18 Apr AACR23: Phase 1 trial of IO-108, an antagonist antibody targeting LILRB2 (ILT4), as monotherapy and in combination with pembrolizumab in adult patients with advanced relapsed or refractory solid tumors
MedicalResearch.com Interview with:
Matthew H. Taylor, MD
Earle A. Chiles Research Institute
Providence Cancer Institute
MedicalResearch.com: What is the background for this study? What is the importance of ILT4 or LILRB2 in tumor growth?
- ILT4, also known as LILRB2, is expressed on myeloid cells, including monocytes, DCs, macrophages and neutrophils. LILRB2 expressing myeloid cells promote tumor immune evasion and contribute to anti-PD1 resistance, making this a promising target to reverse myeloid-mediated immune suppression in the TME.
- IO-108 is a fully human IgG4 therapeutic antibody that binds to LILRB2 with high affinity and specificity, and blocks binding of LILRB2 to multiple cancer-relevant ligands. This blockade causes re-programming of immune suppressive myeloid cells to pro-inflammatory in the tumor microenvironment leading to the activation of T cells.
- This first-in-human, open-label Phase 1 study of IO-108 as monotherapy or in combination with pembrolizumab was designed to learn about safety, tolerability and preliminary efficacy of IO-108 as monotherapy or in combination with a PD-1 inhibitor in patients with advanced, metastatic solid tumors. The study was also designed to find a dose of IO-108 that is safe and efficacious to be tested in patients with various solid tumors.
MedicalResearch.com: What are the main findings?
a. The Phase 1 data show encouraging clinical activity and a favorable safety profile for IO-108 as a monotherapy and when combined with pembrolizumab, demonstrating the utility of IO-108 as a new therapeutic modality to address key unmet needs for patients with solid tumors that do not respond to, develop resistance to, or relapse following, treatment with T cell checkpoint inhibitors. Specifically,
- Treatment with IO-108 was well tolerated to the highest evaluated dose (1800 mg Q3W); the maximum tolerated dose was not reached.
- Among 23 evaluable patients (11 monotherapy, 12 combination therapy plus 1 crossover), results showed 1 complete response and 4 stable disease patients in the monotherapy arm and 3 partial responses and 4 stable disease patients in the combination arm.
- The 4 responding patients remain on study with an ongoing treatment duration of 8 to 12+ months as of abstract submission.
- Clinical benefit correlated with baseline characteristics and post-treatment changes in PD biomarkers including reprogramming of myeloid cells and activation of T cells.
MedicalResearch.com: What should readers take away from your report?
- The study objective of safety & tolerability has been established– treatment with IO-108 was well-tolerated to the maximum administered dose (1800 mg Q3W)
- There are early and clear signs of efficacy with durable responses observed in patients treated with both IO-108 monotherapy and in combination with pembrolizumab.
- am very encouraged by these results, particularly the complete response to IO-108 monotherapy treatment in a Merkel cell carcinoma patient who had progressed on prior anti-PD1 treatments.
- These findings suggest that LILRB2 is a critically important immunotherapy target and validate our existing myeloid cell biology research.
MedicalResearch.com: What recommendations do you have for future research as a results of this study?
a. The Phase 1 dose escalation data for IO-108 presented at AACR supports further clinical development of IO-108.
b.The preliminary recommended Phase 2 dose (RP2D) is 1200 mg Q3W which is projected to achieve full receptor occupancy in at least 90% of patients.
c. The ongoing IO-108 Phase 1 study is actively enrolling several biomarker-driven dose expansion cohorts, using RP2D of IO-108 as a monotherapy and in combination with anti-PD-1 antibodies (pembrolizumab, cemiplimab or tislelizumab), both in the U.S. and China.
MedicalResearch.com: Is there anything else you would like to add? Any disclosures?
a. Treating patients who are refractory to treatment with T-cell immune checkpoint inhibitors remains an ongoing challenge across many tumor types.
b. I am very encouraged by these results. As a clinician, I look forward to better understanding the clinical utility of IO-108 in various tumor types as the clinical development program advances.
c. I have the following relevant financial relationships to disclose:
- Consultant for: Bristol Myers Squibb, Eisai Inc, Bayer, Pfizer, Merck, Genzyme, Regeneron, Array Biopharma, Blueprint Medicines, Immune-Onc Therapeutics, Exelixis, Cascade Prodrug.
- Speaker’s Bureau for: Bristol Myers Squibb, Eisai Inc, Merck, Blueprint Medicines.
- Grant/Research support from: Bristol-Myers Squibb, Eisai, Merck, Pfizer, ISA Therapeutics, Immune-Onc, Exelixis, and Simcha Therapeutics.
AACR 2023 presentation:
Matthew H. Taylor, Manish R. Patel, John D. Powderly, Paul Woodard, Luke Chung, Hongyu Tian, Xiang Hong, Kyu Hong, Donna Valencia, Tao Huang, Xiao Min Schebye, Charlene Liao, Aung Naing; Abstract CT040: A first-in-human phase 1 trial of IO-108, an antagonist antibody targeting LILRB2 (ILT4), as monotherapy and in combination with pembrolizumab in adult patients with advanced relapsed or refractory solid tumors: Dose escalation study. Cancer Res 15 April 2023; 83 (8_Supplement): CT040. https://doi.org/10.1158/1538-7445.AM2023-CT040
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