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Published on: February 8, 2018
Blocking TIM-3 in Treatment-refractory Advanced Solid Tumors: A Phase Ia/b Study of LY3321367 with or without an
James J Harding1, Victor Moreno2, Yung-Jue Bang3
1Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York. hardinj1@mskcc.org.
Purpose:
T-cell immunoglobulin and mucin-domain-containing molecule-3 (TIM-3) blunts anticancer immunity and mediates resistance to programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors. We assessed a novel, first-in-class, TIM-3 mAb, LY3321367, alone or in combination with the anti-PD-L1 antibody, LY300054 in patients with advanced solid tumor.
Patients And Methods:
This open-label, multicenter, phase Ia/b study aimed to define the safety/tolerability and recommended phase II dose (RP2D) of LY3321367 with or without LY300054. Secondary objectives included pharmacokinetics/pharmacodynamics, immunogenicity, and efficacy. Biomarkers were assessed in exploratory analysis.
Results:
No dose-limiting toxicities were observed in the monotherapy (N = 30) or combination (N = 28) dose escalation. LY3321367 treatment-related adverse events (≥2 patients) included pruritus, rash, fatigue, anorexia, and infusion-related reactions. Dose-proportional increase in LY3321367 concentrations was not affected by either LY300054 or antidrug antibodies (observed in 50%-70% of patients). Pharmacokinetic/pharmacodynamic modeling indicated 100% target engagement at doses ≥600 mg. LY3321367 RP2D was 1,200 mg biweekly for four doses followed by 600 mg every 2 weeks thereafter. In the non-small cell lung cancer monotherapy expansion cohort, outcomes varied by prior anti-PD-1 therapy response status: anti-PD-1/L1 refractory patients [N = 23, objective response rate (ORR) 0%, disease control rate (DCR) 35%, progression-free survival (PFS) 1.9 months] versus anti-PD-1/L1 responders (N = 14, ORR 7%, DCR 50%, PFS 7.3 months). In combination expansion cohorts (N = 91), ORR and DCR were 4% and 42%; CD8 infiltration in paired biopsies increased in approximately half these patients.
Conclusions:
LY3321367 exhibited acceptable safety profile with favorable pharmacokinetics/pharmacodynamics but only modest antitumor activity. The therapeutic relevance of TIM-3 blockade requires further investigation.
Insights
A novel T-cell immunoglobulin and mucin-3 (TIM-3) antibody, LY3321367, showed an acceptable safety profile in patients with advanced solid tumors. While demonstrating favorable pharmacokinetics, its antitumor activity was modest, warranting further investigation into TIM-3 blockade therapy.
Area of Science:
- Immunotherapy
- Oncology
- Clinical Trials
Background:
- T-cell immunoglobulin and mucin-domain-containing molecule-3 (TIM-3) is a key regulator of anticancer immunity.
- TIM-3 blockade is a potential strategy to overcome resistance to existing immunotherapies like PD-1/PD-L1 inhibitors.
Purpose of the Study:
- To evaluate the safety, tolerability, and recommended Phase II dose (RP2D) of LY3321367, a novel TIM-3 mAb.
- To assess LY3321367 alone or in combination with anti-PD-L1 (LY300054) in patients with advanced solid tumors.
- To explore pharmacokinetic/pharmacodynamic properties, immunogenicity, and preliminary efficacy.
Main Methods:
- Open-label, multicenter, Phase Ia/b study involving dose escalation and expansion cohorts.
- Patients received LY3321367 monotherapy or in combination with LY300054.
- Safety, pharmacokinetics, pharmacodynamics, immunogenicity, and efficacy endpoints were assessed.
Main Results:
- No dose-limiting toxicities were observed; common adverse events included pruritus, rash, and fatigue.
- Pharmacokinetic/pharmacodynamic modeling confirmed target engagement at doses ≥600 mg, establishing an RP2D of 1,200 mg biweekly.
- Modest antitumor activity was observed, with varied responses in non-small cell lung cancer patients based on prior anti-PD-1/L1 therapy, and increased CD8 infiltration in approximately half of combination-treated patients.
Conclusions:
- LY3321367 demonstrated an acceptable safety profile and favorable pharmacokinetics/pharmacodynamics.
- The observed antitumor activity was modest, suggesting that the therapeutic relevance of TIM-3 blockade needs further investigation.
- Further studies are required to fully elucidate the potential of TIM-3 inhibition in cancer treatment.
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