To enhance the antitumor efficacy of TCR-engineered MAGE-A1-specific CD4+ T cells, Zhang, Tang, Kinsella, et al. co-engineered the cells with a chimeric CD8β co-receptor with a CD28 intracellular tail. The inclusion of CD8/CD28 chimera enhanced cytokine production, T cell persistence, and tumor control in an immunodeficient mouse model while preserving stem-like transcriptional features. Further optimization of the CD28 binding motifs improved tumor control in vivo, increased intratumoral T cell accumulation, and reduced exhaustion. Similar effects were observed in PRAME- and WT1-specific TCR T cells in vitro.
Contributed by Lauren Hitchings
ABSTRACT: Adoptive transfer of T cells engineered with tumor-specific T cell receptors (TCRs) has shown limited efficacy in solid tumors, hindered by insufficient persistence, tumor trafficking, and dependence on tumor-associated co-stimulatory ligands. In a phase I trial (NCT04639245) for patients with metastatic MAGE-A1-expressing tumors and adequate organ function; one participant received treatment, which was well-tolerated. In this case and NSG murine models, infusion of CD4/CD8 T cells co-expressing a class-I MAGE-A1-specific TCR and CD8αβ, failed to control tumor progression. To enhance function downstream of TCR signaling, here we investigate the adaptability of TCR components to synthetic modification. Leveraging the obligate co-expression of CD8αβ required for class-I TCR function in CD4 T cells, we identify CD8β as a tractable site for engineering without loss of function. In vitro screening demonstrates incorporation of the CD28 intracellular tail, yielding a CD8/CD28 chimeric co-receptor, most effectively enhances cytokine production, T cell persistence, and tumor control in immunodeficient murine models while preserving stem-like transcriptional features compared to native CD8β. Further rational modification of the CD28 binding motifs improves tumor control in vivo with increased intratumoral accumulation and reduced exhaustion. This benefit also extends to PRAME and WT1-specific TCRs in vitro supporting generalizability.
Author Info: (1) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. Current affiliation: Link Cell Therapies, South San Franc
Author Info: (1) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. Current affiliation: Link Cell Therapies, South San Francisco, Francisco, CA, USA. (2) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. (3) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. (4) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. (5) Department of Medicine, Division of Hematology and Oncology, University of Washington School of Medicine, Seattle, WA, USA. Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. (6) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. Current affiliation: Takeda, Cambridge, MA, USA. (7) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. Current affiliation: Bristol Myers Squibb, Seattle, WA, USA. (8) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. Current affiliation: Herbold Computational Biology Program, Fred Hutchinson Cancer Center, Seattle, WA, USA. (9) Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. (10) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. (11) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. (12) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. Current affiliation: Genetech, San Diego, CA, USA. (13) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. (14) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. (15) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. (16) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. (17) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA. (18) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. (19) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. (20) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. (21) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. Current affiliation: Internal Medicine, Rush University Chicago, Chicago, IL, USA. (22) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. (23) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. Current affiliation: Stanford University, 450 Jane Stanford Way, Stanford, CA, USA. (24) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. Medical Scientist Training Program, University of Washington, Seattle, WA, USA. Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA. (25) Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA, USA. (26) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. Department of Immunology, University of Washington, Seattle, WA, USA. (27) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. Department of Medicine, Division of Hematology and Oncology, University of Washington School of Medicine, Seattle, WA, USA. Department of Immunology, University of Washington, Seattle, WA, USA. (28) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. (29) Translational Science & Therapeutics Division, Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. achapuis@fredhutch.org. Department of Medicine, Division of Hematology and Oncology, University of Washington School of Medicine, Seattle, WA, USA. achapuis@fredhutch.org.
