RE:RE:RE:Resistance to ADCs in the treatment of solid tumors ADCs are composed of an antibody linked to a chemotherapy payload, allowing targeted delivery of the chemotherapy. In the last decade, several antibody–drug conjugates have improved treatment options in breast cancer. However, patients usually progress on these agents.
Trastuzumab emtansine, known as T-DM1, was the first antibody–drug conjugate approved for use in breast cancer.
The next antibody–drug conjugate approved for use in breast cancer was sacituzumab govitecan (SG), composed of a monoclonal antibody targeting TROP-2 that is connected via a cleavable linker to SN-38, an irinotecan metabolite.
Finally, trastuzumab deruxtecan (T-DXd) was most recently the second antibody–drug conjugate approved for use in HER2+ advanced breast cancer and has also defined a new class of “HER2-low” disease.
Potential mechanisms of resistance can be categorized based on the complex structure of antibody-drug conjugates. Given the complexity of ADCs, resistance mechanisms have been described or suggested targeting different components of the ADC. Mechanisms involving decreased antigen expression, decreased ADC trafficking and processing, resistance to the cytotoxic payload, and the increased efflux of the agent out of the cell.
Consequently, ADCs have already been approved in hematology and clinical oncology, such as the above trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan (SG) for the treatment of both estrogen failed and metastatic breast cancer, and enfortumab vedotin (EV) for the treatment of urothelial carcinoma. And has been referenced, the efficacy of ADCs is limited by the emergence of resistance due to antigen-related resistance, failure of internalization, impaired lysosomal function, and other mechanisms. Research is underway overcome this resistance, by using already registered regiems such as bispecific ADCs and the combination of ADCs with immune-checkpoint inhibitors. With the addition of pelareorep, and with the subsequent approval of pelareorep by the FDA, the issues of ADC resistance and T-cell exhaustion, has a much higher probability of being overcome, and the effectiveness of therapy could be further enhanced through the synergistic addition of immune checkpoint inhibitors, to the ADC + pelareorep combination.