Published in Blood: Isoplexis’ Single-Cell Proteomics Provides Insight into Mechanism of Action for Venetoclax and Azacytidine in Acute Myeloid Leukemia Treatment

Adoptive T-cell therapy, and chimeric antigen receptor T cell therapy (CAR-T) in particular, have seen remarkable success in treating B-cell malignancies.1 But for patients with acute myeloid leukemia (AML), the same success has not yet been achieved – with inadequate target antigens, low mutational rate and high disease heterogeneity often being the cause.1

In a study recently published in the journal Blood, researchers examined a new immune-mediated mechanism of action for venetoclax and azacytidine for treating AML and highlighted the therapeutic potential of combined venetoclax/azacytidine and adoptive T cell therapy for patients suffering from relapsed AML post-chemotherapy.1

Though treatment-naïve patients showed a recovery rate of almost 70% following combined venetoclax/azacytidine therapy, patients who had received chemotherapy and relapsed prior to venetoclax/azacytidine therapy did not have persistent response. The team explored the therapeutic potential of combining adoptive T cell therapy with venetoclax/azacytidine treatment for patients who had previously received chemotherapy. Therefore, the question was two-fold: will this new therapeutic option work in vivo and what is the mechanistic driver of patient relapse following chemotherapy?

During the study, researchers used IsoPlexis’ single-cell proteomics to help determine the relationship between T cell quality and polyfunctionality, post-chemotherapy relapse, and response to venetoclax/azacytidine treatment.

Single-Cell Cytokine Analysis Revealed Predictive Polyfunctionality Biomarker of Therapeutic Efficacy

T cells were obtained from the blood of healthy individuals and the bone marrow of patients with AML. CD8+ T cells were then separated and stimulated with interleukin-2 (IL-2) for 24 hours in order to induce a measurable immune response in the samples. Then, using the IsoPlexis IsoLight system, a walk-away automated bench top instrument for functional multi-omics, highly multiplexed single-cell analysis of secreted cytokines and chemokines was performed. The polyfunctional strength index (PSI), which reflects the ability of T cells to carry out multiple functions2, was calculated and the results were analyzed using the IsoSpeak bioinformatics platform.1

By using IsoPlexis’ single-cell functional proteomics platform, researchers discovered that the CD8+ T cells of treatment-naïve patients had higher PSI and overall functionality compared to those of patients who received chemotherapy and relapsed.

“Using single-cell analysis of secreted cytokines, the cytokine profile and PSI of CD8+ T cells from patients with newly diagnosed and relapsed AML stimulated ex vivo with IL-2 were determined as a marker of T-cell functionality”1

They concluded that chemotherapy reduced T cell functionality and thus decreased the efficacy of the combined venetoclax/azacytidine treatment. Through the use of IsoPlexis’ technology, the team clarified how T cell quality and functionality contribute to the efficacy of the T cell and combination therapy, providing mechanistic insights for the optimization of curative medicines.

Conclusion

This new study in Blood highlights the importance of using single-cell proteomics to enhance therapy development pipelines and improve therapy quality.  Despite the common belief that running a single-cell proteomics study can be expensive and time consuming, IsoPlexis’ scalable, end-to-end automated platform makes single-cell and bulk highly multiplexed proteomics accessible to virtually every lab. The IsoPlexis technology fills a critical gap in the industry, allowing researchers to access new layers of biological data and gain deeper access to in vivo biology. IsoPlexis’ highly multiplexed functional proteomics system delivers what you need the most across the board: high quality results, while saving time and resources.

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References

  1. Jong Bok Lee, Dilshad H. Khan, Rose Hurren, Mingjing Xu, Yoosu Na, Hyeonjeong Kang, Sara Mirali, Xiaoming Wang, Marcela Gronda, Yulia Jitkova, Neil MacLean, Andrea Arruda, Zoe Alaniz, Marina Y. Konopleva, Michael Andreeff, Mark D. Minden, Li Zhang, Aaron D. Schimmer; Venetoclax enhances T cell–mediated antileukemic activity by increasing ROS production. Blood2021; 138 (3): 234–245. doi: https://doi.org/10.1182/blood.2020009081
  2. Creelan, B.C., Wang, C., Teer, J.K. et al. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nat Med 27, 1410–1418 (2021).
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