Ex vivo photodynamic therapy approach using a nanovesicular photosensitizer to allow safe autotransplantation of ovarian tissue from leukemia patients

Moghassemi, Saeid;Dadashzadeh. Arezoo;Andrade Amorim, Christiani
(2022) The 38th Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE) — Location: Italy (3.July.2022)

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STUDY QUESTION: Is it possible to purge leukemia cells from ovarian tissue (OT) fragments before transplantation? SUMMARY ANSWER: Our photodynamic therapy (PDT) approach showed to efficiently destroy leukemia cells from tumor-infiltration mimicking models (TIMs), indicating the feasibility of this technique to purge OT samples. WHAT IS KNOWN ALREADY: Autotransplantation of the cryopreserved OT is the most suitable option to preserve fertility for prepubertal girls and women that require immediate cancer treatment. Up to now, more than 200 live births have already been reported after OT cryopreservation and transplantation. Leukemia is the 12th most common cancer in Europe among prepubertal girls and women of reproductive age and in 2020, the estimated number of new leukemia cases was higher than 33,000 in girls between 0 and 19 years old. Unfortunately, once their health has been restored, autotransplantation of cryopreserved OT for leukemia patients is not advised due to the high risk of transferring malignant cells back to the patient, leading to leukemia recurrence. STUDY DESIGN, SIZE, AND DURATION: To safely transplant the OT from leukemia patients and restore their fertility, our goal here was to develop a PDT strategy to eliminate leukemia ex vivo. To this end, we designed OR141-loaded niosomes (ORN) to create the most effective formulation for ex vivo purging OT fragments from acute myelogenous leukemia cells (n=4). Moreover, to ensure that such treatments are not harmful to follicle survival and development to be deemed a potential fertility restoration alternative, the effect of the ORN-based PDT purging procedure on follicles was assessed after xenografting the photodynamic treated OT in SCID mice (n=5). The work was carried out between September 2020 and April 2022, at the Catholic University of Louvain. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: After establishing the best ORN formulation, our PDT approach was used to eradicate HL60 cells from ex vivo TIMs prepared by microinjection of cancer cell suspension in ovarian fragments. The purging efficiency was evaluated by droplet digital polymerase chain reaction and immunohistochemical analyses. Additionally, we evaluated the effect of ORN-based PDT on follicle density, survival, development, and tissue quality in terms of fibrotic areas and vascularization after 7-day xenotransplantation to SCID mice. MAIN RESULTS AND THE ROLE OF CHANCE: The ex vivo purging of TIMs demonstrated that the PDT strategy with ORN could selectively eradicate the malignant cells from tissue fragments without affecting ovarian tissue normal cells, as evidenced by PCR and immunohistochemical analysis. Regarding the effect of our PDT approach on follicle population and OT quality, our results after xenotransplantation revealed no significant difference between the follicle density of control (non-treated, grafted OT) and ORN-treated groups (2.38 ± 0.63 and 3.21 ± 1.94 morphologically normal follicles/mm2, respectively). In addition, the results showed that the control and ORN-treated ovarian tissue can be equally vascularized (7.65±1.45 % and 9.89±2.21 %, respectively). Moreover, the proportion of fibrotic area in control and ORN-treated groups was 15.96±5.94 %, and 13.32±3.05 %, which is not significantly different from the pre-graft fragments (14.22±6.65 %). LIMITATIONS, REASONS FOR CAUTION: This study did not use OT fragments from leukemia patients, but TIMs created after injection of HL60 cells in OT from healthy patients. Therefore, while the results are promising, it still remains to assess if our PDT approach will be equally successful to eliminate malignant cells from leukemia patients. WIDER IMPLICATIONS OF THE FINDINGS: Our results showed that the purging procedure causes no significant impairing effect on follicles development and tissue quality, suggesting our novel PDT procedure could be a promising strategy to destroy leukemia cells in fragments of ovarian tissue allowing its safe transplantation in cancer survivors. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the Fonds National de la Recherche Scientifique de Belgique (the Excellence of Science (FNRS-EOS), number 30443682 (Ph.D. scholarship awarded to S.M.), and FNRS-PDR Convention grant number T.0004.20 awarded to C.A.A.), Fondation Louvain (Ph.D. scholarship awarded to A.D.), and Foundation Against Cancer (grant 2018-042 awarded to A.C.). The authors declare no competing interests.
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Moghassemi, S., Dadashzadeh. Arezoo, & Andrade Amorim, C. (2022). Ex vivo photodynamic therapy approach using a nanovesicular photosensitizer to allow safe autotransplantation of ovarian tissue from leukemia patients. The 38th Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE), Italy. https://hdl.handle.net/2078.5/242715