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G2 - Immune Targeting and Approaches with Genetically-Modified Cells and Cell Therapies (Including CAR-T, CAR-NK, TCR editing)

8: Long Term Safety and Integration Site Analysis Over a Large Cohort of Patients Treated with T Cells Modified by Lentiviral or Gammaretroviral Gene Addition

Type: Oral Abstract Session

Presentation Details
Session Title: Clinical Trials Spotlight Symposium

CART therapy has benefitted tens of thousands of cancer patients, but recent data has raised concerns about safety following observations of secondary T cell malignancies after treatment. Long-term follow-up (LTFU) is mandated for recipients of many gene therapies, and is intended to identify delayed toxicities and clarify mechanisms of cell product persistence. Here we summarize LTFU for 780 patients, including longitudinal tracking for 182 patients via integration site sequence analysis to quantify behavior of transduced cell clones. We analyzed 780 patients treated in modified T cell trials at the University of Pennsylvania between 2001 and 2023. With 1323 patient years of follow up, 21 (2.69%) of patients had a second primary malignancy. Tumor types included myelodysplastic syndrome (2) and acute myeloid leukemia (3); diffuse large B cell lymphoma (1), anaplastic large cell lymphoma (1), skin cancer (1 basal cell, 1 squamous cell, 1 melanoma); prostate (2), lung (3), neuroendocrine (1), thymoma (1) and uncategorized neoplasms (3). Median onset time was 1.86 years (range 51 days - 8.7 years). One case of anaplastic large cell lymphoma of the stomach was observed 344 days after infusion and was considered unrelated to CAR T cells with no detectable CAR product in lesional tissue. There were no instances of T cell malignancies related to the product reported. Integration site sequence analysis allowed characterization of possible insertional mutagenesis and quantification of clone sizes. Gene addition by both lentiviral and gammaretroviral vectors was analyzed. Comparison of these data to measures of vector copy number per cell clarified the extent of expansion of gene modified T cells within the full blood cell population. One extreme example, reported previously, involved integration within the TET2 gene and sharp clonal expansion, so that at the peak the TET2 clone comprised ~27% of all blood cells, both gene modified and unmodified. This case was distinctive in that the subject was already mutant in the other TET2 allele, helping explain the strong response. While notable for the expansion and dominance, this was a non-transformed clonal population of T cells that subsequently contracted. Further analysis of the remaining subjects showed that even modestly expanded clones were rare. Other than the previously described TET2 patient, maximum clone sizes, taking account of both gene modified and unmodified cells, averaged 0.16% over all samples analyzed to date, with a maximum of 1.3 %. Modest effects of integration on cell growth could be detected—there was increased frequency of integration in specific genes after T cell infusion, and cells with integration in specific genes were associated with longer persistence and modest clonal expansion. However, in our data, no example of vector insertion was associated with transformation or clinically concerning clonal skewing. In summary, we observed no examples of pathogenic insertional mutagenesis.

Plain Language Summary
A large cohort of patients were treated with CART therapy and no adverse events associated with insertional mutagenesis were detected.

Frederic D. Bushman1, Joseph Fraietta1,2, Amy Marshall2, Jan Joseph Melenhorst3, Aoife M. Roche1, John K. Everett1, Sonja Zolnoski1, Walter Rogal2, Cory Czuczman2, The CART Therapy Team2, Carl H. June2,4, Elizabeth Hexner2, Julie Jadlowsky2

1Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA,2Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA,3Cleveland Clinic Lerner College of Medicine, Cleveland, OH,4Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA"

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