Preclinical InVivo Data Integrated in a Modeling Network Informs a Refined Clinical Strategy for a CD3 T-Cell Bispecific in Combination with Anti-PD-L1

Sánchez, J. G.; Nicolini, Valeria; Fahrni, Linda; Waldhauer, Inja; Walz, Antje-Christine; Jamois, Candice; Fowler, Stephen C.; Simon, Silke; Klein, Christian; Umaña, Pablo; Friberg, Lena E.; Frances, Nicolas

doi:10.1208/s12248-022-00755-5

Cited by 2 publications

(2 citation statements)

References 40 publications

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“…Combining the TCE with anti-PD-L1 therapy reduced both the rate and time to tumor regrowth, and a translational PK/PD model was developed to quantify these processes and predict clinical response of the combination versus monotherapy. 104 …”

Section: Optimization Of Efficacy and Safety During The Clinical Deve...mentioning

confidence: 99%

Strategies for clinical dose optimization of T cell-engaging therapies in oncology

Ball

Dovedi

Vajjah

et al. 2023

mAbs

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Innovative approaches in the design of T cell-engaging (TCE) molecules are ushering in a new wave of promising immunotherapies for the treatment of cancer. Their mechanism of action, which generates an in trans interaction to create a synthetic immune synapse, leads to complex and interconnected relationships between the exposure, efficacy, and toxicity of these drugs. Challenges thus arise when designing optimal clinical dose regimens for TCEs with narrow therapeutic windows, with a variety of dosing strategies being evaluated to mitigate key side effects such as cytokine release syndrome, neurotoxicity, and on-target off-tumor toxicities. This review evaluates the current approaches to dose optimization throughout the preclinical and clinical development of TCEs, along with perspectives for improvement of these strategies. Quantitative approaches used to aid the understanding of dose-exposure-response relationships are highlighted, along with opportunities to guide the rational design of next-generation TCE molecules, and optimize their dose regimens in patients.

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Section: Optimization Of Efficacy and Safety During The Clinical Deve...mentioning

confidence: 99%

Strategies for clinical dose optimization of T cell-engaging therapies in oncology

Ball

Dovedi

Vajjah

et al. 2023

mAbs

View full text Add to dashboard Cite

show abstract

“…Initial results from clinical trials are promising, but release of further results is needed to definitively show safety and efficacy. Some authors have suggested that CPIs and BiTEs should be considered as a combination therapy earlier in treatment development pipelines such that maximum tolerated dose studies of monotherapy and combination can be run in parallel [ 31 ].…”

Section: Checkpoint Inhibitorsmentioning

confidence: 99%

Combination therapies for the optimisation of Bispecific T-cell Engagers in cancer treatment

Zhu

Middleton

2023

Immunotherapy Advances

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Bispecific T-cell engagers (BiTEs) redirect endogenous T-cell populations to cells expressing tumour associated antigens to induce tumour cell killing. This inherently relies upon a cytotoxic T-cell population that is able to be recruited. In many cancers, immune checkpoints and other immunosuppressive factors in the tumour microenvironment lead to a population of anergic T-cells which cannot be redirected to tumour killing and thus impede the efficacy of BiTE therapy. Furthermore, there is evidence that BiTE therapy itself can increase immune checkpoint expression, and this is thought to be a major escape mechanism for the BiTE therapy blinatumomab. To overcome these inadequate T-cell responses, BiTEs may be combined with checkpoint inhibitors, chemotherapy, costimulatory molecules or oncolytic viruses. Study of these combinations is needed to expand the use of BiTEs in solid malignancies. This review covers the rationale, preclinical evidence and any clinical trials for these combination therapies and a few other less studied combinations.

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Preclinical InVivo Data Integrated in a Modeling Network Informs a Refined Clinical Strategy for a CD3 T-Cell Bispecific in Combination with Anti-PD-L1

Cited by 2 publications

References 40 publications

Strategies for clinical dose optimization of T cell-engaging therapies in oncology

Strategies for clinical dose optimization of T cell-engaging therapies in oncology

Combination therapies for the optimisation of Bispecific T-cell Engagers in cancer treatment

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