Uterine cancers, which largely comprise endometrial cancer and uterine sarcoma, are a considerable health concern affecting women worldwide. The prognosis for patients with advanced or recurrent uterine cancer is still poor, despite recent improvements in our understanding of the biology of uterine cancer and the development of novel treatment approaches.
In recent years, novel treatment approaches such as immunotherapy for microsatellite-instable tumors and a combination of immunotherapy and antiangiogenic agents for microsatellite-stable tumors have improved dramatically . Using antibody-drug conjugates (ADCs) is one potential strategy that has surfaced recently. By combining the specificity of monoclonal antibodies with the cytotoxic power of chemotherapeutic drugs, these cutting-edge therapeutic agents open up a new treatment option for uterine cancer .
Understanding antibody-drug conjugates
ADCs are a relatively novel class of anticancer agents that consist of three main components:
Cytotoxic payload (chemotherapeutic drug).
ADCs are frequently referred to as the “Trojan Horses” of the therapeutic arsenal, because of their potential to deliver cytotoxic payloads into the tumor region, thus renovating chemotherapy into targeted therapy. The monoclonal antibody delivers the medication right to the tumor site by selectively identifying and attaching to particular antigens expressed on the surface of cancer cells. The linker, which joins the antibody with the drug, is made to be stable outside of the target cancer cell but unstable inside of it. Once the ADC is internalized inside the cancer cell, the linker is cleaved, releasing the cytotoxic drug to cause cell death .
Clinical developments and success stories
Although the use of ADCs in the treatment of uterine cancer is still in its infancy, there have been major developments and promising outcomes in preclinical and clinical trials. The safety and effectiveness of ADCs in treating uterine cancer are now the subject of numerous trials. Preclinical research has demonstrated that the ADC trastuzumab emtansine (T-DM1) is more effective in uterine carcinomas and sarcomas than either trastuzumab alone or the combination of trastuzumab and pertuzumab .
Trastuzumab duocarmazine (SYD985), another ADC that targets HER2, has been studied in endometrial cancer. Trastuzumab duocarmazine combines trastuzumab with the toxic payload duocarmycin through a cleavable linker. The "bystander killing effect" results from the linker being broken down by tumor proteases and the release of the membrane-permeable active toxin. This results in the death of nearby non-antigen-expressing tumor cells in addition to the HER2-positive cells .
In vitro and in vivo studies showed that trastuzumab duocarmazine has greater anticancer activity against carcinosarcoma cell lines as well as xenografts. In the phase II clinical trial (NCT04205630), trastuzumab duocarmazine is currently being assessed as a single agent in patients with HER2-positive endometrial cancer that has progressed after receiving first-line platinum-based chemotherapy .
In phase I and II clinical studies, another ADC known as mirvetuximab soravtansine has demonstrated promising outcomes for the treatment of folate receptor alpha-positive (FRα+) endometrial cancer. The FRα antibody precisely targets and attaches to cancer cells expressing the FRα protein, directly delivering the cytotoxic drug to the tumor site. This targeted therapy has exhibited substantial anti-tumor activity and a manageable safety profile .
In an open-label, phase II study the clinical efficacy of sacituzumab govitecan is being assessed in subjects with persistent or recurrent endometrial carcinoma (ClinicalTrials.gov Identifier: NCT04251416). A humanized anti-Trop2 antibody called sacituzumab govitecan is linked to the active irinotecan metabolite (SN-38) via a cleavable linker. This drug is currently being studied in serous and endometroid endometrial cancer, because of the encouraging outcomes seen in breast and bladder cancer.
Furthermore, ongoing investigations aim to recognize additional target antigens expressed by uterine cancer cells. This may encourage further development of more effective ADCs. By expanding the array of targeted antigens, researchers can expand the accuracy and effectiveness of ADC therapy, eventually benefiting patients with uterine cancers .
Advantages of antibody-drug conjugates in uterine cancer treatment
ADC offers the following advantages in uterine cancer patients to improve treatment outcomes:
A targeted approach to ADCs can reduce the side effects of conventional chemotherapy and damage to healthy cells. ADC selectively delivers the cytotoxic drug to cancer cells and reduces systemic toxicity.
ADCs are a combination of a highly specific antibody and a potent cytotoxic drug that helps ADCs to efficiently target and eliminate cancer cells. This approach improves response rates and reduces the risk of tumor resistance, a substantial challenge in cancer treatment.
ADCs can be designed to target particular antigens that are overexpressed on uterine cancer cells. This creates prospects for personalized medicine, where treatment plans can be customized to individual patients based on their specific tumor characteristics, resulting in enhanced outcomes.
ADCs can be used as a part of combination therapies. They can be used in conjunction with other therapeutic modalities like chemotherapy, radiation therapy, or immunotherapy to provide synergistic effects that improve the effectiveness of the entire course of treatment [3,4].
The introduction of antibody-drug conjugates signifies a substantial breakthrough in cancer treatment, offering a personalized and targeted approach for patients with uterine cancers. These cutting-edge therapeutic agents could improve patient outcomes, reduce systemic toxicity, and open the door to more potent combination therapies. The early success stories of ADCs in clinical trials encourage the future of uterine cancer treatment even though the area is still developing.
1. Filippova, O. et al. 'The current clinical approach to newly diagnosed uterine cancer'. Expert Rev Anticancer Ther. (2020) 20(7), 581–590. DOI: 10.1080/14737140.2020.1782750.
2. Criscitiello, C. et al. 'Antibody–drug conjugates in solid tumors: a look into novel targets'. Journal of Hematology & Oncology. (2021) 14(1), 20. DOI: 10.1186/s13045-021-01035-z.
3. Nerone, M. et al. 'Advancing antibody-drug conjugates in gynecological malignancies: myth or reality?'. Explor Target Antitumor Ther. (2022) 3(2), 149–171. DOI: 10.37349/etat.2022.00077.
4. Tolcher, A. et al. 'The evolving landscape of antibody-drug conjugates in gynecologic cancers'. Cancer Treatment Reviews. (2023) 116. DOI: 10.1016/j.ctrv.2023.102546.