To understand the factors influencing the efficacy of clinically relevant bispecific T cell engagers (BiTEs), researchers engineered a mouse strain partially humanized at the CD3ε locus. Antitumor responses induced by BiTE molecules were dependent on the proliferation and activation of CD8+ T cells that were present at baseline, and were thus stronger in immunogenic, “hot” tumors. CD4+ T cells also contributed, but were dominantly immunosuppressive. Combining BiTEs with anti-PD-1, anti-CTLA-4, and agonist 4-1BB enhanced antitumor responses and overcame resistance in the KPC model of “cold” immunotherapy-refractory tumors.
Contributed by Lauren Hitchings
ABSTRACT: Therapeutic approaches are needed to promote T cell-mediated destruction of poorly immunogenic, "cold" tumors typically associated with minimal response to immune checkpoint blockade (ICB) therapy. Bispecific T cell engager (BiTE) molecules induce redirected lysis of cancer cells by polyclonal T cells and have demonstrated promising clinical activity against solid tumors in some patients. However, little is understood about the key factors that govern clinical responses to these therapies. Using an immunocompetent mouse model expressing a humanized CD3_ chain (huCD3e mice) and BiTE molecules directed against mouse CD19, mouse CLDN18.2, or human EPCAM antigens, we investigated the pharmacokinetic and pharmacodynamic parameters and immune correlates associated with BiTE efficacy across multiple syngeneic solid-tumor models. These studies demonstrated that pretreatment tumor-associated T cell density is a critical determinant of response to BiTE therapy, identified CD8(+) T cells as important targets and mediators of BiTE activity, and revealed an antagonistic role for CD4(+) T cells in BiTE efficacy. We also identified therapeutic combinations, including ICB and 4-1BB agonism, that synergized with BiTE treatment in poorly T cell-infiltrated, immunotherapy-refractory tumors. In these models, BiTE efficacy was dependent on local expansion of tumor-associated CD8(+) T cells, rather than their recruitment from circulation. Our findings highlight the relative contributions of baseline T cell infiltration, local T cell proliferation, and peripheral T cell trafficking for BiTE molecule-mediated efficacy, identify combination strategies capable of overcoming resistance to BiTE therapy, and have clinical relevance for the development of BiTE and other T cell engager therapies.
Author Info: (1) Amgen Research, Thousand Oaks, CA 91320, USA. Inflammation and Oncology Therapeutic Area, Amgen, Thousand Oaks, CA 91320, USA. (2) Amgen Research, Thousand Oaks, CA 91320, USA.
Author Info: (1) Amgen Research, Thousand Oaks, CA 91320, USA. Inflammation and Oncology Therapeutic Area, Amgen, Thousand Oaks, CA 91320, USA. (2) Amgen Research, Thousand Oaks, CA 91320, USA. Inflammation and Oncology Therapeutic Area, Amgen, South San Francisco, CA 94080, USA. (3) Amgen Research, Thousand Oaks, CA 91320, USA. Inflammation and Oncology Therapeutic Area, Amgen, South San Francisco, CA 94080, USA. (4) Amgen Research, Thousand Oaks, CA 91320, USA. Inflammation and Oncology Therapeutic Area, Amgen, Thousand Oaks, CA 91320, USA. (5) Amgen Research, Thousand Oaks, CA 91320, USA. Inflammation and Oncology Therapeutic Area, Amgen, South San Francisco, CA 94080, USA. (6) Amgen Research, Thousand Oaks, CA 91320, USA. Translational Safety and Bioanalytical Sciences, Amgen, South San Francisco, CA 94080, USA. (7) Amgen Research, Thousand Oaks, CA 91320, USA. Inflammation and Oncology Therapeutic Area, Amgen, South San Francisco, CA 94080, USA. (8) Amgen Research, Thousand Oaks, CA 91320, USA. Inflammation and Oncology Therapeutic Area, Amgen, South San Francisco, CA 94080, USA. (9) Amgen Research, Thousand Oaks, CA 91320, USA. Inflammation and Oncology Therapeutic Area, Amgen, South San Francisco, CA 94080, USA. (10) Amgen Research, Thousand Oaks, CA 91320, USA. Inflammation and Oncology Therapeutic Area, Amgen, South San Francisco, CA 94080, USA. (11) Amgen Research, Thousand Oaks, CA 91320, USA. Inflammation and Oncology Therapeutic Area, Amgen, Thousand Oaks, CA 91320, USA. (12) Amgen Research, Thousand Oaks, CA 91320, USA. Amgen Research GmbH, Munich 81477, Germany. (13) Amgen Research, Thousand Oaks, CA 91320, USA. Therapeutic Discovery, Amgen, South San Francisco, CA 94080, USA. (14) Amgen Research, Thousand Oaks, CA 91320, USA. Therapeutic Discovery, Amgen, South San Francisco, CA 94080, USA. (15) Amgen Research, Thousand Oaks, CA 91320, USA. Therapeutic Discovery, Amgen, South San Francisco, CA 94080, USA. (16) Amgen Research, Thousand Oaks, CA 91320, USA. Pharmacokinetics and Drug Metabolism, Amgen, South San Francisco, CA 94080, USA. (17) Amgen Research, Thousand Oaks, CA 91320, USA. Translational Safety and Bioanalytical Sciences, Amgen, South San Francisco, CA 94080, USA. (18) Amgen Research, Thousand Oaks, CA 91320, USA. Inflammation and Oncology Therapeutic Area, Amgen, South San Francisco, CA 94080, USA. (19) Amgen Research, Thousand Oaks, CA 91320, USA. oliviern@amgen.com Jackson.egen@gmail.com. Inflammation and Oncology Therapeutic Area, Amgen, South San Francisco, CA 94080, USA. (20) Amgen Research, Thousand Oaks, CA 91320, USA. oliviern@amgen.com Jackson.egen@gmail.com. Inflammation and Oncology Therapeutic Area, Amgen, South San Francisco, CA 94080, USA.
