CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* Age ≥ 18 years at the time of informed consent
* Histologically confirmed PDAC (metastatic or locally advanced, unresectable)
* Measurable disease according to RECIST v1.1
* Disease progression during or after at least one prior line of systemic standard therapy for advanced PDAC
* CD318 expression in tumor tissue confirmed by central immunohistochemistry (IHC)
* ECOG performance status of 0 or 1
* Adequate bone marrow, renal, and hepatic function as defined in the protocol
* Life expectancy of at least 12 weeks
* Willingness and ability to comply with study procedures and follow-up
* Written informed consent obtained prior to any study-specific procedures-

Exclusion Criteria:

* Prior treatment with CAR T cells or other genetically modified cell therapies
* Active uncontrolled infection, including active hepatitis B or C infection or HIV infection
* Known symptomatic or untreated central nervous system (CNS) metastases
* Clinically significant cardiovascular disease, including recent myocardial infarction (within 6 months), unstable angina, or uncontrolled arrhythmia
* History of autoimmune disease requiring systemic immunosuppressive therapy
* Current or recent (within 4 weeks) participation in another interventional clinical trial
* Pregnant or breastfeeding women
* Any condition that, in the opinion of the investigator, would interfere with the patients ability to comply with study requirements or would compromise safety

主要终点：Incidence and severity of dose-limiting toxicities (DLTs) and adverse events (AEs) after CD318-CAR-T cell infusion. · Assessment of safety and tolerability of autologous CD318-CAR-T cells by determining the incidence, severity, and relationship to treatment of DLTs and AEs, graded according to NCI CTCAE version 5.0. · From CAR-T cell infusion through Day 28 after the last infusion in each subject.
次要终点：Objective response rate (ORR)；Duration of response (DoR)；Progression-free survival (PFS)；Overall survival (OS)；CAR-T cell expansion and persistence in peripheral blood；Serum cytokine profile

• CD318-CAR-T: Phase I dose escalation with Phase IIa expansion (dual dosing) · EXPERIMENTAL · Single experimental cohort receiving autologous CD318-targeted CAR-T cells after lymphodepletion. The study proceeds sequentially in two stages: (1) Phase I dose escalation using a Bayesian Optimal Interval (BOIN) design to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) with a single infusion; (2) Phase IIa expansion at the RP2D employing a predefined dual-dosing schedule (two infusions) to further evaluate safety and preliminary efficacy. Participants are not assigned in parallel to different regimens.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with limited therapeutic options and a five-year survival rate below 10 % in advanced stages. Standard treatments, such as multi-agent chemotherapy, provide only marginal survival benefits and are often associated with significant toxicity. Novel approaches are urgently needed. The ResCPa study is a first-in-human, multicenter, phase I/IIa investigator-initiated trial evaluating the safety, feasibility, and preliminary efficacy of autologous CD318-targeted chimeric antigen receptor (CAR) T-cell therapy in patients with metastatic or locally advanced PDAC that has progressed after standard-of-care treatment. CD318 (also known as CDCP1) is highly expressed in primary and metastatic PDAC tissue but rarely found in healthy tissues, making it a promising and potentially safe immunotherapy target. Preclinical studies have shown potent anti-tumor activity of CD318-CAR-T cells in vitro and in PDAC mouse models without target-specific toxicity. Eligible patients will undergo tumor tissue screening for CD318 expression. Those meeting the criteria will proceed to leukapheresis for autologous T-cell collection. The CD318-CAR construct, optimized in preclinical work, will be introduced via a GMP-produced lentiviral vector, and CAR-T cells will be expanded using automated manufacturing (CliniMACS Prodigy). Following lymphodepleting chemotherapy, patients will receive CD318-CAR-T cells in a dose-escalation design to determine the recommended phase II dose, with the option of dual dosing. The primary objectives are to assess safety, tolerability, and feasibility of manufacturing and delivering CD318-CAR-T cells. Secondary objectives include preliminary anti-tumor activity (objective response rate, progression-free survival, overall survival), CAR-T cell expansion and persistence, and immunological correlates of response or resistance. Patients will be followed for at least 12 months post-infusion, with extended safety follow-up per regulatory requirements. In parallel, an extensive translational research program will investigate CAR-T cell phenotypes, tumor microenvironment changes, and mechanisms of treatment resistance using single-cell multi-omics, spatial proteomics and transcriptomics, organoid co-culture models, and microbiome profiling. Insights from these studies aim to guide optimization of next-generation CAR-T therapies for PDAC and other solid tumors. This trial is conducted by a German academic-industrial consortium including the University Hospital Tübingen, Miltenyi Biotec, University Hospital Freiburg, Klinikum rechts der Isar (TUM), Berlin Institute of Health (BIH), and other partners. The study is supported by the German Federal Ministry of Education and Research (BMBF) within the "National Decade Against Cancer" initiative.