Bladder cancer remains a leading cause of cancer death worldwide and is associated with substantial impacts on patient quality of life, morbidity, mortality, and cost to the healthcare system. Gross hematuria frequently precedes the diagnosis of bladder cancer. Non-muscle-invasive bladder cancer (NMIBC) is managed initially with transurethral resection of a bladder tumor (TURBT), followed by a risk stratified approach to adjuvant intravesical therapy (IVe), and is associated with an overall survival of 90%. However, cure rates remain lower for muscle invasive bladder cancer (MIBC) owing to a variety of factors. NMIBC and MIBC groupings are heterogeneous and have unique pathological and molecular characteristics. Indeed, The Cancer Genome Atlas project identified genetic drivers and luminal and basal molecular subtypes of MIBC with distinct treatment responses. For NMIBC, IVe immunotherapy (primarily BCG) is the gold standard treatment for high grade and high risk NMIBC to reduce or prevent both recurrence and progression after initial TURBT; novel trials incorporate immune checkpoint inhibitors. IVe gene therapy and combination IVe chemotherapy have recently been completed, with promising results. For localized MIBC, essential goals are improving care and reducing morbidity following cystectomy or bladder preserving strategies. In metastatic disease, advances in understanding of the genomic landscape and tumor microenvironment have led to the implementation of immune checkpoint inhibitors, targeted treatments, and antibody-drug conjugates. Defining better selection criteria to identify the patients most likely to benefit from a specific treatment is an urgent need.

Advances in diagnosis and treatment of bladder cancer.

The treatment of cancer patients has dramatically changed over the past decades with the advent of monoclonal antibodies, immune-checkpoint inhibitors, bispecific antibodies, and innovative T-cell therapy. Antibody-drug conjugates (ADCs) have also revolutionized the treatment of cancer. Several ADCs have already been approved in hematology and clinical oncology, such as trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan (SG) for the treatment of metastatic breast cancer, and enfortumab vedotin (EV) for the treatment of urothelial carcinoma. The efficacy of ADCs is limited by the emergence of resistance due to different mechanisms, such as antigen-related resistance, failure of internalization, impaired lysosomal function, and other mechanisms. In this review, we summarize the clinical data that contributed to the approval of T-DM1, T-DXd, SG, and EV. We also discuss the different mechanisms of resistance to ADCs, as well as the ways to overcome this resistance, such as bispecific ADCs and the combination of ADCs with immune-checkpoint inhibitors or tyrosine-kinase inhibitors.

/pdf/mechanisms-of-resistance-to-antibody-drug-conjugates-6qtya9rv.pdf

Mechanisms of Resistance to Antibody-Drug Conjugates

Understanding the activity of antibody–drug conjugates in primary and secondary brain tumours

Simple Summary A rapidly emerging new approach to treat cancer involves collection of patient immune white blood cells and genetic re-programming of the cells to express a new cancer-detecting receptor called a CAR. This approach has revolutionized the treatment of some blood cancers, whereas solid tumours, which account for 90% of all cancers, are proving much more difficult to treat using this approach. A major challenge in this respect relates to the identification of targets that differentiate cancer from healthy cells. In a partner review, we consider clinical data already collected when CAR technology has been applied against solid tumours that express 30 different targets. Here, we explore emerging candidates for which such clinical data are not available yet, but where other data provide information about potential suitability as future clinical targets. Abstract Immunotherapy with CAR T-cells has revolutionised the treatment of B-cell and plasma cell-derived cancers. However, solid tumours present a much greater challenge for treatment using CAR-engineered immune cells. In a partner review, we have surveyed data generated in clinical trials in which patients with solid tumours that expressed any of 30 discrete targets were treated with CAR-based immunotherapy. That exercise confirms that efficacy of this approach falls well behind that seen in haematological malignancies, while significant toxic events have also been reported. Here, we consider approximately 60 additional candidates for which such clinical data are not available yet, but where pre-clinical data have provided support for their advancement to clinical evaluation as CAR target antigens.

https://www.mdpi.com/2072-6694/15/4/1171/pdf?version=1677028855

CAR-Based Immunotherapy of Solid Tumours—A Survey of the Emerging Targets

Antibody-drug conjugates (ADCs) represent a cornerstone in the treatment of many cancers nowadays. ADCs fulfill their function by binding a target on tumor cell membrane to deliver a cytotoxic payload; in addition, those moieties capable of crossing cancer cell membranes can achieve near-by cells that do not express the target antigen, exerting the so-called "bystander" cytotoxic effect. The presence of a specific target antigen expressed on cancer cells has been for long considered crucial for ADCs and commonly required for the inclusion of patients in clinical trials with ADCs. To date, only ado-trastuzumab-emtansine, fam-trastuzumab deruxtecan-nxki, and mirvetuximab soravtansine-gynx are approved according to the expression of a target antigen in solid tumors, while the clinical use of other ADCs (eg, sacituzumab govitecan) is not conditioned by the presence of a specific biomarker. Given the ever-growing number of approved ADCs and those under investigation, it is essential to find new biomarkers to guide their use, especially in those settings for which different ADCs are approved to establish the best therapeutic sequence based on robust biomarkers. Hence, this work addresses the role of target antigens in predicting response to ADCs, focusing on examples of antigens' targetability according to their expression on cancer cells' surface or to the presence of specific target aberrations (eg, mutation or over-expression). New methods for the assessment and quantification of targets' expression, like molecular imaging and in vitro assays, might be key tools to improve biomarker analysis and eventually deliver better outcomes by refined patient selection.

Predicting Response to Antibody Drug Conjugates: A Focus on Antigens' Targetability.

Abstract Purpose: The antibody–drug conjugate enfortumab vedotin (EV) releases a cytotoxic agent into tumor cells via binding to the membrane receptor NECTIN-4. EV was recently approved for patients with metastatic urothelial carcinoma (mUC) without prior assessment of the tumor receptor status as ubiquitous NECTIN-4 expression is assumed. Our objective was to determine the prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET). Experimental Design: Membranous NECTIN-4 protein expression was measured (H-score) by IHC in PRIM and corresponding MET (N = 137) and in a multicenter EV-treated cohort (N = 47). Progression-free survival (PFS) after initiation of EV treatment was assessed for the NECTIN-4–negative/weak (H-score 0–99) versus moderate/strong (H-score 100–300) subgroup. The specificity of the NECTIN-4 IHC staining protocol was validated by establishing CRISPR-Cas9–induced polyclonal NECTIN-4 knockouts. Results: In our cohort, membranous NECTIN-4 expression significantly decreased during metastatic spread (Wilcoxon matched pairs P < 0.001; median H-score = 40; interquartile range, 0–140), with 39.4% of MET lacking membranous NECTIN-4 expression. In our multicenter EV cohort, absence or weak membranous NECTIN-4 expression (34.0% of the cohort) was associated with a significantly shortened PFS on EV (log-rank P < 0.001). Conclusions: Membranous NECTIN-4 expression is frequently decreased or absent in mUC tissue. Of note, the clinical benefit of EV strongly depends on membranous NECTIN-4 expression. Thus, our results are of highest clinical relevance and argue for a critical reconsideration of the current practice and suggest that the NECTIN-4 receptor status should be determined (ideally in a metastatic/progressive lesion) before initiation of EV. See related commentary by Aggen et al., p. 1377

https://aacrjournals.org/clincancerres/article-pdf/doi/10.1158/1078-0432.CCR-22-1764/3260061/ccr-22-1764.pdf

Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance

Introduction A proportion of patients affected by advanced head and neck squamous cell carcinoma suffer from an inadequate response to targeted therapies. Examination of the underlying processes requires scientific methods addressing the complexity and heterogeneity of this tumor entity. Due to the immature specific immune system the Hen’s Egg Test on Chorioallantoic Membrane (so-called CAM assay) allows xenotransplantation of foreign cells and tissues to identify resistance mechanisms and adaptation processes. 

Examination of three-dimensional xenografts derived from HNSCC and Melanoma cell lines deploying the CAM assay

Establishment Of A Chick Chorioallantoic Membrane (CAM) Assay-Based Patient-Derived 3D In-Vivo Tumor Model For Pre-Clinical Testing Of Novel Therapeutic Approaches In Ovarian Cancer

Introduction Systemic treatment of head and neck squamous cell carcinoma (HNSCC) is based on chemotherapy, anti-PD-1 immunotherapy and EGFR inhibition. New targeted therapies with antibody-drug conjugates (ADC) have improved progression-free and overall survival in other oncological entities, such as the ADC sacituzumab govitecan (SG) directed against the cell surface antigen TROP2 in metastatic triple-negative breast cancer. There is evidence that HNSCC tumors express TROP2 and other ADC targets. 

Targeted therapy with the antibody-drug conjugate sacituzumab-govitecan as a promising treatment strategy for head and neck squamous cell carcinoma

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Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance

Examination of three-dimensional xenografts derived from HNSCC and Melanoma cell lines deploying the CAM assay

Establishment Of A Chick Chorioallantoic Membrane (CAM) Assay-Based Patient-Derived 3D In-Vivo Tumor Model For Pre-Clinical Testing Of Novel Therapeutic Approaches In Ovarian Cancer

Targeted therapy with the antibody-drug conjugate sacituzumab-govitecan as a promising treatment strategy for head and neck squamous cell carcinoma