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Characterization of bispecific antibodies that drive synthetic agonistic receptor-transduced T cells to mediate specific and conditional therapy in human pancreatic cancer models
Characterization of bispecific antibodies that drive synthetic agonistic receptor-transduced T cells to mediate specific and conditional therapy in human pancreatic cancer models
Adoptive T cell therapy, namely chimeric antigen receptor (CAR) T cell therapy has been a groundbreaking and effective treatment of relapsed or refractory haematological malignancies. Still, many patients do not respond or relapse with treatment-resistant disease. Additionally, toxicities such as cytokine release syndrome remain problematic. Cancer heterogeneity, beyond cancer types and inter-patient differences, is present within every individual patient. This heterogeneity, especially in the context of solid tumors, has meant that targeted immunotherapies have fared relatively poorly, creating a need for a modular platform with a capacity to target multiple antigens simultaneously and/or sequentially. Likewise, treatment-related toxicities have limited the therapeutic efficacy and breadth of patient selection. To tackle these caveats through a modular and controllable approach, we equipped T cells with synthetic agonistic receptors (SARs) that are only activated when a tumor-associated antigen and a cross-linking bispecific antibody (BiAb) specific for both SAR T cell and tumor cell are also present. The SAR itself is constituted of an inert extracellular domain in the form of EGFRvIII, that is fused to the T cell activating domains CD28 and CD3ζ. The BiAb employed is a trivalent CrossMab, with two binding arms (2 x Fab) for the tumor-associated antigen (mesothelin), and one binding arm for the SAR receptor (EGFRvIII). We showed that BiAb triggering of the SAR is conditional upon the binding of the second BiAb specificity. What is particularly advantageous with this approach is that T cell activation may only occur when the BiAb is present and in proximity to the antibody-targeted tumor cell. This conditional T cell activation is an inherent safety feature of the platform, whereby if unwanted levels of T cell activation are observed, depletion of the BiAb from the system could result in the reversal of said activation, thus managing the potential toxicity. This work was able to determine the validity and efficacy of the approach. Through the generation of several human pancreatic cancer models, and extensive in vitro and in vivo testing, the platform could be characterized. Its translational relevance and significance as a next-generation adoptive T cell therapy with the potential to plug some gaping pitfalls of current ACT approaches were also shown.
Adoptive T cell therapy, Bispecific antibodies, Pancreatic cancer
Benmebarek, Mohamed-Reda
2021
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Benmebarek, Mohamed-Reda (2021): Characterization of bispecific antibodies that drive synthetic agonistic receptor-transduced T cells to mediate specific and conditional therapy in human pancreatic cancer models. Dissertation, LMU München: Faculty of Medicine
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Abstract

Adoptive T cell therapy, namely chimeric antigen receptor (CAR) T cell therapy has been a groundbreaking and effective treatment of relapsed or refractory haematological malignancies. Still, many patients do not respond or relapse with treatment-resistant disease. Additionally, toxicities such as cytokine release syndrome remain problematic. Cancer heterogeneity, beyond cancer types and inter-patient differences, is present within every individual patient. This heterogeneity, especially in the context of solid tumors, has meant that targeted immunotherapies have fared relatively poorly, creating a need for a modular platform with a capacity to target multiple antigens simultaneously and/or sequentially. Likewise, treatment-related toxicities have limited the therapeutic efficacy and breadth of patient selection. To tackle these caveats through a modular and controllable approach, we equipped T cells with synthetic agonistic receptors (SARs) that are only activated when a tumor-associated antigen and a cross-linking bispecific antibody (BiAb) specific for both SAR T cell and tumor cell are also present. The SAR itself is constituted of an inert extracellular domain in the form of EGFRvIII, that is fused to the T cell activating domains CD28 and CD3ζ. The BiAb employed is a trivalent CrossMab, with two binding arms (2 x Fab) for the tumor-associated antigen (mesothelin), and one binding arm for the SAR receptor (EGFRvIII). We showed that BiAb triggering of the SAR is conditional upon the binding of the second BiAb specificity. What is particularly advantageous with this approach is that T cell activation may only occur when the BiAb is present and in proximity to the antibody-targeted tumor cell. This conditional T cell activation is an inherent safety feature of the platform, whereby if unwanted levels of T cell activation are observed, depletion of the BiAb from the system could result in the reversal of said activation, thus managing the potential toxicity. This work was able to determine the validity and efficacy of the approach. Through the generation of several human pancreatic cancer models, and extensive in vitro and in vivo testing, the platform could be characterized. Its translational relevance and significance as a next-generation adoptive T cell therapy with the potential to plug some gaping pitfalls of current ACT approaches were also shown.