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In The Lancet, the FANCOLEN-1 study by Paula Río and colleagues2 took the approach, and risk, of infusing genetically modified cells into patients with Fanconi anaemia without any previous conditioning.2 Patients with this rare disease encounter major toxicities following exposure to cytotoxic agents due to their impaired DNA repair mechanisms.3 Only the well-defined Fanconi anaemia complementation group A (with mutations in FANCA) was selected for their clinical trial;2 it is the most frequent variant (60–80% of patients with Fanconi anaemia), with early disease onset, and a high incidence of leukaemia and solid tumours.4,5 In these patients, genomic instability often leads to bone marrow failure (BMF). [...]it is associated with morbidity with grade 3–4 acute and chronic graft-versus-host disease of 12% and 8%, respectively, and treatment-related mortality ranging from 5% to 18% with ASCT from a matched related donor, and 14% to 47% from an unrelated donor.8,10 Almost all transplant patients receive chemotherapy conditioning with approximately 10% receiving radiation therapy.11 According to the EBMT registry (509 patients), the 15-year cumulative incidence of secondary malignancy has been reported at 21% for patients alive 1 year or more after transplant, and 34% at 20 years.10 It is also noteworthy that ASCT for patients with DNA repair deficiencies calls for low intensity conditioning, experienced transplanters, and expertise when using haploidentical donors.12 Therefore, while curative, ASCT is also associated with substantial side-effects and mortality, underscoring the need for non-toxic treatment strategies. JGI/Jamie Grill via Getty Images I report grants paid to my institution from TheCell: Cell, Tissue and Gene Therapy Network, Fonds de recherche Quebec-Sante, BioCanRx, Cancer Research Society, Medicament-Quebec, Canadian Institutes of Health Research, HMR Foundation, Infilise Foundation, Quebec Ministry of Economy, Innovation and Energy and some of this funding is for clinical trials mostly in the area of cancer immunotherapy; speakers fees from CEL for health care; and advisory board fees from VOR.
Advances in genetic cell modifications are performed routinely in research laboratories, but clinical translation requires refinements, particularly in the context of human cell administration. Chemotherapy is used to promote engraftment by making space for autologous corrected cells, but it can cause toxic effects and might increase the risk of secondary malignancies.1 The ability to perform genetic corrections without the use of conditioning would be an immense advancement. In The Lancet, the FANCOLEN-1 study by Paula Río and colleagues2 took the approach, and risk, of infusing genetically modified cells into patients with Fanconi anaemia without any previous conditioning.2 Patients with this rare disease encounter major toxicities following exposure to cytotoxic agents due to their impaired DNA repair mechanisms.3 Only the well-defined Fanconi anaemia complementation group A (with mutations in FANCA) was selected for their clinical trial;2 it is the most frequent variant (60–80% of patients with Fanconi anaemia), with early disease onset, and a high incidence of leukaemia and solid tumours.4,5 In these patients, genomic instability often leads to bone marrow failure (BMF).
Rio and colleagues' open-label, investigator-initiated, phase 1/2 clinical trial conducted in Spain2 is the first human study to demonstrate short-term and long-term engraftment (up to 7 years post-infusion) of genetically modified Fanconi anaemia cells administered without any conditioning regimen to treat BMF. Nine patients (seven boys and two girls, median age of 5 years [IQR 3·5–6·5]) were enrolled and eight were evaluable since one patient showed bacterial graft contamination. Gradual genetic and phenotypic correction was observed in haematopoietic cells from six of the eight patients. In addition, FANCOLEN-1 attained its primary efficacy endpoint of 0.1 vector copy per peripheral blood or bone marrow cell at 2 years post-injection in five (63%) patients, with gene marking present in all blood lineages. There were nine serious adverse events (grade 3–4) in six patients, but only one was related to medicinal product infusion.
The cells infused were functional in vitro upon resistance to DNA-damaging agents, and could rectify in a few instances, or stabilise the BMF syndrome. Although five of the seven patients with long-term follow-up had to undergo alternative treatment, the two patients with the highest engraftment levels had polyclonal reconstitution and displayed improved blood counts to the point that they did not need treatment, a major feat.
Importantly, FANCA-lentivirus corrected blood cells had their DNA repair function restored and, as a result, should have lost their cancerogenic potential. Although this result will need clinical confirmation in long-term studies, the potential clinical benefit is appealing. Nevertheless, modified cells from only a few patients showed a proliferative advantage sufficient for complete gene correction, and the bulk of haematopoiesis remained of Fanconi anaemia origin in most patients. One patient also had a cytogenetic abnormality (1q-gain) in non-corrected cells where viral transduction was not implicated. Nevertheless, the risk associated with persistence of Fanconi anaemia cells highlights the need for complete replacement of FANCA-defective blood cells. Additionally, FANCOLEN-1 did not identify genotoxic events or high-risk insertions, and lentiviruses are usually considered safe, but following more patients, and for longer periods of time, is needed to completely dismiss safety concerns.6
How can this strategy be improved? The authors propose to infuse more cells. Indeed, two of the three patients infused with a large number of cells (240 000 or more CD34+ cells/kg) yielded almost complete engraftment with transduced cells persisting up to 7 years post-infusion. In addition, these two patients saw their blood counts stabilise and even increase in one case. Although scientifically sound, this hypothesis is based on the outcomes of only two patients. The phase 2 clinical trial (FANCOLEN-II: NCT04248439) will administer high numbers of CD34+ gene corrected cells in a larger number of early-stage patients with Fanconi anaemia to confirm the impact of this strategy.
In the current trial, patient cells were initially required to have BMF before cell infusion. However, the low cell yields obtained when cell collection is performed in the context of profound cytopenia, and cryopreservation associated cell loss when cells are collected early in the disease, prompted a protocol amendment to collect stem cells earlier and infuse them fresh immediately after genetic modification. This implies that cell collection, transduction, and infusion must occur before very low blood counts develop. Such an approach requires detection and treatment of Fanconi anaemia before its haematological deterioration, which could be challenging.5,7,8 In addition, treatment decision requires solid predictors of poor patient outcomes since 20% of patients with Fanconi anaemia do not develop BMF by age 10 years and some variants might cause a mild disease.9 Another obstacle is the high cost of gene therapy interventions that must be weighed against medical and societal benefits as well as other therapeutic alternatives.
Allogeneic stem cell transplantation (ASCT) is currently the preferred treatment option for patients with Fanconi anaemia with BMF, preferably before any signs of malignant transformation.8 ASCT replaces host defective haematopoietic cells by non-Fanconi anaemia donor cells in almost all patients and treats cytopenia. Nevertheless, it is associated with morbidity with grade 3–4 acute and chronic graft-versus-host disease of 12% and 8%, respectively, and treatment-related mortality ranging from 5% to 18% with ASCT from a matched related donor, and 14% to 47% from an unrelated donor.8,10 Almost all transplant patients receive chemotherapy conditioning with approximately 10% receiving radiation therapy.11 According to the EBMT registry (509 patients), the 15-year cumulative incidence of secondary malignancy has been reported at 21% for patients alive 1 year or more after transplant, and 34% at 20 years.10 It is also noteworthy that ASCT for patients with DNA repair deficiencies calls for low intensity conditioning, experienced transplanters, and expertise when using haploidentical donors.12 Therefore, while curative, ASCT is also associated with substantial side-effects and mortality, underscoring the need for non-toxic treatment strategies.
Some patients with Fanconi anaemia can have milder disease and their disease can go unrecognised until diagnosis in adulthood.7,13 This is another patient population where the ability to correct Fanconi anaemia defects gradually with lentiviral-modified CD34+ cells without the risk of chemotoxicity could represent a substantial advance. Importantly, other genetic disorders where corrected cells display a proliferative advantage should also benefit from such a conditioning-free non-toxic modality.
JGI/Jamie Grill via Getty Images
I report grants paid to my institution from TheCell: Cell, Tissue and Gene Therapy Network, Fonds de recherche Quebec-Sante, BioCanRx, Cancer Research Society, Medicament-Quebec, Canadian Institutes of Health Research, HMR Foundation, Infilise Foundation, Quebec Ministry of Economy, Innovation and Energy and some of this funding is for clinical trials mostly in the area of cancer immunotherapy; speakers fees from CEL for health care; and advisory board fees from VOR. I am the Chief Scientific Officer and Board member of C3i, a not-for-profit organisation that develops and manufactures cost-effective state-of-the-art integrated cell and gene therapies for clinical implementation. I am CEO, and Board member (unpaid) of the CellCAN Network, a non-profit organisation created under the Government of Canada's Networks of Centers of Excellence. I am Director of the University Institute for Hematology-Oncology and Cell Therapy. As a full Professor of Medicine at the Université de Montréal, I have a research laboratory developing novel cell therapy approaches.
©2025. Elsevier Ltd