Combining antibody-drug conjugates with immunotherapy in solid tumors: current landscape and future perspectives

Nicolò, Eleonora; Giugliano, Federica; Ascione, Liliana; Tarantino, Paolo; Corti, Chiara; Tolaney, Sara M.; Cristofanilli, Massimo; Curigliano, Giuseppe

doi:10.1016/j.ctrv.2022.102395

Cited by 104 publications

(56 citation statements)

References 96 publications

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“…Given the strong biological rationale, one of the most interesting is the combination with immunotherapy. 50 T-DXd has shown to exert immunomodulating activity, enhancing antitumor immunity and ultimately synergizing with anti-programmed death-ligand 1 (PD-L1). 51 In the BEGONIA trial, T-DXd was evaluated as first-line treatment in combination with durvalumab for patients with HR-negative/HER2-low mBC, demonstrating a promising response rate (8/12, all partial responses, 87.5% ongoing at data cutoff), with responses observed regardless of PD-L1 expression.…”

Section: Adcs In Her2-low Bcmentioning

confidence: 99%

The HER2-low revolution in breast oncology: steps forward and emerging challenges

et al. 2023

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Approximately half of breast cancers (BCs), historically categorized as human epidermal growth factor receptor 2 (HER2)-negative, have low expression of HER2 defined as an immunohistochemical (IHC) score of 1+ or 2+ with negative in situ hybridization. Retrospective evidence suggest that HER2-low BC does not represent a distinct subtype from a biological and prognostic perspective. Nonetheless, it currently constitutes an essential biomarker to guide treatment selection and its introduction has led to reconsidering the binary classification of HER2 status according to which only patients with HER2-positive BC were thought to derive benefit from anti-HER2 therapies. Trastuzumab deruxtecan has recently been approved by the U.S. Food and Drug Administration for the treatment of patients with HER2-low metastatic BC based on the results of the DESTINY-Breast04 phase III trial, and other antibody–drug conjugates (ADCs) targeting HER2 are showing promising results. Treatment paradigms for both triple-negative and hormone receptor-positive BCs exhibiting HER2-low expression are thus rapidly evolving. Given its therapeutic implications, it is essential to accurately recognize the level of HER2 expression, and the development of more sensitive and reliable methods for HER2 testing and scoring is warranted, especially since the minimum threshold of HER2 expression required for T-DXd efficacy is currently under investigation. Given the signs of activity of T-DXd even in patients with HER2-0 (IHC 0) disease, an evolution in the way we define HER2-low is anticipated. Considering the expansion of the therapeutic armamentarium for BC patients, with several ADCs approaching the clinic, research efforts are needed to clarify whether the expression level of targets can enrich for responders to a given ADC as well as to understand mechanisms of resistance with the goal of optimizing the sequencing of ADCs.

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Section: Adcs In Her2-low Bcmentioning

confidence: 99%

The HER2-low revolution in breast oncology: steps forward and emerging challenges

et al. 2023

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“…Combination therapies are also being studied to increase ADCC, assess target expression, and improve drug internalization of ADCs. An example includes a combination of ADCs and ICIs to enhance activity and ADCC [ 113 ], such as the mentioned KATE2 and KATE3/MP42319 (NCT04740918) trials combining T-DM1 and an ICI [ 91 ]. Another example is a phase 1, single-arm study (NCT03523572) that combined T-DXd with nivolumab in 52 patients with pretreated HER2+ and HER2-low breast cancer [ 114 ].…”

Section: Mechanisms Of Resistancementioning

confidence: 99%

Overcoming Resistance to HER2-Directed Therapies in Breast Cancer

Schlam

Tarantino

Tolaney

2022

Cancers

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Human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for around 15% of all breast cancers and was historically associated with a worse prognosis compared with other breast cancer subtypes. With the development of HER2-directed therapies, the outcomes of patients with HER2-positive disease have improved dramatically; however, many patients present with de novo or acquired resistance to these therapies, which leads to early recurrences or progression of advanced disease. In this narrative review, we discuss the mechanisms of resistance to different HER2-targeted therapies, including monoclonal antibodies, small tyrosine kinase inhibitors, and antibody-drug conjugates. We review mechanisms such as impaired binding to HER2, incomplete receptor inhibition, increased signaling from other receptors, cross-talk with estrogen receptors, and PIK3CA pathway activation. We also discuss the role of the tumor immune microenvironment and HER2-heterogeneity, and the unique mechanisms of resistance to novel antibody-drug conjugates. A better understanding of these mechanisms and the potential strategies to overcome them will allow us to continue improving outcomes for patients with breast cancer.

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“…To better characterize this phenomenon in mAb and target specific scenarios, the expression of the glycoepitope should be carefully monitored following the treatment in pre-clinical models and during clinical trials whenever possible. Furthermore, a potential therapeutic approach to circumvent this problem could be to combine the ADC treatment with other therapies, such as immunotherapies, to help eradicate cells negative for the ADC-glycoepitope [131]. In this regard, it is intriguing that preclinical studies with the PODO447-ADC targeting Podxl have shown that residual tumors remaining after ADC treatment fail to express the Podxl polypeptide rather than maintaining its expression and simply altering its glycosylation [100].…”

Section: Discussionmentioning

confidence: 99%

Antibody-Drug Conjugates Targeting Tumor-Specific Mucin Glycoepitopes

Brassard¹,

Hughes²,

Roskelley³

et al. 2022

Front. Biosci. (Landmark Ed)

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Finding the ideal epitope to target is a key element for the development of an antibody-drug conjugate (ADC). To maximize drug delivery to tumor cells and reduce side effects, this epitope should be specific to cancer cells and spare all normal tissue. During cancer progression, glycosylation pathways are frequently altered leading to the generation of new glycosylation patterns selective to cancer cells. Mucins are highly glycosylated proteins frequently expressed on tumors and, thus, ideal presenters of altered glycoepitopes. In this review, we describe three different types of glycoepitopes that are recognized by monoclonal antibodies (mAb) and, therefore, serve as ideal scaffolds for ADC; glycan-only, glycopeptide and shielded-peptide glycoepitopes. We review pre-clinical and clinical results obtained with ADCs targeting glycoepitopes expressed on MUC1 or podocalyxin (Podxl) and two mAbs targeting glycoepitopes expressed on MUC16 or MUC5AC as potential candidates for ADC development. Finally, we discuss current limits in using glycoepitope-targeting ADCs to treat cancer and propose methods to improve their efficacy and specificity.

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Combining antibody-drug conjugates with immunotherapy in solid tumors: current landscape and future perspectives

Cited by 104 publications

References 96 publications

The HER2-low revolution in breast oncology: steps forward and emerging challenges

The HER2-low revolution in breast oncology: steps forward and emerging challenges

Overcoming Resistance to HER2-Directed Therapies in Breast Cancer

Antibody-Drug Conjugates Targeting Tumor-Specific Mucin Glycoepitopes

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