Therapeutic Potential of Antibody-Drug Conjugate-Based Therapy in Head and Neck Cancer: A Systematic Review

Perrotti, Vittoria; Caponio, Vito Carlo Alberto; Mascitti, Marco; Muzio, Lorenzo Lo; Piattelli, Adriano; Rubini, Corrado; Capone, Emily; Sala, Gianluca

doi:10.3390/cancers13133126

Cited by 17 publications

(15 citation statements)

References 111 publications

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“…Similarly, ADCs targeting different surface markers (EGFR, c-MET, HER2, etc.) conjugated to the PBD toxin or the microtubule inhibitor Auristatin, did not progress due to toxicity concerns [ 14 ]. Only the EGFR inhibitor cetuximab and the PD-1/PD-L1 immune checkpoint inhibitors pembrolizumab, nivolumab, and durvalumab, improve survival in recurrent or metastatic HNSCC [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

“…In fact, immunotoxin translation to the clinic has been jeopardized by severe off-target toxicities, especially because of their high immunogenicity and reduced targeting capacity, which limits their long-term use in patients [ 12 , 13 ]. On the other hand, different ADCs have also been tested for the treatment of HNSCC, such as ABBV-321, an EGFR-targeting antibody conjugated to a pyrrolobenzodiazepine (PBD) dimer cytotoxic molecule [ 14 ]. Nevertheless, ADCs present important drug leakage during circulation, also limiting their clinical use [ 15 – 17 ].…”

Section: Introductionmentioning

confidence: 99%

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CXCR4-targeted nanotoxins induce GSDME-dependent pyroptosis in head and neck squamous cell carcinoma

Rioja-Blanco

Arroyo‐Solera

Álamo

et al. 2022

J Exp Clin Cancer Res

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Background Therapy resistance, which leads to the development of loco-regional relapses and distant metastases after treatment, constitutes one of the major problems that head and neck squamous cell carcinoma (HNSCC) patients currently face. Thus, novel therapeutic strategies are urgently needed. Targeted drug delivery to the chemokine receptor 4 (CXCR4) represents a promising approach for HNSCC management. In this context, we have developed the self-assembling protein nanotoxins T22-PE24-H6 and T22-DITOX-H6, which incorporate the de-immunized catalytic domain of Pseudomonas aeruginosa (PE24) exotoxin A and the diphtheria exotoxin (DITOX) domain, respectively. Both nanotoxins contain the T22 peptide ligand to specifically target CXCR4-overexpressing HNSCC cells. In this study, we evaluate the potential use of T22-PE24-H6 and T22-DITOX-H6 nanotoxins for the treatment of HNSCC. Methods T22-PE24-H6 and T22-DITOX-H6 CXCR4-dependent cytotoxic effect was evaluated in vitro in two different HNSCC cell lines. Both nanotoxins cell death mechanisms were assessed in HNSCC cell lines by phase-contrast microscopy, AnnexinV/ propidium iodide (PI) staining, lactate dehydrogenase (LDH) release assays, and western blotting. Nanotoxins antitumor effect in vivo was studied in a CXCR4+ HNSCC subcutaneous mouse model. Immunohistochemistry, histopathology, and toxicity analyses were used to evaluate both nanotoxins antitumor effect and possible treatment toxicity. GSMDE and CXCR4 expression in HNSCC patient tumor samples was also assessed by immunohistochemical staining. Results First, we found that both nanotoxins exhibit a potent CXCR4-dependent cytotoxic effect in vitro. Importantly, nanotoxin treatment triggered caspase-3/Gasdermin E (GSDME)-mediated pyroptosis. The activation of this alternative cell death pathway that differs from traditional apoptosis, becomes a promising strategy to bypass therapy resistance. In addition, T22-PE24-H6 and T22-DITOX-H6 displayed a potent antitumor effect in the absence of systemic toxicity in a CXCR4+ subcutaneous HNSCC mouse model. Lastly, GSDME was found to be overexpressed in tumor tissue from HNSCC patients, highlighting the relevance of this strategy. Conclusions Altogether, our results show that T22-PE24-H6 and T22-DITOX-H6 represent a promising therapy for HNSCC patients. Remarkably, this is the first study showing that both nanotoxins are capable of activating caspase-3/GSDME-dependent pyroptosis, opening a novel avenue for HNSCC treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CXCR4-targeted nanotoxins induce GSDME-dependent pyroptosis in head and neck squamous cell carcinoma

Rioja-Blanco

Arroyo‐Solera

Álamo

et al. 2022

J Exp Clin Cancer Res

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“…Those components are connected using a linker with a specific binding ability (summarized in [ 28 ]). Currently, ADCs are investigated in head & neck cancer (e.g., Trastuzumab Deruxtecan—target: HER2; Losatuxizumab vedotin—target: EGFR) (summarized in [ 29 ]). Another ADC that is currently analyzed in head & neck squamous cell carcinoma is Sacituzumab Govitecan-hziy, which targets Trop-2 [ 26 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…Currently, ADCs are investigated in head & neck cancer (e.g., Trastuzumab Deruxtecan—target: HER2; Losatuxizumab vedotin—target: EGFR) (summarized in [ 29 ]). Another ADC that is currently analyzed in head & neck squamous cell carcinoma is Sacituzumab Govitecan-hziy, which targets Trop-2 [ 26 , 29 ]. Future clinical studies have to investigate whether this Trop-2 ADC can add any benefit to the current standard of care.…”

Section: Discussionmentioning

confidence: 99%

Impact of Spatially Heterogeneous Trop-2 Expression on Prognosis in Oral Squamous Cell Carcinoma

Erber

Spoerl

Mamilos

et al. 2021

IJMS

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Oral cancer often presents with aggressive behavior and a high risk of recurrence and metastasis. For oral squamous cell carcinoma (OSCC), which is the most frequent histological subtype, therapy strategies include surgery, radiation therapy, chemotherapy, immune checkpoint inhibitors, and EGFR inhibitors. Recently, a Trop-2 antibody-drug conjugate (ADC) has been approved in the United States of America for the treatment of advanced triple-negative breast cancer. However, this ADC has also been tested in other solid tumors including head & neck squamous cell carcinoma. The prognostic impact of Trop-2 has already been reported for several cancers. We studied the prognostic influence of Trop-2 protein expression on OSCC patients’ survival. The cohort comprised n = 229 OSCC patients with available archived tumor tissue and corresponding non-neoplastic oral mucosa tissue. Using immunohistochemistry, we investigated Trop-2 expression in both the central and peripheral regions of each tumor and in corresponding non-neoplastic oral mucosa. In patients suffering from OSCC with combined high central and low peripheral Trop-2 expression, five-year overall survival (OS) was 41.2%, whereas 55.6% of OSCC patients who presented lower central and/or higher peripheral tumoral Trop-2 expression were alive after five years (p = 0.075). In multivariate Cox regression, the expression pattern of high central tumoral and lower peripheral Trop-2 expression was significantly correlated with impaired OS (HR = 1.802, 95%-CI: 1.134–2.864; p = 0.013) and recurrence-free survival (RFS) (HR = 1.633, 95%-CI: 1.042–2.560; p = 0.033), respectively, when adjusting for co-variables. Hence, Trop-2 may serve as an independent prognostic biomarker in OSCC. In subsequent studies, the pathophysiological meaning of downregulated Trop-2 expression in the OSCC periphery has to be analyzed.

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“…However, their clinical applicability to treat head and neck cancers still is unclear. 60 Some limitations in this review should be mentioned such as the language barrier, due to all evidence found was published in English, which eliminated the inclusion of available evidence published in any other language. However, it is useful to highlight that no restrictions about languages were performed; moreover, since most evidence is published in English, it is more likely that evidence meeting the eligibility criteria is published in this language.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Options in Unresectable Oral Squamous Cell Carcinoma: A Systematic Review

Anaya¹,

Amador²,

Acosta³

2021

CMAR

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Purpose This review describes the current scientific evidence of therapeutic options in unresectable oral squamous cell carcinoma. Methods This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We searched MEDLINE (Via PubMed) to identify studies assessing treatments for unresectable oral squamous cell carcinoma. The methodological quality assessment of the included studies was performed using the Joanna Briggs Institute (JBI) checklist tool. The evidence was organized and presented using tables and narrative synthesis. Results Thirty-three studies met the eligibility criteria. Most studies had an observational design. The sample size varied from 16 to 916 participants. The methodology quality of the included studies ranged from 2.5 to 10 using the JBI tool. Overall, the optimal treatment of patients with unresectable oral cancer is challenging, so there is a sprinkling of studies assessing a variety of therapeutic options, such as radiotherapy, chemotherapy, concurrent chemoradiotherapy, immunotherapy, targeted therapy plus chemotherapy or radiotherapy, and gene therapy plus chemotherapy. Conclusion There is lacking evidence about the benefits of some therapeutic options for unresectable oral squamous cell carcinoma. Overall, these patients can be treated using a multimodal approach such as concurrent chemoradiotherapy or induction chemotherapy followed by chemoradiotherapy, which have shown good clinical outcomes. However, other options could be considered depending on the assessment of risk/benefits, tumor extension, and patient values and preferences.

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Therapeutic Potential of Antibody-Drug Conjugate-Based Therapy in Head and Neck Cancer: A Systematic Review

Cited by 17 publications

References 111 publications

CXCR4-targeted nanotoxins induce GSDME-dependent pyroptosis in head and neck squamous cell carcinoma

CXCR4-targeted nanotoxins induce GSDME-dependent pyroptosis in head and neck squamous cell carcinoma

Impact of Spatially Heterogeneous Trop-2 Expression on Prognosis in Oral Squamous Cell Carcinoma

Therapeutic Options in Unresectable Oral Squamous Cell Carcinoma: A Systematic Review

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