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Updated: Aug 26, 2025
Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
Preclinical InVivo Data Integrated in a Modeling Network Informs a Refined Clinical Strategy for a CD3 T-Cell
Javier Sánchez1,2, Valeria Nicolini3, Linda Fahrni3
1Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland. javier.sanchez_fernandez@roche.com.
Abstract:
TYRP1-TCB is a CD3 T-cell bispecific (CD3-TCB) antibody for the treatment of advanced melanoma. A tumor growth inhibition (TGI) model was developed using mouse xenograft data with TYRP1-TCB monotherapy or TYRP1-TCB plus anti-PD-L1 combination. The model was translated to humans to inform a refined clinical strategy. From xenograft mouse data, we estimated an EC50 of 0.345 mg/L for TYRP1-TCB, close to what was observed in vitro using the same tumor cell line. The model showed that, though increasing the dose of TYRP1-TCB in monotherapy delays the time to tumor regrowth and promotes higher tumor cell killing, it also induces a faster rate of tumor regrowth. Combination with anti-PD-L1 extended the time to tumor regrowth by 25% while also decreasing the tumor regrowth rate by 69% compared to the same dose of TYRP1-TCB alone. The model translation to humans predicts that if patients' tumors were scanned every 6 weeks, only 46% of the monotherapy responders would be detected even at a TYRP1-TCB dose resulting in exposures above the EC90. However, combination of TYRP1-TCB and anti-PD-L1 in the clinic is predicted to more than double the overall response rate (ORR), duration of response (DoR) and progression-free survival (PFS) compared to TYRP1-TCB monotherapy. As a result, it is highly recommended to consider development of CD3-TCBs as part of a combination therapy from the outset, without the need to escalate the CD3-TCB up to the Maximum Tolerated Dose (MTD) in monotherapy and without gating the combination only on RECIST-derived efficacy metrics.
Insights
Combining TYRP1-TCB with anti-PD-L1 significantly improves melanoma treatment outcomes. This combination therapy enhances overall response rate, duration of response, and progression-free survival compared to TYRP1-TCB alone.
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- TYRP1-TCB is a CD3 T-cell bispecific antibody investigated for advanced melanoma.
- Understanding its efficacy in combination with anti-PD-L1 is crucial for clinical strategy.
Purpose of the Study:
- To develop and translate a tumor growth inhibition (TGI) model for TYRP1-TCB in melanoma.
- To predict the clinical efficacy of TYRP1-TCB monotherapy versus combination therapy with anti-PD-L1.
Main Methods:
- A TGI model was built using mouse xenograft data for TYRP1-TCB monotherapy and combination therapy.
- The model was translated to humans to simulate clinical outcomes.
- Pharmacokinetic/pharmacodynamic (PK/PD) parameters, including EC50, were estimated.
Main Results:
- The model estimated an EC50 of 0.345 mg/L for TYRP1-TCB in xenografts.
- Combination therapy extended tumor regrowth time by 25% and reduced regrowth rate by 69% compared to monotherapy.
- Human translation predicted that combination therapy could more than double ORR, DoR, and PFS versus monotherapy.
Conclusions:
- Combination therapy with TYRP1-TCB and anti-PD-L1 demonstrates superior predicted clinical efficacy in advanced melanoma.
- Early development of CD3-TCBs as combination therapy is recommended, without prior monotherapy dose escalation.
- Clinical trial design should consider combination therapy from the outset for optimal patient benefit.
