PD1 Knockout CAR T-Cell Therapy Well-Tolerated, Yields Durable Response in DLBCL

shRNA-mediated PD1 gene knock-down anti-CD19 chimeric antigen receptor (CAR) T-cell therapy had an acceptable safety profile with some signs of clinical activity in patients with relapsed/refractory B-cell malignancies.

Data from the phase 2 trial evaluating the therapy in China were presented by Hong Cen, MD, Guangxi Medical University Affiliated Tumor Hospital and Oncology Medical Center, at the European Society of Medical Oncology (ESMO) Congress 2022, September 9-13, in Paris, France.

“PD-1/PD-L1 binding can inhibit T cell activation. Many studies have proved that blockade of PD-1/ PD-L1 axis is effective to enhance the function of CAR-T cells. However, this strategy has mainly been studied in vitro and the antitumor properties of CAR-T cells that continuously knock down PD-1 in vivo have not been thoroughly investigated,” Cen said during his presentation.

The trial enrolled 16 patients with relapsed/refractory B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL; n = 8), B-cell acute lymphocytic leukemia (B-ALL; n = 4), follicular lymphoma (FL; n = 2), chronic lymphocytic leukemia (CLL; n = 1), and high-grade B-cell lymphoma (HGBL; n = 1).

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The PD1 knock-out CAR T-cell therapy had a manageable safety profile, with no cases of neurotoxicity and 11 cases (68.8%) of cytokine release syndrome (CRS). Most cases of CRS were mild, with 7 cases of grade 1 and 4 cases of grade 2 CRS. There were no deaths due to treatment-related adverse events (AEs).

The investigators found that most participants had an increase in interleukin-6 (IL6) levels after CAR T-cell infusion. These levels varied greatly between participants and were not necessarily correlated with CRS severity. Furthermore, 2 patients that did not experience CRS had IL6 levels greater than 1000 pg/mL. Cen and colleagues also found that change in c-reactive protein and ferritin was not as significant after CAR T-cell infusion.

“Using cytokines may be difficult to predict occurrence and severity of CRS,” Cen said.

Cen and colleagues found that 6 patients achieved a complete response (CR), 3 with B-ALL, 2 with BLBCL, and 1 with FL. Four patients achieved a partial response (PR), 3 with DLBCL and 1 with FL. Three patients that achieved a CR, 2 with DLBCL and 1 with FL, have a continuing response for durations of 36, 34, and 29 months. The 3 other patients that achieved a CR with B-ALL relapsed on days 59, 78, and 110 after infusion.

“PD1 gene knock-down anti-CD19 CAR-T therapy showed acceptable safety and anti-tumor activity in patients with relapsed or refractory CD19+ B cell malignancies,” Cen concluded.

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REFERENCE

Cen H, Ke Q, Li D, et al. shRNA-mediated PD1 gene knock-down anti-CD19 CAR-T cell therapy for relapsed/refractory b cell malignancies. Presented at: ESMO 2022 Congress, September 9-13, Paris, France. Abstract #619O.