Editorial: Antibody-drug Conjugates in Solid and Hematologic Malignancies

Khalil Saleh^1*Ayush Raman²Michele Zanoni^3*

• ¹International Department, Gustave Roussy Cancer Campus, Villejuif, France
• ²National Cancer Institute, NIH, Bethesda, United States
• ³Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy

The therapeutic landscape of hematological and solid tumors underwent to a profound improvement over the last decades, marked by the advent of immunotherapies such as immune checkpoint inhibitors in solid tumors and lymphomas, as well as adoptive T-cell therapies like chimeric antigen receptor (CAR) T-cells and bispecific antibodies. As part of this revolution, antibody-drug conjugates (ADCs) have rapidly emerged as a novel class of therapeutic agents that combine the specificity of monoclonal antibodies with the cytotoxic potential of chemotherapeutic drugs covalently bonded with an engineered chemical linker (1). This approach allows precise delivery of cytotoxic drugs to cancer cells taking advances of the antibody's specificity for target antigens, thus minimizing systemic toxicity (2).More than 200 ADCs are currently in different stages of clinical trials, with 15 approvals already granted in 2024 in multiple solid tumors including breast, gynecological, and urothelial cancers, as well as hematologic malignancies (3)(4)(5)(6)(7). Despite ADCs hold great promise in cancer treatment, the mechanisms underlying their activity remain still not fully understood. In addition, the clinical efficacy of these agents is often limited by the emergence of acquired resistance and by the poor characterization of their interactions with the tumor microenvironment (TME) constituting a critical barrier to the full realization of their therapeutic potential. This Research Topic includes two reviews and three research articles that examine the mechanisms of action and resistance of several approved or under development ADCs. Furthermore, they discuss the potential interactions between ADCs and the TME, 32 as well as predictive factors influencing treatment response. Long et al. made an overview of the 33 structural components and functional variations of ADCs, detailing how antibody specificity, linker 34 stability, and payload potency are essential to efficacy. This work also introduces the next-generation 35 ADCs, including bispecific ADCs, probody-drug conjugates, immune-stimulating antibody-drug 36 conjugates (ISACs), degrader-antibody conjugates (DACs), and dual-payload ADCs. These novel 37 designs allow to improve tumor selectivity, payload release, and immunomodulatory activity, thereby 38 addressing limitations inherent to first-generation ADCs. Finally, the authors also emphasize the 39 challenges of off-target effects and systemic toxicities, which remain one of the major issues despite 40 the improved precision of newer ADCs. This critical point is further discussed by the clinical 41 observations of O'Sullivan et al., who reported the development of hepatopulmonary syndrome (HPS) 42 as a novel adverse effect during prolonged treatment with ado-trastuzumab emtansine (T-DM1) in 43 patients with HER2-positive breast cancer. In this case series, four patients who had received long-44 term treatment with T-DM1 developed hypoxemia and portal hypertension, consistent with HPS, a 45 condition that previously was never associated with ADCs. These findings emphasize the necessity for 46 continuous surveillance and long-term toxicity assessments to chronic exposure to ADCs for the 47 discovery of latent and less common toxicities not revealed during initial clinical trials. Parallel to 48 concerns about safety, ADCs have shown to be effective in the treatment of tumors refractory to 49 chemotherapy. In a case report of Xue Song and colleagues described the rapid and complete remission 50 achieved with gemtuzumab-ozogamicin (GO) in a pediatric patient with refractory systemic 51 mastocytosis and AML::ETO-positive AML. This case highlighted the therapeutic value of GO as an 52 effective salvage therapy in pediatric patients with rare and refractory hematologic malignancies 53 supporting also further clinical explorations of ADCs in rare and high-risk settings. These data suggest 54 that ADCs are emerging as a promising strategy for the treatment of patients who develop resistance 55 to standard therapies. In bladder cancer, known for its high recurrence and limited treatment response, 56ADCs have demonstrated a remarkable efficacy. In the review article of Zhang F et al., the authors 57 discussed key advances in urothelial carcinoma, with a particular focus on the clinical impact of 58 enfortumab vedotin (targeting NECTIN-4) and sacituzumab govitecan (targeting TROP-2), which have 59 profoundly changed outcomes in patients unresponsive to chemotherapy or immunotherapy. 60Enfortumab vedotin has dramatically changed the treatment landscape of patients with metastatic 61 urothelial carcinoma in combination with pembrolizumab, a programed-death 1 inhibitor, in a 62 chemotherapy-free regimen that dethroned after several decades platinum-based chemotherapy in the TROPiCS-04 trial, the FDA and Gilead withdrawn the approval of sacituzumab govitecan in urothelial 65 carcinoma (9). Furthermore, a potential step forward consists in the integration of ADCs with immune 66 checkpoint inhibitors. Nevertheless, authors report that still several challenges need to be addressed. 67These include off-target toxicities, antigen heterogeneity, and the need for better patient selection. The 68 future of ADCs design and optimization lies in refining their components, enhancing target specificity, 69 and aligning therapies with predictive biomarkers. Despite the expression of the specific target antigen 70 remains the primary selection criterion for ADC use, its predictive value is often imperfect. Indeed, 71 response to ADC treatment remains heterogeneous, with some patients expressing high levels of the 72 target antigen showing limited benefit, while others with lower expression levels experience significant 73 responses. In a case report of Feng H et al, a woman with HER2-low metastatic clear-cell endometrial 74 carcinoma who underwent relapse after surgery, chemotherapy, and radiotherapy, showed a complete 75 response to the HER2-targeting ADC disitamab vedotin. This data suggests that also HER2-low 76 endometrial cancers, usually considered ineligible for anti-HER2-targeted therapies, may benefit from 77 ADC approaches. These results underscore the need for more sophisticated biomarker models that 78 might incorporate, for example, antigen density and internalization efficiency. Furthermore, novel 79 approaches of spatial and molecular profiling of tumors, along with liquid biopsy, may offer promising 80 tools to stratify patients and personalize ADC therapy. In conclusion, this Research Topic offers a 81 comprehensive overview of ADCs as a powerful modality in the treatment of both solid and 82 hematologic malignancies that combine the precision of targeted therapies with the potency of 83 cytotoxic drugs. However, significant challenges remain to be investigate in order to fully unlock the 84 potential of ADCs in cancer therapy.