BCL-2 Inhibitor Venetoclax Shows Synergistic Effects on CD8 T Cell Proliferation and Blast Death in Vitro When Combined with Anti PD-1 Checkpoint Inhibitor

Background

Acute myeloid leukemia (AML) is a hematologic malignancy with significant heterogeneity characterized by various genetic mutations and translocations, rendering its treatment highly complicated. Of the numerous factors predicting prognosis, age plays a big role in determining the course of treatment (Juliusson et al. Blood 2009). Median age of 68 (NIH, 2024) poses a challenge to successful treatment induction with exponentially higher mortality rate in elderly patients (Walter et al. Journal of Clinical Oncology 2011) . Median survival rate 4.6 months and 1-year survival rate of 28% in patients age over 70 treated with cytarabine-based chemotherapy. BCL-2 inhibitors, such as venetoclax, have been recently approved for treating newly diagnosed and relapsed AML, improving outcomes for patients over 60 (Pollyea et al. Bone Marrow Transplant 2021). Although BCL-2 inhibition and its effects on T cell proliferation has been demonstrated in the past (Cheng et al. Oncogene 2004), the effects on CD 8 T cell proliferation when combined with checkpoint inhibitors, such as anti PD-1, are yet to be explored.

Methods

Splenocytes from a mouse model of AML with FLT3-ITD, TET2 mutations and wild type mice were collected for T cell proliferation assays. Treatment groups included: venetoclax alone and with azacitidine. On Day 3, the cells were harvested and stained for flow cytometry. CD 8 T cells were defined as CD3+CD8+CD4- and proliferation was quantified with Cell Trace Violet staining. AML blasts were defined as CD3-CD11b+.

Results

Flow cytometry analysis showed significantly increased CD8 T cell proliferation in venetoclax-treated murine AML groups in vitro, and more AML blast deaths when combined with anti PD-1 compared to the standard combination with azacitidine.

Conclusion

We found a higher population of proliferated CD 8 T cells and more blast deaths in venetoclax-treated groups when combined with anti PD-1, than azacitidine-combined groups. However, same analysis showed less T reg cell survival in azacitidine, warranting further investigation on the mechanism of the higher CD 8 T cell proliferation and increased blast deaths when Venetoclax is used with anti PD-1.

Lind:Intellia Therapeutics: Research Funding.