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CD8+ chimeric antigen receptor T cells manufactured in absence of CD4+ cells exhibit hypofunctional phenotype.


ABSTRACT:

Background

Cell culture conditions during manufacturing can impact the clinical efficacy of chimeric antigen receptor (CAR) T cell products. Production methods have not been standardized because the optimal approach remains unknown. Separate CD4+ and CD8+ cultures offer a potential advantage but complicate manufacturing and may affect cell expansion and function. In a phase 1/2 clinical trial, we observed poor expansion of separate CD8+ cell cultures and hypothesized that coculture of CD4+ cells and CD8+ cells at a defined ratio at culture initiation would enhance CD8+ cell expansion and simplify manufacturing.

Methods

We generated CAR T cells either as separate CD4+ and CD8+ cells, or as combined cultures mixed in defined CD4:CD8 ratios at culture initiation. We assessed CAR T cell expansion, phenotype, function, gene expression, and in vivo activity of CAR T cells and compared these between separately expanded or mixed CAR T cell cultures.

Results

We found that the coculture of CD8+ CAR T cells with CD4+ cells markedly improves CD8+ cell expansion, and further discovered that CD8+ cells cultured in isolation exhibit a hypofunctional phenotype and transcriptional signature compared with those in mixed cultures with CD4+ cells. Cocultured CAR T cells also confer superior antitumor activity in vivo compared with separately expanded cells. The positive impact of CD4+ cells on CD8+ cells was mediated through both cytokines and direct cell contact, including CD40L-CD40 and CD70-CD27 interactions.

Conclusions

Our data indicate that CD4+ cell help during cell culture maintains robust CD8+ CAR T cell function, with implications for clinical cell manufacturing.

SUBMITTER: Lee SY 

PROVIDER: S-EPMC10660840 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Publications

CD8<sup>+</sup> chimeric antigen receptor T cells manufactured in absence of CD4<sup>+</sup> cells exhibit hypofunctional phenotype.

Lee Sang Yun SY   Lee Dong Hoon DH   Sun Wei W   Cervantes-Contreras Francisco F   Basom Ryan S RS   Wu Feinan F   Liu Si S   Rai Richa R   Mirzaei Hamid R HR   O'Steen Shyril S   Green Damian J DJ   Shadman Mazyar M   Till Brian G BG  

Journal for immunotherapy of cancer 20231120 11


<h4>Background</h4>Cell culture conditions during manufacturing can impact the clinical efficacy of chimeric antigen receptor (CAR) T cell products. Production methods have not been standardized because the optimal approach remains unknown. Separate CD4<sup>+</sup> and CD8<sup>+</sup> cultures offer a potential advantage but complicate manufacturing and may affect cell expansion and function. In a phase 1/2 clinical trial, we observed poor expansion of separate CD8<sup>+</sup> cell cultures and  ...[more]

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