypoSti.CAR-T that could effectively expand and survive in hypoxic TME ,offering enhanced efficacy and safety for solid tumors in animal models. Further clinical development is warranted to validate these promising preclinical results. So we conduct this clinical trial in order to test the the safety profiles and anti-tumor activities of CD73/AXL.HypoSti.CAR-T cell in vivo. In dose escalation period, at least 12 eligible patients will be enrolled and receive 3 doses of CD73/AXL.HypoSti.CAR-T cell therapy (1 × 10\^6 cells/ kg, 3 × 10\^6 cells/kg, 1 × 10\^7 cells/kg) according to the "3+3" principle. In dose expansion period, additional at most 21 eligible patients will be enrolled to receive CD73/AXL.HypoSti.CAR-T cell infusion at RP2D, which is determined by data from dose escalation period, including occurrence of dose limiting toxicities (DLT), pharmacokinetics/pharmacodynamics, efficacy and other parameters, to furtherly evaluate the safety and efficacy profiles of CD73/AXL.HypoSti.CAR-T cell therapy.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
30
Dose escalation: Dose1 (1×10\^6 cells/kg) , Dose 2(3×10\^6 cells/kg) ,Dose 3 (1×10\^7cells/kg); Dose expansion: RP2D.
Administered intravenously at dose of 100-200mg/m2 on day -5 .
Administered intravenously at a total dose of 15-30mg/kg on day -3 and day -2 .
Administered intravenously at dose of 30mg/m2/d on day -3 and day -2.
Biotherapeutic Department, Chinese PLA General Hospital
Beijing, Beijing Municipality, China
Phase 1: Incidence of treatment related adverse events (TRAEs).
TRAEs are defined as any medical events since the initiation of CD73/AXL.HypoSti.CAR-T cell therapy . Cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS) will be evaluated according to the standards released by American Society for Transplantation and Cellular Therapy (ASTCT) criteria in 2019, and the others will be graded by common terminology criteria for adverse events (CTCAE) V5.0.
Time frame: Up to 12 months
Phase 1:Incidence of dose limiting toxicities (DLTs).
DLTs are defined as CD73/AXL.HypoSti.CAR-T cell therapy related adverse events within the first 28 days that meet the following criteria: * Grade 4 CRS or grade 3 CRS that is not resolved to grade 2 or lower within 2 weeks; * Grade 3 ICANS lasting for ≥7 days or Grade 4 ICANS; * Any other Grade ≥4 and Grade 3 AEs related to the CD73/AXL.HypoSti.CAR-T infusion that lasts for ≥14 days, except hematology toxicity.
Time frame: Up to 28 days after infusion.
Phase 1: RP2D
The recommended dose for phase 2 was determined through phase 1 study.
Time frame: Up to 12 months.
Phase 2: Objective response rate (ORR) .
ORR includes complete response(CR) and partial response (PR), as defined by investigators according to investigators Response Evaluation Criteria in Solid Tumours 1.1 (RECIST 1.1) or Immune Response Evaluation Criteria in Solid Tumours (iRECIST) criteria.
Time frame: Up to 3 years.
Phase 1 and phase 2: Pharmacokinetics:Number and copy number of CD73/AXL.HypoSti.CAR-T cells .
Number and copy number of CD73/AXL.HypoSti.CAR-T cells were assessed by number in peripheral blood. Blood samples were collected before and one year after cell infusion (until CD73/AXL.HypoSti.CAR-T cells were not detected for two consecutive times) to detect the number and copy number of CD73/AXL.HypoSti.CAR-T cells, and to evaluate the pharmacokinetics of CD73/AXL.HypoSti.CAR-T.
Time frame: Up to 12 months.
Phase 1 and phase 2: Pharmacodynamics: Peak level of cytokines in serum.
The cytokines mainly include interleukin-2 (IL-2 ), IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), C reactive protein (CRP), ferritin. Peak was defined as the maximum post-baseline level of the cytokine.
Time frame: Up to 28 days after infusion.
Phase 2:Progression Free Survival (PFS)
PFS is defined as the time from the initiation of CD73/AXL.HypoSti.CAR-T cell therapy to documented disease progression or death.
Time frame: Up to 3 years.
Phase 2:Time to response (TTR).
TTR is defined as the time from the initiation of CD73/AXL.HypoSti.CAR-T cell therapy to first assessed CR or PR by investigators according to RECIST 1.1or iRECIST criteria.
Time frame: Up to 3 years.
Phase 2:Duration of response (DOR) .
DOR is defined as the time from objective response until documented tumor progression among responders.
Time frame: Up to 3 years.
Phase 2:Overall Survival (OS)
OS is defined as the time from the initiation of CD73/AXL.HypoSti.CAR-T cell therapy to documented disease progression or death.
Time frame: Up to 3 years.
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