CD318-targeted CAR-T Cell Therapy in Patients With Pancreatic Cancer (ResCPa)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with a steadily increasing incidence and a poor prognosis. Standard chemotherapy regimens such as FOLFIRINOX or gemcitabine plus nab paclitaxel provide only modest survival benefits and are often associated with substantial toxicity. PDAC is characterized by aggressive tumor biology, early metastasis, and marked resistance to conventional therapies, underscoring the need for novel strategies.

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematologic malignancies but has yet to achieve similar success in solid tumors. Challenges include the lack of highly specific tumor antigens, poor trafficking and persistence of CAR T cells, immune evasion in the tumor microenvironment, and tumor antigen heterogeneity.

CD318, also known as CDCP1, is a promising target for PDAC immunotherapy. It is highly expressed in primary and metastatic PDAC tissues but shows minimal expression in healthy tissues. Preclinical studies have demonstrated that CD318 targeted CAR T cells can induce potent anti tumor activity in vitro and in PDAC mouse models without detectable target specific toxicity.

The ResCPa study is a first in human, multicenter, phase I/IIa investigator initiated clinical trial designed to evaluate the safety, feasibility, and preliminary efficacy of autologous CD318 targeted CAR T cells in patients with metastatic or locally advanced PDAC refractory to standard of care therapy. The study will also conduct an extensive translational research program to understand CAR T cell function and resistance mechanisms in solid tumors.

Eligible patients will be screened for CD318 expression in tumor tissue. Those meeting inclusion criteria will undergo leukapheresis for T cell collection. Autologous T cells will be genetically modified using a GMP manufactured lentiviral vector encoding the CD318 CAR and expanded using automated manufacturing on the CliniMACS Prodigy platform at the University Hospital Tuebingen GMP facility.

Following lymphodepleting chemotherapy, patients will receive CAR T cells in a dose escalation design using the Bayesian Optimal Interval method to determine the maximum tolerated dose or recommended phase II dose. Dose limiting toxicities will be closely monitored and predefined stopping rules applied. Both single and dual dosing regimens may be used.

Primary objectives are to assess the safety, tolerability, and feasibility of manufacturing and delivering CD318 CAR T cells. Secondary objectives are to evaluate preliminary antitumor activity, CAR T cell expansion and persistence, and immune correlates of response or resistance. Exploratory objectives include biomarker discovery, characterization of the tumor microenvironment, and microbiome analyses.

Translational research will include

• Immune monitoring by single cell multi omics profiling of CAR T cell products and longitudinal blood samples to evaluate phenotype, activation status, metabolic fitness, and exhaustion markers.
• Tumor microenvironment analyses using spatial proteomics, spatial transcriptomics, and imaging mass cytometry of tumor biopsies before and after treatment to assess immune infiltration, antigen expression, and stromal architecture.
• Patient derived organoid and xenograft models to study CAR T cytotoxicity, antigen recognition, and resistance mechanisms in vitro and in vivo.
• Microbiome profiling of stool and tumor samples using shotgun metagenomics and 16S rRNA sequencing to explore associations with response or resistance.
• Characterization of innate like T cell subsets such as gamma delta T cells, NKT cells, and MAIT cells within CAR T products and exploration of CD318 targeting in these populations.

The trial is coordinated by the University Hospital Tuebingen in collaboration with Miltenyi Biotec, University Hospital Freiburg, Klinikum rechts der Isar TUM, Max Delbrueck Center Berlin, and other partners. It is funded by the German Federal Ministry of Education and Research BMBF under the National Decade Against Cancer initiative. A Data Safety Monitoring Board will oversee patient safety, and a patient advisory board will be involved in study oversight and dissemination of results.

If successful, this trial could establish CD318 CAR T therapy as a new treatment option for PDAC and provide insights to optimize future CAR T approaches for solid tumors. Findings may also have relevance for other cancer types, accelerating the development and clinical application of advanced cellular immunotherapies.