Optimizing the safety of antibody-drug conjugates for patients with solid tumours
Paolo Tarantino1,2,3,4, Biagio Ricciuti3,5, Shan M Pradhan6
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Abstract:
Over the past 5 years, improvements in the design of antibody-drug conjugates (ADCs) have enabled major advances that have reshaped the treatment of several advanced-stage solid tumours. Considering the intended rationale behind the design of ADCs, which is to achieve targeted delivery of cytotoxic molecules by linking them to antibodies targeting tumour-specific antigens, ADCs would be expected to be less toxic than conventional chemotherapy. However, most ADCs are still burdened by off-target toxicities that resemble those of the cytotoxic payload as well as on-target toxicities and other poorly understood and potentially life-threatening adverse effects. Given the rapid expansion in the clinical indications of ADCs, including use in curative settings and various combinations, extensive efforts are ongoing to improve their safety. Approaches currently being pursued include clinical trials optimizing the dose and treatment schedule, modifications of each ADC component, identification of predictive biomarkers for toxicities, and the development of innovative diagnostic tools. In this Review, we describe the determinants of the toxicities of ADCs in patients with solid tumours, highlighting key strategies that are expected to improve tolerability and enable improvements in the treatment outcomes of patients with advanced-stage and those with early stage cancers in the years to come.
Insights
Antibody-drug conjugates (ADCs) offer targeted cancer therapy but face toxicity challenges. Ongoing research focuses on improving ADC safety and efficacy for solid tumors in both early and advanced stages.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Antibody-drug conjugates (ADCs) have revolutionized solid tumor treatment over the past five years.
- ADCs are designed for targeted delivery of cytotoxic payloads to tumor cells via tumor-specific antigens.
- Despite their targeted nature, ADCs exhibit significant off-target and on-target toxicities, alongside other adverse effects.
Purpose of the Study:
- To review the determinants of ADC toxicities in patients with solid tumors.
- To highlight strategies for improving ADC tolerability and treatment outcomes.
- To discuss the application of ADCs in both early and advanced-stage cancers.
Main Methods:
- Review of current literature on ADC design and clinical applications.
- Analysis of factors contributing to ADC-related toxicities.
- Examination of ongoing research and clinical trials for safety improvements.
Main Results:
- Improvements in ADC design have led to significant advances in treating advanced solid tumors.
- Toxicities associated with ADCs include payload-related effects, on-target toxicities, and poorly understood adverse events.
- Current strategies to enhance ADC safety involve dose/schedule optimization, component modification, biomarker identification, and advanced diagnostics.
Conclusions:
- Addressing ADC toxicities is crucial for expanding their clinical use, including in curative settings and combination therapies.
- Improved tolerability of ADCs is expected to enhance treatment outcomes for patients with early and advanced-stage solid tumors.
- Continued research into ADC safety and efficacy will shape future cancer treatment paradigms.
More Related Videos
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...