“Triple” Combination of Targeting Methyltransferase, BCL-2 and PD-1 Facilitates Therapeutic Responses in Acute Myeloid Leukemia (AML)

• Published in: Blood 2020-11, Vol.136 (Supplement 1), p.9-10
• Main Authors: Zeng, Zhihong, Herbrich, Shelley, Cai, Tianyu, Cavazos, Antonio, Manzella, Taylor, Ma, Helen, Kuruvilla, Vinitha Mary, Hayes, Kala, Matthews, Jairo A., DiNardo, Courtney D., Daver, Naval, Konopleva, Marina
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2020-142031

Background The long-term survival of AML, especially of older AML patients, under the established therapies remains poor. A recent breakthrough therapy of selective BCL-2 inhibitor venetoclax with hypomethylating agents (HMA) azacitidine or decitabine is approved to treat older and unfit patients with AML (DiNardo et.al. EHA 2020). This combination induces responses in > 65% of older AML patients, but the responses in relapsed/refractory AML patients are sub-optimal. Upregulation of programmed death-1 (PD-1) in T-cells is associated with AML immune-suppression, and combination of anti-PD-1 with azacitidine has activity in relapsed/refractory AML (Daver et. al. Cancer Discovery 2019). Recent pre-clinical findings indicate that venetoclax preserved T-cells immunity by sparing central memory T-cells and enhanced activity of anti-PD-1 antibodies in immune-competent mouse models in vivo (Mathew et.al. Blood 2018). In this study, we tested the hypothesis that PD-1 inhibition facilitates the depth and duration of response to venetoclax and HMA combination by reactivating T-cells mediated immunity against AML. Results We collected peripheral blood (PB) samples from trial patients before and after receiving the treatment of decitabine and venetoclax (Dec_Ven) (NCT03404193) and examined the percentage of AML blasts and T-cells by multi-parameter flow cytometry. The combination of Dec_Ven effectively reduced PB CD33+/CD34+cells from 46 ± 15% at baseline (BL) to 27 ± 16% at 2.3 days (Day 1 - 3) (time point 1, or T1), and 15 ± 13% at 5.5 days (Day 3 - 8) (T2), and increased CD3+ T-cells: 28 ± 10% (BL), 54 ± 13% (T1) and 59 ± 19 % (T2), (BL vs.T1, CD33/CD34+, p = 0.001; CD3+, p = 0.02, n = 6). The reduction of CD33+/CD34+ positively correlated with the depletion of circulating blasts (R = 0.64, p = 0.0001). Further analyzing the T-cells subsets among CD4helper cells and CD8cytotoxic cells, we found that Dec_Ven therapy promoted an activated T-cells phenotype by upregulating CD69 and PD-1 in both CD4and CD8cells in early time point samples, and led to T-cells exhaustion, as indicated by persistent expression of PD-1 at later time-point when CD69 was undetectable (PD-1 in CD3+CD4+ cells: 13 ± 2%, n = 6 (BL), 15 ± 3%, n = 6 (T1) and 22 ± 7%, n = 5 (T2); PD-1 in CD3+CD8+ cells: 14 ± 3%, n = 6 (BL), 27 ± 5%, n = 6, (T1), 29 ± 9%, n =5 (T2), BL vs. T1, p = 0.05). The persistent expression of PD-1 is a hallmark of T-cells exhaustion and immunosuppression (Jia et.al. Blood Canc