Dual Targeting of Mesothelin and CD19 with Chimeric Antigen Receptor-Modified T Cells in Patients with Metastatic Pancreatic Cancer

• Published in: Molecular therapy Vol. 28; no. 11; pp. 2367 - 2378
• Main Authors: Ko, Andrew H., Jordan, Alexander C., Tooker, Evan, Lacey, Simon F., Chang, Renee B., Li, Yan, Venook, Alan P., Tempero, Margaret, Damon, Lloyd, Fong, Lawrence, O’Hara, Mark H., Levine, Bruce L., Melenhorst, J. Joseph, Plesa, Gabriela, June, Carl H., Beatty, Gregory L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.11.2020; American Society of Gene & Cell Therapy
• Subjects: Antigens, CD19 - immunology; B cells; CD19; chimeric antigen receptor; GPI-Linked Proteins - antagonists & inhibitors; Humans; Immunotherapy, Adoptive - adverse effects; Immunotherapy, Adoptive - methods; Lymphocyte Depletion - methods; Mesothelin; Neoplasm Metastasis; Neoplasm Staging; Original; pancreatic cancer; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - therapy; Pilot Projects; Receptors, Chimeric Antigen - immunology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Treatment Outcome; pancreatic cancer; chimeric antigen receptor; B cells; CD19; mesothelin
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2020.07.017

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. [Display omitted] This study examined the safety/feasibility of administering two separate infusions of CART cells recognizing (1) mesothelin, a tumor-associated antigen, and (2) CD19 to deplete B cells. Treatment was well-tolerated in patients with pancreatic cancer and depleted peripheral B cells but did not improve CART cell anti-tumor activity or persistence.