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:

Dr. Taylor

Matthew H. Taylor, MD
Earle A. Chiles Research Institute
Providence Cancer Institute
Portland, OR

MedicalResearch.com: What is the background for this study? What is the importance of ILT4 or LILRB2 in tumor growth?

1. 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.
2. 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.
3. 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,

1. 1. Treatment with IO-108 was well tolerated to the highest evaluated dose (1800 mg Q3W); the maximum tolerated dose was not reached.
   2. 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.
   3. The 4 responding patients remain on study with an ongoing treatment duration of 8 to 12+ months as of abstract submission.
   4. 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?

1. The study objective of safety & tolerability has been established– treatment with IO-108 was well-tolerated to the maximum administered dose (1800 mg Q3W)
2. 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.
3. 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.
4. 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:

1. 1. Consultant for: Bristol Myers Squibb, Eisai Inc, Bayer, Pfizer, Merck, Genzyme, Regeneron, Array Biopharma, Blueprint Medicines, Immune-Onc Therapeutics, Exelixis, Cascade Prodrug.
   2. Speaker’s Bureau for: Bristol Myers Squibb, Eisai Inc, Merck, Blueprint Medicines.
   3. Grant/Research support from: Bristol-Myers Squibb, Eisai, Merck, Pfizer, ISA Therapeutics, Immune-Onc, Exelixis, and Simcha Therapeutics.

Citation:

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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Last Updated on April 18, 2023 by