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Dual Targeting of Mesothelin and CD19 with Chimeric Antigen Receptor-Modified T Cells in Patients with Metastatic
Andrew H Ko1, Alexander C Jordan2, Evan Tooker2
1Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Abstract:
B cells infiltrate pancreatic ductal adenocarcinoma (PDAC) and in preclinical cancer models, can suppress T cell immunosurveillance in cancer. Here, we conducted a pilot study to assess the safety and feasibility of administering lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin to target tumor cells along with CART cells redirected against CD19 to deplete B cells. Both CARs contained 4-1BB and CD3ζ signaling domains. Three patients with chemotherapy-refractory PDAC received 1.5 g/m2 cyclophosphamide prior to separate infusions of lentiviral-transduced T cells engineered to express chimeric anti-mesothelin immunoreceptor SS1 (CART-Meso, 3 × 107/m2) and chimeric anti-CD19 immunoreceptor (CART-19, 3 × 107/m2). Treatment was well tolerated without dose-limiting toxicities. Best response was stable disease (1 of 3 patients). CART-19 (compared to CART-Meso) cells showed the greatest expansion in the blood, although persistence was transient. B cells were successfully depleted in all subjects, became undetectable by 7-10 days post-infusion, and remained undetectable for at least 28 days. Together, concomitant delivery of CART-Meso and CART-19 cells in patients with PDAC is safe. CART-19 cells deplete normal B cells but at the dose tested in these 3 subjects did not improve CART-Meso cell persistence.
Insights
This pilot study found that combining chimeric antigen receptor (CAR)-T cells targeting mesothelin and CD19 is safe for pancreatic cancer patients. While B cells were depleted, this approach did not enhance CAR-T cell persistence.
Area of Science:
- Immunotherapy
- Oncology
- Cell Therapy
Background:
- B cells can suppress anti-tumor T cell responses in pancreatic ductal adenocarcinoma (PDAC).
- Chimeric antigen receptor (CAR)-T cell therapy offers a targeted approach to cancer treatment.
Purpose of the Study:
- To evaluate the safety and feasibility of administering dual CAR-T cells (anti-mesothelin and anti-CD19) in patients with PDAC.
- To assess the impact of B cell depletion on CAR-T cell persistence and anti-tumor activity.
Main Methods:
- A pilot study involving three patients with chemotherapy-refractory PDAC.
- Patients received cyclophosphamide followed by infusions of lentiviral-transduced T cells expressing anti-mesothelin (CART-Meso) and anti-CD19 (CART-19) CARs.
- Both CAR constructs incorporated 4-1BB and CD3ζ signaling domains.
Main Results:
- The combined therapy was well-tolerated with no dose-limiting toxicities observed.
- B cells were successfully depleted in all patients within 7-10 days and remained undetectable for at least 28 days.
- CART-19 cells showed greater expansion than CART-Meso cells, but persistence was transient; one patient achieved stable disease.
Conclusions:
- Concomitant administration of CART-Meso and CART-19 cells is a safe strategy in PDAC patients.
- While CART-19 effectively depletes B cells, the tested dose did not improve CART-Meso cell persistence in this small cohort.
- Further research is needed to optimize CAR-T cell dosing and combination strategies for PDAC treatment.
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