Early changes in cDNA could predict response to CD19-targeted CAR T cell therapy in LBCL


Patients who were able to achieve a complete response (CR) to positron emission tomography / computed tomography treatment at 3 months follow-up had CD8 T cell frequencies expressing memory signatures that were 3 times higher than those who obtained partial responses or progressive disease.

When sequencing cell-free DNA on day 7 following infusion, molecular response was found to be significantly associated with clinical response (P = .008). In addition, a CD8 T cell depletion signature was linked (q = 2.8 × 10−149) with a weak molecular response in this population.

“When we examine the characteristics of the infused CAR T cells, we found that samples from patients who were less responsive to treatment had depleted T cells, while those who underwent CR had T cells expressing ‘memory’ signatures. Sattva Neelapu, MD, professor in the Department of Lymphoma and Myeloma, Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center, said in a press release.2 “In addition, 1 T cell depletion cell signature was more frequently found in patients who exhibited poor molecular response, and poor molecular response is generally associated with less positive long-term outcomes.”

Patients with LBCL who remain in CR or PR 3 months after treatment with autologous CAR T cell therapy targeted against CD19 have been shown to have better outcomes than those who have just achieved stable disease or who progress before this time. In the context of B-cell leukemia, phenotypes within the apheresis product and the CAR T cell product have been identified as key cellular characteristics associated with the response. However, this has not been studied in LBCL, nor evaluated systemically using single-cell transcriptomics.

The researchers hypothesized that the heterogeneity of these types of CAR T products could contribute to inter-patient variability in terms of efficacy and toxicity. To further assess this, single-cell analysis was performed on CAR T cells to assess gene expression profiles in cells that had been infused. Investigators collected CAR T cells in infusion bags from 24 patients with LBCL who had received treatment. From there, the genetic profiles were compared to responses to treatment, as determined by a PET / CT scan 3 months after the infusion.

Treatment-related adverse reactions (TRAE), such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), which are often associated with CAR T cell therapy and may interfere with recovery. Additional results indicated that a subset of rare cells with monocyte-like transcriptional characteristics were linked to high-grade ICANS (P = .0002).

“When we examined the infusion product, we found that a cell population exhibiting characteristics similar to myeloid cells, with a monocyte-like transcriptional signature, was associated with the development of high-level neurotoxicity,” Michael Green, PhD, associate professor in the Lymphoma and Myeloma Department, Division of Cancer Medicine at MD Anderson Cancer Center, added in the release. “The detection of these cells can then lead us to identify patients who would be at greater risk of developing neurotoxicity, which will allow us to provide prophylactic treatment with agents that target specific cellular characteristics.”

These results provide insight into which patients will experience either poor results or TRAE with CAR T cell products targeted to CD19, allowing treatment adjustments to increase efficacy and reduce toxicity.

“This study also tells us that some rare and unexpected cells identified by single-cell analysis may be biologically important,” added Linghua Wang, MD, assistant professor in the department of genomic medicine, division of cancer medicine at MD Anderson Cancer Center. in the output. “In the future, we plan to functionally characterize these monocyte-like cells to better understand their specific biological mechanisms underlying these clinical findings.”

The references

  1. Deng Q, Han G, Puebla-Osorio N, et al. Characteristics of anti-CD19 CAR T cell infusions associated with efficacy and toxicity in patients with large B-cell lymphoma. Nat Med. 2020; 26: 1878-1887. doi: 10.1038 / s41591-020-1061-7.
  2. Study identifies characteristics of infused CAR T cells associated with efficacy and toxicity in patients with large B-cell lymphoma. Press release. The University of Texas MD Anderson Cancer Center. October 5, 2020. Accessed October 6, 2020. https://bit.ly/3uTR2rD

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