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260 Investigating cancer cell autonomous CAR T cell therapy resistance in DLBCL in vitro
  1. Fabiana Lueoend,
  2. Youngchul Song,
  3. Beverly Nguyen,
  4. Xiaoyan Li,
  5. Andreas Raue,
  6. Jennifer Brogdon,
  7. Glenn Dranoff,
  8. Matthew Niederst and
  9. Louise Treanor
  1. Novartis Institutes for BiMedical Research, Cambridge, MA, USA


Background CD19 CAR T cell therapy has greatly improved the outcome of r/r DLBCL patients, but durable responses are achieved in only 40% of cases. Relapses can be due to declining T cell fitness and/or cancer cells becoming inherently refractory. However, besides antigen loss, cancer cell autonomous resistance mechanisms are poorly understood.

Methods We generated DLBCL cell lines that are refractory to CD19 targeting CAR T cells by longterm co-culture in vitro. We assessed response to alternative CAR T cells targeting other antigens and performed RNAseq of resistant cancer cell lines to identify yet unknown resistance mechanisms.

Results Our in vitro longterm co-cultures recapitulate common resistance mechanisms observed in the clinics including CD19 loss. Interestingly, we do observe CD19 positive resistance and multiple of our CD19 CAR T cell resistant cell lines had become less sensitive also to alternative CAR T cells. Moreover, our RNAseq data indicate that the majority of transcriptional changes are associated with a common resistant phenotype rather than a specific resistance mechanism (e.g., antigen loss).

Conclusions Our results suggest that besides CD19 loss, DLBCL cells evolve mechanisms to overcome T cell killing which may render them cross-resistant to CAR T cells targeting other antigens. Analysis of our RNAseq data will allow us to characterize these mechanisms.

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