Adoptive transfer of murine T cells expressing a chimeric‐PD1‐Dap10 receptor as an immunotherapy for lymphoma. Issue 3 (27th July 2017)

• Record Type: Journal Article
• Authors: Lynch, Adam; Hawk, William; Nylen, Emily; Ober, Sean; Autin, Pierre; Barber, Amorette
• Is Part Of: Immunology. Volume 152:Issue 3(2017)
• Page Start: 472
• Page End: 483
• Publication Date: 2017-07-27
• Subjects: CD8 T cell -- chimeric antigen receptor -- Dap10 -- immunotherapy -- lymphoma; Immunology -- Periodicals
• DOI: 10.1111/imm.12784
• Languages: English
• ISSNs: 0019-2805

Abstract

Summary: Adoptive transfer of T cells is a promising cancer therapy and expression of chimeric antigen receptors can enhance tumour recognition and T‐cell effector functions. The programmed death protein 1 (PD1) receptor is a prospective target for a chimeric antigen receptor because PD1 ligands are expressed on many cancer types, including lymphoma. Therefore, we developed a murine chimeric PD1 receptor (chPD1) consisting of the PD1 extracellular domain fused to the cytoplasmic domain of CD3ζ. Additionally, chimeric antigen receptor therapies use various co‐stimulatory domains to enhance efficacy. Hence, the inclusion of a Dap10 or CD28 co‐stimulatory domain in the chPD1 receptor was compared to determine which domain induced optimal anti‐tumour immunity in a mouse model of lymphoma. The chPD1 T cells secreted pro‐inflammatory cytokines and lysed RMA lymphoma cells. Adoptive transfer of chPD1 T cells significantly reduced established tumours and led to tumour‐free survival in lymphoma‐bearing mice. When comparing chPD1 receptors containing a Dap10 or CD28 domain, both receptors induced secretion of pro‐inflammatory cytokines; however, chPD1‐CD28 T cells also secreted anti‐inflammatory cytokines whereas chPD1‐Dap10 T cells did not. Additionally, chPD1‐Dap10 induced a central memory T‐cell phenotype compared with chPD1‐CD28, which induced an effector memory phenotype. The chPD1‐Dap10 T cells also had enhanced in vivo persistence and anti‐tumour efficacy compared with chPD1‐CD28 T cells. Therefore, adoptive transfer of chPD1 T cells could be a novel therapy for lymphoma and inclusion of the Dap10 co‐stimulatory domain in chimeric antigen receptors may induce a preferential cytokine profile and T‐cell differentiation phenotype for anti‐tumour therapies. Abstract : T cells expressing a chimeric antigen receptor targeting PD1 ligands (chPD1) secreted pro‐inflammatory cytokines and reduced an established tumour burden in a mouse model of T‐cell lymphoma. Inclusion of a Dap10 co‐stimulatory domain in the chPD1 receptor enhanced pro‐inflammatory cytokine secretion and anti‐tumour efficacy compared with CD28 co‐stimulation.