Genetic instability is a very important parameter to assess during expansion of therapeutic cells. A lot of studies on cell culture-induced genomic instability were done on mesenchymal stromal cells (MSC). Vast majority of these studies concluded that this type of events is relatively rare and could be minimized by expanding MSC in GMP conditions by standard protocol. In 2011 European Cell Products Working Party and the Committee for Advanced Therapies released recommendations for assessment of genetic instabilities in clinical MSC culture. One of potential risks for cell culture-induced abberations is an inherent propensity of individual (patient-specific) MSC to transformation.
Recently, a group of researchers from Brazil, published very interesting case report on emergence of clonal chromosomal instability in clinical MSC culture. The patient was enrolled in clinical trial for cardiac cell therapy, but his MSC product was not released for infusion. The key finding was a history of renal cancer and nephrectomy:
Cytogenetic analysis on a bone marrow sample showed a normal karyotype: 46,XY. However, the MSC at second passage showed a hyperdiploid clone, with clonal trisomies of chromosomes 4, 5, 10 and X. In order to investigate more, another sample from the same patient was used for a second cultivation and, at third passage, these cells showed a clonal translocation t(9;18)(p24;q11).
Another key points here are (a) clonality and (b) recurrence of observed chromosomal abberations. These type of abberations were described in some cancers. Therefore, cell manufacturers had a good reason to say “NO” and not release the product.
Interestingly, it was the only case of cytogenetic abnormalities out of 152 tested bone marrow samples from the patients, enrolled in cardiac clinical trial.
Take home message 1 – history of neoplasm could be (or should be) an exclusion criteria for enrollment in regenerative medicine trials, using autologous MSC. Currently, many MSC trials have history of neoplasms as exclusion criteria.
Take home message 2 – assess your product for cytogenetic abnormalities and think about including it in MSC product release criteria. Follow recommendations.