Unleashing the tumor-specific immune response by immunotherapies such as checkpoint inhibitors or allogeneic stem cell transplantation can result in long lasting tumor regressions. It is thought that T cell responses are responsible for tumor rejection. Here we tested the hypothesis that B cells contribute to tumor regression following immunotherapy by analysing the tumor-specific antibody repertoire in patients suffering from acute myeloid leukemia (AML), a high-risk malignancy with a poor prognosis. These patients receive an allogeneic hematopoietic stem cell transplantation (HSCT) which resets the immune system and can lead to potent graft versus leukemia (GvL) responses.
We selected three patients with high-risk AML who mounted potent GvL responses after allogeneic HSCT. Of these patients we established antibody-producing clonal B cell lines following transduction of memory B cells from peripheral blood with BCL-6 and Bcl-xL and screened those for producing antibodies specifically binding to surface antigens on AML cell lines and AML blasts. A number of antibodies were identified that recognized primary AML blasts isolated from newly diagnosed AML patients, but did not bind to healthy bone marrow, peripheral blood mononuclear cells or tissues such as liver, skin and colon. Strikingly, 40% of these AML-specific antibodies induced direct cell death of cultured AML cell lines and of primary AML blasts. Cytotoxicity of the antibodies was rapid, occurred both at 37°C and 4°C and could be prevented by Cytochalasin D, an actin polymerization inhibitor that stabilizes the cytoskeleton. This, in combination with the observation that cell death could not be prevented by apoptosis inhibitors indicated that the tumor cells were killed through a necrotic pathway like oncosis. Interestingly, most cytotoxic antibodies recognized an antigen, which in normal cells is expressed in the nucleus but in AML cells is present on the membrane.
Together these data indicate that tumor selective antibodies can be elicited following allogeneic HSCT in AML patients with a strong GvL response. The direct cytotoxic activities against tumor cells of a proportion of these antibodies suggest that they contribute to the GvL response.
Citation Format: Marijn Gillissen, Martijn Kedde, Etsuko Yasuda, Sophie Levie, Arjen Bakker, Yvonne Claassen, Martino Bohne, Dave Speijer, Daisy Picavet, Jan Stap, Pauline van Helden, Tim Beaumont, Hergen Spits, Mette Hazenberg. Donor derived cytotoxic antibodies from transplanted AML patients targeting a cell surface expressed nuclear antigen. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B052.