Acute myeloid leukemia (AML) is an aggressive hematological malignancy that has been treated in the same way for the last several decades and typically includes standard chemotherapy protocols as well as bone marrow (BM) transplantation. Despite advances in the field of immunotherapy, AML has been challenging to treat with immune checkpoint inhibitors that target Programmed Death (PD) - 1/PD-Ligand (L) 1 inhibitors.
PD-1 is an immune checkpoint molecule that functions as a negative costimulatory receptor on various lymphocytes1. PD-1 interacts with its ligand PD-L1, which is expressed numerous tissues, and normal PD-1/PD-L1 interactions are important for immune tolerance and responding to infections2. Elevated PD-1 expression on T cells is a marker of cell exhaustion, which is exhibited as poor cytokine production and reduced antigen-specific proliferation3. In AML, CD4+ effector T cells, CD8+ T cells and Tregs in the bone marrow have been shown to have elevated PD-1, and this is likely to drive immunosuppression in the bone marrow, which results in CD8+ T cell dysfunction and poor antitumor responses4. Regulatory T cells (Tregs) and myeloid derived suppressor cells are thought to contribute to this immunosuppressive environment5, and AML patients typically have elevated levels of Tregs in the BM compared with healthy individuals6. AML blasts have also been shown to express PD-L1, especially in relapsed or refractory patients, and this has been associated with poor outcomes7.
Antibody-based PD-1/PD-L1 blockade treatments are being widely used for a diverse array of solid tumors and blood cancers. This type of treatment can restore CD8+ T cell antitumor responses and reverse immunosuppressive environment in the BM. Several clinical trials using PD-1/PD-L1 blockade (ipilimumab or nivolimumab) have been carried out in AML patients, especially relapsed patients, either as a monotherapy or in combination with chemotherapy or following bone marrow transplantation8,9. There continues to be a subset of AML patients that do not respond or respond poorly to PD-1/PD-L1 blockade. This type of treatment can be costly and lead to a poor prognosis in the absence of a robust response, so ex vivo tests are being developed that can evaluate the likelihood of a patient to respond to PD-1/PD-L1 blockade treatments. One approach includes ex vivo evaluation of a patient’s AML blasts and autologous T cells in the presence of different drugs or therapeutics, like a PD-1/PD-L1 inhibitor. T cell responses against AML cells can be measured in this test and used to better predict the likelihood that a patient would respond to such a treatment.
As new treatment options become available to AML patients, better ex vivo screening methods are critical to matching the right treatment to each patient. These methods not only help maximize treatment efficacy, but they also help avoid unnecessary and costly treatments that can hurt the long-term prognosis of a patient.
1. Blackburn SD, Shin H, Haining WN, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection., Nat Immunol, 2009, vol. 10 1(pg. 29-37)
2. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity., Annu Rev Immunol, 2008, vol. 26 (pg. 677-704)
3. Wherry EJ, Ha SJ, Kaech SM, et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection., Immunity, 2007, vol. 27 4(pg. 670-684).
4. Williams P, Basu S, Garcia-Manero G, Hourigan CS, Oetjen KA, Cortes JE, Ravandi F, Jabbour EJ, Al-Hamal Z, Konopleva M, Ning J, Xiao L, Hidalgo Lopez J, Kornblau SM, Andreeff M, Flores W, Bueso-Ramos C, Blando J, Galera P, Calvo KR, Al-Atrash G, Allison JP, Kantarjian HM, Sharma P, Daver NG. The distribution of T-cell subsets and the expression of immune checkpoint receptors and ligands in patients with newly diagnosed and relapsed acute myeloid leukemia. Cancer. 2019 May 1;125(9):1470-1481.
5. Mussai F, De Santo C, Abu-Dayyeh I, Booth S, Quek L, McEwen-Smith RM, et al. Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment. Blood. (2013) 122:749–58.
6. Henghui Z, Yixiang H, Jianbo W, Kang Y, Laixi B, Yan Z, et al. Elevated frequencies of CD4+ CD25+ CD127lo regulatory T cells is associated to poor prognosis in patients with acute myeloid leukemia. Int J Cancer. (2011) 129:1373–81.
7. Annibali O., Crescenzi A., Tomarchio V., Pagano A., Bianchi A., Grifoni A., Avvisati G. PD-1 /PD-L1 checkpoint in hematological malignancies. Leuk. Res. 2018;67:45–55
8. Daver N., Garcia-Manero G., Basu S., Boddu P.C., Alfayez M., Cortes J.E., Konopleva M., Ravandi-Kashani F., Jabbour E., Kadia T.M., et al. Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Non-randomized, Open-label, Phase 2 Study. Cancer Discov. 2018 doi: 10.1158/2159-8290.CD-18-0774.
9. Albring J.C., Inselmann S., Sauer T., Schliemann C., Altvater B., Kailayangiri S., Rössig C., Hartmann W., Knorrenschild J.R., Sohlbach K., et al. PD-1 checkpoint blockade in patients with relapsed AML after allogeneic stem cell transplantation. Bone Marrow Transplant. 2017;52:317–320