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Ferrata Storti Foundation
Haematologica 2021 Volume 106(5):1330-1342
Cell Therapy & Immunotherapy
Leukemia vaccine overcomes limitations of checkpoint blockade by evoking clonal T-cell responses in a murine acute myeloid leukemia model
Dina Stroopinsky,1* Jessica Liegel,1* Manoj Bhasin,1* Giulia Cheloni,1 Beena Thomas,1 Swati Bhasin,1 Ruchit Panchal,1 Haider Ghiasuddin,1 Maryam Rahimian,1 Myrna Nahas,1 Shira Orr,1 Marzia Capelletti,1 Daniela Torres,1 Cansu Tacettin,1 Matthew Weinstock,1 Lina Bisharat,1 Adam Morin,1 Kathleen M. Mahoney,2 Benjamin Ebert,2 Richard Stone,2 Donald Kufe,2 Gordon J. Freeman,2 Jacalyn Rosenblatt1# and David Avigan1#
1Beth Israel Deaconess Medical Center, Harvard Medical School and 2Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
*DS, JL and MB contributed equally as co-first authors. #JR and DA contributed equally as co-senior authors.
ABSTRACT
We have developed a personalized vaccine in which patient- derived leukemia cells are fused to autologous dendritic cells, evoking a polyclonal T-cell response against shared antigens and neoantigens. We postulated that the dendritic cell/acute myeloid leukemia fusion vaccine would demonstrate synergy with checkpoint blockade by expanding tumor antigen-specific lymphocytes that would provide a critical substrate for checkpoint blockade-mediated activation. Using an immunocompetent murine leukemia model, we examined the immunological response to and therapeutic efficacy of vaccination in conjunction with checkpoint blockade with respect to leukemia engraft- ment, disease burden, survival and the induction of tumor-specific immunity. Mice treated with checkpoint blockade alone had rapid pro- gression of leukemia and only a modest extension of survival. Vaccination with dendritic cell/acute myeloid leukemia fusions resulted in the expansion of tumor-specific lymphocytes and disease eradication in a subset of animals, while the combination of vaccination and check- point blockade induced a fully protective tumor-specific immune response in all treated animals. Vaccination followed by checkpoint blockade resulted in upregulation of genes regulating activation and pro- liferation in memory and effector T cells. Long-term survivors exhibited increased T-cell clonal diversity and were resistant to subsequent tumor challenge. The combination of dendritic cell/acute myeloid leukemia fusion vaccine and checkpoint blockade treatment offers unique synergy, inducing durable activation of leukemia-specific immunity, protection from lethal tumor challenge and the selective expansion of tumor-reac- tive clones.
Introduction
While acute myeloid leukemia (AML) is often initially sensitive to cytotoxic thera- py, responses are typically transient because of the presence of clonal populations with intrinsic resistance to chemotherapy.1 The potency of cell-based immunothera- py for patients with AML is supported by the observation that allogeneic transplan- tation is uniquely curative for a subset of patients, being mediated by alloreactive lymphocytes.2 However, therapeutic efficacy is limited by associated toxicity of graft- versus-host disease arising from the lack of specificity of the immune response.3 A major area of investigation is the development of immunotherapeutic strategies to
Correspondence:
DINA STROOPINSKY
dstroopi@bidmc.harvard.edu
Received: May 20, 2020. Accepted: December 11, 2020. Pre-published: February 4, 2021.
https://doi.org/10.3324/haematol.2020.259457
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