Biologic activity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic stem cell transplantation

Abstract

Through an immune-mediated graft-versus-leukemia effect, allogeneic hematopoietic stem cell transplantation (HSCT) affords durable clinical benefits for many patients with hematologic malignancies. Nonetheless, subjects with high-risk acute myeloid leukemia or advanced myelodysplasia often relapse, underscoring the need to intensify tumor immunity within this cohort. In preclinical models, allogeneic HSCT followed by vaccination with irradiated tumor cells engineered to secrete GM-CSF generates a potent antitumor effect without exacerbating the toxicities of graft-versus-host disease (GVHD). To test whether this strategy might be similarly active in humans, we conducted a Phase I clinical trial in which high-risk acute myeloid leukemia or myelodysplasia patients were immunized with irradiated, autologous, GM-CSF-secreting tumor cells early after allogeneic, nonmyeloablative HSCT. Despite the administration of a calcineurin inhibitor as prophylaxis against GVHD, vaccination elicited local and systemic reactions that were qualitatively similar to those previously observed in nontransplanted, immunized solid-tumor patients. While the frequencies of acute and chronic GVHD were not increased, 9 of 10 subjects who completed vaccination achieved durable complete remissions, with a median follow-up of 26 months (range 12-43 months). Six long-term responders showed marked decreases in the levels of soluble NKG2D ligands, and 3 demonstrated normalization of cytotoxic lymphocyte NKG2D expression as a function of treatment. Together, these results establish the safety and immunogenicity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic HSCT, and raise the possibility that this combinatorial immunotherapy might potentiate graft-versus-leukemia in patients.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Clinical protocol schema for vaccination early after allogeneic HSCT. Bu, busulfan; Flu, fludarabine; MTX, methotrexate; PBSC, peripheral blood stem cells.

Fig. 2.

Irradiated, GM-CSF secreting, autologous leukemia cells elicit local vaccine reactions early after allogeneic HSCT. (Top Left) Dermal cellular infiltrates, magnification 20× 20 (H&E). (Top Right) Eosinophil degranulation and lymphocyte infiltrates, magnification 500× (H&E). (Middle and Bottom) CD4, CD8, CD1a, and CD20, magnification 250×. Arrows denote dendritic cells.

Fig. 3.

DTH reactions to irradiated, autologous, nontransduced leukemia cells following vaccination. CD4, CD8, and CD1a, magnification 500×; CD20, magnification 250×.

Fig. 4.

Vaccination after HSCT is associated with an antileukemic immune response in the bone marrow. (Left) Arrows depict eosinophil infiltrates, magnification 400×. (Right) CD3, magnification 400×.

Fig. 5.

Clinical responses to vaccination after HSCT are linked with marked decreases in soluble MICA and MICB. (A) Longitudinal analysis of patient MYTX-14. Small upward arrows denote vaccinations. (B) Patient MYTX-23. (C) Patient MYTX-12. (D) Hematologic malignancy subjects that achieved clinical remissions to HSCT alone.

Fig. 6.

Clinical responses to vaccination after HSCT are associated with normalization of NKG2D surface expression. Peripheral blood mononuclear cells were obtained before HSCT and after vaccination, and NKG2D expression on NK cells (CD56+, CD3–) and CD8+ T cells (CD8+, CD3+) was determined with flow cytometry. (A) Patient MYTX-19. (B) Patient MY-TX-26.