A Polyvalent Cellular Vaccine Induces T-cell Responses Against Specific Self-antigens Overexpressed in Chronic Lymphocytic B-cell Leukemia

Abstract

B cell-derived chronic lymphocytic leukemia (CLL) is an incurable disease that requires innovative therapeutic regimens. Experimental approaches of immunotherapy aiming at induction of systemic T-cell responses have been developed. Trioma cells provide a potent vaccine derived from malignant B cells that allows multiple antigens (Ags) from the parental tumor to be ingested by Ag-presenting cells. Like other strategies using modified whole tumor cells, this approach induces polyvalent responses. Using trioma cell-pulsed dendritic cells (DCs) for T-cell activation in vitro, we asked whether specific Ags overexpressed by CLL can be identified as target structures of such responses and what is the nature of these Ags. Expression levels of several genes in CLL samples were quantitated by reverse transcriptase-polymerase chain reaction. T lymphocytes were polyvalently stimulated by trioma-pulsed DCs and specificities were tested by determining cytokine secretion in the presence of target cells transfected with RNA coding for those Ags that were found to be overexpressed. We demonstrate that DCs pulsed with the modified tumor cells efficiently activate T lymphocytes against CLL and that overexpressed Ags related to leukemogenesis, such as BCL-2, MDM2, and ETV5, serve as targets for those T cells. Immune escape by Ag loss or mutation is less likely to occur if immunity is directed against altered self-proteins that are involved in malignant transformation. Therefore, vaccines based on modified tumor cells such as triomas hold promise for immunotherapy of CLL and other malignancies. Polyvalent vaccines originally designed as individualized therapeutics may be more broadly applicable, at least in patients showing similar Ag patterns.

Trifunctional Bispecific Antibodies Induce Tumor-Specific T Cells and Elicit a Vaccination Effect

“…These data indicate that treatment with the trifunctional bsAb mounted a polyvalent cellular response. It has been reported by our group and others that polyvalent antitumor immunity is superior to monoclonal responses (42,45,46). Therefore, the immunizing effect of trifunctional bsAbs provides the invaluable advantage that tumor immune escape, for example, by selection of antigen loss variants, is less likely to occur.…”

Potent CD4+ T cell-associated antitumor memory responses induced by trifunctional bispecific antibodies in combination with immune checkpoint inhibition

“…This was shown by challenging mice with the parental melanoma cell line B16F0, which did not express the antigens recognized by the trAb used for vaccination. Polyvalent immune responses are thought to be superior to immunity against single TAAs because tumor immune escape due to antigen loss becomes less likely [34, 35]. …”

EBV-gp350 Confers B-Cell Tropism to Tailored Exosomes and Is a Neo-Antigen in Normal and Malignant B Cells—A New Option for the Treatment of B-CLL

“…These exosomes do not contain gp350 and, therefore, the T cells must have recognized cellular antigens. To test whether T cells specific for B-CLL-associated antigens had been reactivated, we incubated them with irradiated EBV-negative B-blasts [22] from an HLA-A2-matched donor as a negative control or B-blasts loaded with HLA-A2 restricted peptides derived from B-CLLassociated antigens, namely MDM [23], ETV5 [24] and PU.1 [25]. As shown in Figure 4D, peptide-loaded B-blasts were efficiently lysed by the T cells stimulated with CD154+/gp350+ exosomes whereas B blasts not loaded with peptides were completely ignored.…”