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Published on: November 11, 2016
Epigenetic Reprogramming Potentiates ICAM1 Antibody Drug Conjugates in Preclinical Models of Melanoma
Peng Zhang1,2,3, Changjuan Tao4,5, Ye Lu3
1Department of Medical Oncology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, 310022, China.
Abstract:
Therapeutic benefits and underlying biomechanism(s) of antibody drug conjugates (ADC) in combination with other targeted therapeutics are largely unknown. Here, the synergy between ADC and epigenetic drug decitabine (DAC), a clinically approved DNA methylation inhibitor, in multiple preclinical models of melanoma specifically investigated. Mechanistically, the underlying biomechanisms of how DAC cooperatively worked with ICAM1 antibody conjugated DNA topoisomerase I inhibitor DXd (I1-DXd) is elucidated. DAC treatment significantly enhanced anti-tumor efficacy of I1-DXd by upregulating antigen expression, enhancing antibody internalization and potentiating tumor sensitivity by epigenetically reprogramming of melanoma. Meanwhile, I1-DXd/DAC combination also exerted regulatory effects on tumor microenvironment (TME) by enhancing tumor infiltration of innate and adaptive immune cells and improving penetration of ADCs with a boosted antitumor immunity. This study provides a rational ADC combination strategy for solid tumor treatment.
Insights
This study reveals that combining antibody drug conjugates (ADCs) with decitabine (DAC) enhances melanoma treatment by improving drug delivery and boosting antitumor immunity. This combination therapy offers a promising strategy for solid tumors.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Antibody drug conjugates (ADCs) are effective targeted therapies, but their combination with other agents requires further investigation.
- The synergistic mechanisms between ADCs and epigenetic drugs like decitabine (DAC) in melanoma are not well understood.
Purpose of the Study:
- To investigate the therapeutic synergy between ADCs and decitabine (DAC) in preclinical melanoma models.
- To elucidate the underlying biomechanisms of DAC's cooperation with ICAM1-targeted ADC (I1-DXd).
Main Methods:
- Utilized multiple preclinical melanoma models.
- Investigated the effects of DAC combined with I1-DXd on antigen expression, antibody internalization, and tumor sensitivity.
- Analyzed the impact on the tumor microenvironment (TME) and immune cell infiltration.
Main Results:
- Decitabine (DAC) significantly enhanced the anti-tumor efficacy of I1-DXd.
- DAC upregulated antigen expression, improved antibody internalization, and increased tumor sensitivity via epigenetic reprogramming.
- The combination therapy modulated the TME, enhancing immune cell infiltration and ADC penetration, leading to boosted antitumor immunity.
Conclusions:
- Decitabine (DAC) synergizes with antibody drug conjugates (ADCs) like I1-DXd in melanoma by enhancing drug delivery and immune response.
- This combination represents a rational therapeutic strategy for solid tumors, particularly melanoma.
- Epigenetic reprogramming by DAC is a key mechanism driving the enhanced efficacy of ADC combination therapy.
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