Assessing T-cell engagers efficacy in vivo: Versatility of BRGSF-HIS mice

Immuno-oncology has become the focus of many oncology research studies and drug development pipelines in the last decade. As previously discussed in one of our commentaries, cancer immunotherapies have been developed to try and prevent tumor cells from escaping immune cells, and allow these last ones to fight back.

The promises of T-cell engagers

In addition to developing compounds to prevent tumor cells from cheating the immune system by targeting immune checkpoints (also called ICP blockade), T-cell engagers (TCEs) are also being developed to physically recruit T cells to the tumor site.¹ TCEs, single compounds targeting the T-cell co-receptor CD3 and a tumor-specific antigen, have shown great promise in preclinical and clinical studies, but as for any type of compounds, testing their efficacy and safety in preclinical settings remains a challenge, and requires the availability of relevant and reliable preclinical models.²

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T-cell engager efficacy assessment in BRGSF-HIS model

The BRGSF-HIS mice represent a reliable model to assess TCEs’ safety, in particular their ability to induce cytokine release and CRS-like features.³ Indeed, these mice show several specific features rendering them particularly versatile: their myeloid compartment can be boosted in vivo, their lymphoid and myeloid compartments are functional, they are radioresistant, and they exhibit a prolonged lifespan, providing a broad therapeutic window.

As an example, bispecific targeting of T-cell co-receptor CD3 and B-cell surface molecule CD20 in a B-cell lymphoma model induced tumor growth inhibition in BRGS-HIS mice.

Efficacy assessment of antiCD3-antiCD20 T-cell engager in a B-cell lymphoma model.

14-week-old BRGS-HIS mice were injected s.c. with 5x10⁶ luciferase-expressing human Daudi cells (African-American Burkitt′s B-lymphoma). At D3 and D7 post-cell inoculation, mice were injected i.v. with PBS (HIS-CTL in black), anti-human CD3 antibody (HIS-aCD3 in blue; 1mg/kg), anti-human CD20 antibody (HIS-aCD20 in red; 1 mg/kg), or anti-human CD3/CD20 TCE (HIS-TCE in green; 1 mg/kg). Immunodeficient BRGS mice were also inoculated as a control (BRGS-CTL in purple). Tumor cell expansion was followed by bioluminescence in vivo measurements.

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Interestingly, targeting CD3 or CD20 alone did not prevent tumor growth, suggesting that recruitment of T cells to the tumor B cells by the TCE is needed to achieve tumor growth inhibition. Of note, the response to TCE treatment in BRGSF-HIS mice was shown to be donor-dependent (not shown), which could reflect the variability of responses observed in patients.

As the BRGSF-HIS mice immune system contains human cells, and these mice allow for the tumor growth of a variety of human cancer cells, human immune targets and human tumor antigens are co-expressed in this model. This means that virtually any compound’s efficacy and/or safety could be tested in BRGSF-HIS mice, regardless of its specific target(s).

Of note, the BRGSF-HIS model is available at genOway, designer and provider of multiple preclinical models in several research areas, including immuno-oncology, metabolism, cardiovascular diseases, and neuroscience.

References:

1. Zhou S, Liu M, Ren F, Meng X, Yu J. The landscape of bispecific T cell engager in cancer treatment. Biomark Res. 2021 May 26;9(1):38.
2. Pandiella A, Calvo E, Moreno V, Amir E, Templeton A, Ocana A. Considerations for the clinical development of immuno-oncology agents in cancer. Front Immunol. 2023 Aug 11;14:1229575.
3. ‍https://www.genoway.com/science/publications/commentary/assess-t-cell-engagers