Cytoreductive conditioning intensity linked to post-gene therapy clonal, TCR diversity

Cytoreductive conditioning intensity linked to post-gene therapy clonal, TCR diversity

Published Date: 20/7/17

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medwireNews: In patients with adenosine deaminase deficient-severe combined immunodeficiency (ADA-SCID) receiving gammaretroviral gene therapy, the intensity of cytoreductive conditioning could have a bearing on the success of the procedure, in terms of clonal diversity and the T-cell receptor (TCR) repertoire, research indicates.

Among 15 children treated with gammaretroviral gene therapy following cytoreduction with busulfan, the higher the dose of the conditioning agent, the greater the clonal and TCR diversity, as assessed by vector integration site and TCR β-chain rearrangement sequencing, respectively, where both correlations were statistically significant.

“These data are consistent with the fact that ADA-SCID has seen multiple unsuccessful gene therapy trials without conditioning and multiple successful trials with conditioning, and they further underscore the importance of effective cytoreduction in treating this disease with gene therapy”, say Donald Kohn, from the University of California, Los Angeles in the USA, and team.

The administered CD34+ cell dose of busulfan also correlated positively with clonal and TCR rearrangement diversity, but only the latter association was significant. By contrast, age at treatment showed a significant inverse association with both parameters, such that younger patients had more diverse transduced cell clones and TCRs.

“As these metrics correlate with therapeutic success […], our results suggest that treating ADA-SCID patients with gene therapy earlier could result in better immunity”, the researchers write in Blood.

They also examined common insertion sites and found “clear evidence of genotoxicity”, but in the absence of any dysplastic changes in the periphery.

Vectors frequently integrated near proto-oncogenes, with MECOM and LMO2 the most commonly targeted genes. Also, clones with integrations near MECOM, LMO2 and other cancer-related genes were on average more abundant than other clones.

Nonetheless, these clones remained stable over time, and did not expand to the point of clonal dominance or dysplasia. And no patient developed leukaemia or showed any signs of dysplasia during the follow-up period ranging from 3 to 9 years.

One patient even developed clonal dominance in the first couple of years post-transplant – with a single vector-marked clone accounting for around 85% of clones – but the patient remains well and shows no signs of dysplasia, Kohn et al report.

They write: “It is not known why clonal transformations have not occurred in ADA-SCID, despite the clear demonstration, both in this paper and those from other trials using gammaretroviral vectors for ADA-SCID, of expanded clones with integrants near proto-oncogenes that have caused leukoproliferation in every other disorder that had high frequencies of integrations of gammaretroviral vectors.

“One can speculate that the myeloid abnormalities that have been observed in ADA-deficiency may limit leukoproliferation.”

© 2019 Springer Healthcare Ltd

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