CXCR4-gerichtete Endoradiotherapie von hämatologischen Erkrankungen

Zusammenfassung

Der C-X-C Chemokinrezeptor 4 (CXCR4) spielt sowohl in der Physiologie als auch Pathologie des Menschen eine wichtige Rolle, so z. B. in der Embryo- und Organogenese, im Rahmen des Homings von Stamm- und Progenitorzellen in das Knochenmark oder bei der Orchestration der Entzündungsantwort auf inflammatorische oder infektiöse Prozesse. Da eine Überexpression des Rezeptors für über 20 verschiedene Tumorentitäten nachgewiesen werden konnte und dieser sowohl die Tumorigenese als auch Metastasierung fördert, stellt er eine hochinteressante Zielstruktur für die Onkologie dar.

Für die nicht invasive Bildgebung von CXCR4 wurden in den letzten Jahren mehrere spezifische Radiotracer für diesen Chemokinrezeptor entwickelt, wobei der klinisch bisher am häufigsten eingesetzte PET-Tracer ⁶⁸Ga-Pentixafor an der TU München in der Arbeitsgruppe von Hans-Jürgen Wester entwickelt wurde. Als therapeutischer Partner steht dem ⁶⁸Ga-Pentixafor das Pentixather zur Seite, das für therapeutische Zwecke mit α- und β-Emittern markiert werden kann.

Das CXCR4-gerichtete theranostische Konzept konnte erfolgreich in die Klinik transferiert werden. Bis heute wurden über 40 Endoradiotherapien mit ⁹⁰Y- oder ¹⁷⁷Lu-markiertem Pentixather durchgeführt, wobei die größte Erfahrung für den Einsatz bei hämatologischen Neoplasien wie dem Multiplen Myelom, dem diffusen großzelligen B-Zell-Lymphom und der akuten myeloischen Leukämie besteht. Die CXCR4-gerichtete Endoradiotherapie ist hierbei Teil der Konditionierungstherapie vor geplanter Stammzelltransplantation und hat sich als gut verträgliche, nebenwirkungsarme Option auch bei extensiv vorbehandelten Patienten erwiesen. Zukünftige Studien (z. B. die COLPRIT-Studie) werden weiteren Aufschluss über die Wirksamkeit und den Stellenwert der Pentixather-Therapie bei hämatologischen Erkrankungen liefern.

Abstract

C-X-C motif chemokine receptor 4 (CXCR4) plays a crucial role in many physiologic as well as pathologic conditions including embryo- and organogenesis, homing of hematologic stem and progenitor cells to the bone marrow niche and orchestration of leukocyte trafficking as part of the immune response to inflammatory or infectious processes. Since CXCR4 is also overexpressed by more than 20 different tumor entities and fosters both tumor growth and invasiveness as well as metastasis, it represents a very attractive target in oncology.

During the last decade, a multitude of specific, CXCR4-directed radiotracers have been introduced. Most clinical experience exists for ⁶⁸Ga-Pentixafor, which has been developed by the group of Hans-Jürgen Wester at TU Munich. As a therapeutic companion, Pentixather can be labelled with both α- and β-emitting radionuclides.

CXCR4-directed theranostics has been successfully transferred to the clinic. To date, more than 40 cycles of endoradiotherapy with ⁹⁰Y- or ¹⁷⁷Lu-labelled Pentixather have been administered with most experience existing for hematologic disease like multiple myeloma, diffuse large B cell lymphoma or acute myeloid leukemia.

First results demonstrated that endoradiotherapy can be safely performed as part of the conditioning regimen prior to autologous or allogeneic stem cell transplantation and can achieve high tumor cell kill even in heavily pre-treated patients with very advanced stages of disease. Further prospective studies to evaluate the efficacy of CXCR4-directed endoradiotherapy (e. g. the phase I/II COLPRIT trial) are about to be initiated and will provide further evidence on synergistic multimodality treatment in hematologic neoplasms.

Schlüsselwörter

Chemokin - Chemokinrezeptor - CXCR4 - Multiples Myelom - DLBCL - AML - Theranostik - Pentixafor - Pentixather - Endoradiotherapie

Keywords

chemokine - chemokine receptor - CXCR4 - multiple myeloma - DLBCL - AML - theranostics - Pentixafor - Pentixather - endoradiotherapy

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