Pathological complete response and potential for bladder preservation by theranostic instillation therapy targeting CXCR4 in combination with systemic chemotherapy: The Bladder BRIDGister experience.
Authors: Wirtz Ralph M. , Storz Enno , von Brandenstein Melanie , Friedersdorff Frank , Barski Dimitri , Otto Thomas , Waldner Michael , Graff Johannes , Veltrup Elke , Hake Roland , Eidt Sebastian , Roggisch Jenny , Rieger Constantin , Koch Stefan , Ecke Thorsten , Greifenstein Lukas , Heidenreich Axel , Baum Richard P 
Published: February 2025

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Background:
Patients with muscle invasive urothelial carcinoma (MIBC) achieving pathological complete response (pCR) upon neoadjuvant chemotherapy (NACT) have improved prognosis. Previously we did show that luminal tumors respond better to NACT (Ecke et al 2022), while chemoresistant tumors express radioligand targets CXCR4 and FAP. First-in-Human treatment of chemotherapy resistant T4 MIBC using two cycles of Lu
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FAP combined with one cycle of pembrolizumab results in durable complete response (Baum et al, submitted). The objective of this study was to eradicate treatment naïve T2a MIBC with limited probability to respond to chemotherapy by adding intravesical Lu
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CXCR4 instillation into the bladder before first NACT cycle to justify subsequent adopted clinical trials.
Methods:
A reference cohort (n=100) for subtype classification was constructed. RNA from FFPE tissues was extracted, relative gene expression of luminal and non-luminal target were analyzed by RT-qPCR. FFPE tissue from initial TURB of MIBC patients under evaluation for subsequent therapy were analyzed accordingly and individual target mRNA were added to the cluster analysis to determine subtype and target expression level. PET/CT Imaging by Ga
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CXCR4 was performed in selected patients. In case of tumor specific, high uptake subsequent Lu
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CXCR4 was instilled one week before initiation of ddMVAC. Response was evaluated by Ga
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CXCR4 PET/CT and control resections by TURB.
Results:
A luminal pT2 G3 MIBC patient with elevated CXCR4 expression level by RT-qPCR and validated by immunohistochemistry, who was predicted to be unresponsive to NACT, was selected for CXCR4 instillation therapy. Subsequent Ga
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CXCR4 whole body PET/CT proved tumor specific uptake and excluded nodal involvement as well as distant metastasis. Thereafter 4GB Lu
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CXCR4 was applied via catheter as intravesical Radio-Ligand-Therapy (iRLT) followed by three cycles ddMVAC. Thereafter a control Ga
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CXCR4 was performed before starting the planned second cycle of iRLT and ddMVAC. Intravesical Ga
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CXCR4 PET/CT revealed complete response, with no tumor uptake being visible anymore. TURB including muscle tissue revealed complete absence of malignancy with only inflammatory immune reaction being left after RLT based NACT.
Conclusions:
Combination of molecular in vitro diagnostics identifies high risk MIBC with elevated CXCR4 target gene expression, that exhibit high radioligand uptake in vivo and are amenable for intensified treatment by adding iRLT to systemic ddMVAC treatment. First clinical results are promising and justify clinical approaches as part of phase 1 / 2 clinical trials within the Bladder BRIDGister study group with the ultimate goal of bladder preservation after pCR to neoadjuvant combination therapies.