Cytotoxic properties of radionuclide-conjugated Cetuximab without and in combination with external irradiation in head and neck cancer cells in vitro

Eke, Iris; Ingargiola, Mirjam; Förster, Claudia; Kunz-Schughart, Leoni A.; Baumann, Michaël; Runge, Roswitha; Freudenberg, Robert; Kotzerke, Jörg; Heldt, Jan‐Martin; Pietzsch, Hans‐Jürgen; Steinbach, Jörg; Cordes, Nils

doi:10.3109/09553002.2014.899446

Cited by 8 publications

(6 citation statements)

References 26 publications

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“…Based on this success different approaches for development of anti-EGFR based theragnostics was studied using different antibodies, chelators and radionuclide combinations for radioimmunotherapy of EGFR expressing tumor entities [ 19 – 26 ]. Further, preclinical rationales for combined anti-EGFR EndoRT with EBRT were developed [ 13 , 27 – 29 ].…”

Section: Introductionmentioning

confidence: 99%

Combined external beam radiotherapy with carbon ions and tumor targeting endoradiotherapy

et al. 2018

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External beam radiotherapy (EBRT) with carbon ions and endoradiotherapy using radiolabeled tumor targeting agents are emerging concepts in precision cancer therapy. We report on combination effects of these two promising strategies.Tumor targeting 131I-labelled anti-EGFR-antibody (Cetuximab) was used in the prototypic EGFR-expressing A431 human squamous cell carcinoma xenograft model. A 131I-labelled melanin-binding benzamide derivative was utilized targeting B16F10 melanoma in an orthotopic syngeneic C57bl6 model. Fractionated EBRT was performed using carbon ions in direct comparison with conventional photon irradiation.Tumor uptake of 131I-Cetuximab and 131I-Benzamide was enhanced by fractionated EBRT as determined by biodistribution studies. This effect was independent of radiation quality and significant for the small molecule 131I-Benzamide, i.e., >30% more uptake in irradiated vs. non-irradiated melanoma was found (p<0.05). Compared to each monotherapy, dual combination with 131I-Cetuximab and EBRT was most effective in inhibiting A431 tumor growth. A similar trend was seen for 131I-Benzamide and EBRT in B16F10 melanoma model. Addition of 131I-Benzamide endoradiotherapy to EBRT altered expression of genes related to DNA-repair, cell cycle and cell death. In contrast, immune-response related pathways such as type 1 interferon response genes (ISG15, MX1) were predominantly upregulated after combined 131I-Cetuximab and EBRT. The beneficial effects of combined 131I-Cetuximab and EBRT was further attributed to a reduced microvascular density (CD31) and decreased proliferation index (Ki-67).Fractionated EBRT could be favorably combined with endoradiotherapy. 131I-Benzamide endoradiotherapy accelerated EBRT induced cytotoxic effects. Activation of immune-response by carbon ions markedly enhanced anti-EGFR based endoradiotherapy suggesting further evaluation of this novel and promising radioimmunotherapy concept.

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Section: Introductionmentioning

confidence: 99%

Combined external beam radiotherapy with carbon ions and tumor targeting endoradiotherapy

et al. 2018

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“…Additionally, Sefl et al showed that neglecting the initial uptake phase will lead to a substantial overestimation of the absorbed dose, and thus, an underestimation of cell survival [ 78 ]. Nonetheless, 15 out of the 27 studies reporting survival vs. dose (52%) evaluated the RP uptake at only a single time-point and neglected biological decay, which can result in an overestimation of the absorbed dose [ 10 , 14 , 35 , 37 , 38 , 39 , 41 , 66 , 79 , 80 , 81 , 82 , 83 , 84 , 85 ].…”

Section: Preclinical Dosimetrymentioning

confidence: 99%

A Review on Tumor Control Probability (TCP) and Preclinical Dosimetry in Targeted Radionuclide Therapy (TRT)

et al. 2022

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Targeted radionuclide therapy (TRT) uses radiopharmaceuticals to specifically irradiate tumor cells while sparing healthy tissue. Response to this treatment highly depends on the absorbed dose. Tumor control probability (TCP) models aim to predict the tumor response based on the absorbed dose by taking into account the different characteristics of TRT. For instance, TRT employs radiation with a high linear energy transfer (LET), which results in an increased effectiveness. Furthermore, a heterogeneous radiopharmaceutical distribution could result in a heterogeneous dose distribution at a tissue, cellular as well as subcellular level, which will generally reduce the tumor response. Finally, the dose rate in TRT is protracted, relatively low, and variable over time. This allows cells to repair more DNA damage, which may reduce the effectiveness of TRT. Within this review, an overview is given on how these characteristics can be included in TCP models, while some experimental findings are also discussed. Many parameters in TCP models are preclinically determined and TCP models also play a role in the preclinical stage of radiopharmaceutical development; however, this all depends critically on the calculated absorbed dose. Accordingly, an overview of the existing preclinical dosimetry methods is given, together with their limitation and applications. It can be concluded that although the theoretical extension of TCP models from external beam radiotherapy towards TRT has been established quite well, the experimental confirmation is lacking. Thus, requiring additional comprehensive studies at the sub-cellular, cellular, and organ level, which should be provided with accurate preclinical dosimetry.

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“…However, SAS and FaDu were already controlled after RIT treatment alone in spheroids as well as 2D cultures. 58,59 The obviously higher RIT efficacy in vitro than in xenografts may be explained by differing RIT doses used in the studies. Regardless of the limitations of efficacy tests, in vitro cell culture models offer important possibilities to study other end points such as cellular binding and uptake 55,57,59 as well as downstream signalling.…”

Section: 65mentioning

confidence: 99%

“…Regardless of the limitations of efficacy tests, in vitro cell culture models offer important possibilities to study other end points such as cellular binding and uptake 55,57,59 as well as downstream signalling. 32,57,58 Accordingly, in vitro models should be used to uncover underlying mechanisms and can give indications on efficacy. However, to evaluate the therapeutic benefit of combined treatment strategies, in vivo studies are inevitable for translation into the clinic.…”

Section: 65mentioning

confidence: 99%

Improving external beam radiotherapy by combination with internal irradiation

Dietrich¹,

Koi²,

Zöphel³

et al. 2015

BJR

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The efficacy of external beam radiotherapy (EBRT) is dose dependent, but the dose that can be applied to solid tumour lesions is limited by the sensitivity of the surrounding tissue. The combination of EBRT with systemically applied radioimmunotherapy (RIT) is a promising approach to increase efficacy of radiotherapy. Toxicities of both treatment modalities of this combination of internal and external radiotherapy (CIERT) are not additive, as different organs at risk are in target. However, advantages of both single treatments are combined, for example, precise high dose delivery to the bulk tumour via standard EBRT, which can be increased by addition of RIT, and potential targeting of micrometastases by RIT. Eventually, theragnostic radionuclide pairs can be used to predict uptake of the radiotherapeutic drug prior to and during therapy and find individual patients who may benefit from this treatment. This review aims to highlight the outcome of pre-clinical studies on CIERT and resultant questions for translation into the clinic. Few clinical data are available until now and reasons as well as challenges for clinical implementation are discussed.

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Cytotoxic properties of radionuclide-conjugated Cetuximab without and in combination with external irradiation in head and neck cancer cells in vitro

Abstract: Our findings show that Cetuximab-conjugated (90)Y has a significant potential to eradicate human SCC cells. A combination of radioimmunotherapeutic compounds and external radiotherapy might be a promising treatment strategy for clinical application.

Cited by 8 publications

References 26 publications

Combined external beam radiotherapy with carbon ions and tumor targeting endoradiotherapy

Combined external beam radiotherapy with carbon ions and tumor targeting endoradiotherapy

A Review on Tumor Control Probability (TCP) and Preclinical Dosimetry in Targeted Radionuclide Therapy (TRT)

Improving external beam radiotherapy by combination with internal irradiation

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