Abstract
Management for high-risk neuroblastoma (NBL) has included autologous hematopoietic stem cell transplant (HSCT) and anti-GD2 immunotherapy, but survival remains around 50%. The aim of this study was to determine if allogeneic HSCT could serve as a platform for inducing a graft-versus-tumor (GVT) effect against NBL with combination immunocytokine and NK cells in a murine model. Lethally irradiated C57BL/6 (B6) x A/J recipients were transplanted with B6 bone marrow on Day +0. On day +10, allogeneic HSCT recipients were challenged with NXS2, a GD2+ NBL. On days +14-16, mice were treated with the anti-GD2 immunocytokine hu14.18-IL2. In select groups, hu14.18-IL2 was combined with infusions of B6 NK cells activated with IL-15/IL-15Rα and CD137L ex vivo. Allogeneic HSCT alone was insufficient to control NXS2 tumor growth, but the addition of hu14.18-IL2 controlled tumor growth and improved survival. Adoptive transfer of ex vivo CD137L/IL-15/IL-15Rα activated NK cells with or without hu14.18-IL2 exacerbated lethality. CD137L/IL-15/IL-15Rα activated NK cells showed enhanced cytotoxicity and produced high levels of TNF-α in vitro, but induced cytokine release syndrome (CRS) in vivo. Infusing Perforin-/- CD137L/IL-15/IL-15Rα activated NK cells had no impact on GVT, whereas TNF-α-/- CD137L/IL-15/IL-15Rα activated NK cells improved GVT by decreasing peripheral effector cell subsets while preserving tumor-infiltrating lymphocytes. Depletion of Ly49H+ NK cells also improved GVT. Using allogeneic HSCT for NBL is a viable platform for immunocytokines and ex vivo activated NK cell infusions, but must be balanced with induction of CRS. Regulation of TNFα or activating NK subsets may be needed to improve GVT effects.
Highlights
Neuroblastoma (NBL) is the most common extracranial solid tumor that occurs in children
Because IC have never been used after allogeneic hematopoietic stem cell transplant (HSCT), we established a major histocompatibility complex (MHC)-mismatched haploidentical allogeneic HSCT model (H-2b ➔ H-2b x H-2a) whereby lethally irradiated B6AJF1 recipients were transplanted with T cell depleted B6 bone marrow (BM) and 0 – 2.5 x 106 B6 T cells on day +0 (Figure 1A)
Analysis of immune reconstitution shows a marked decrease in B220+ B cells in allogeneic HSCT recipients of 2.5 x 106 T cells (Figure 1E), a surrogate of GVHD in other murine allogeneic HSCT models [32, 33], as well as marked decreases in natural killer (NK) cells (Figure 1F) and CD8+ T cells (Figure 1G), the cells that would typically respond to IC bound to tumor [16, 25]
Summary
Neuroblastoma (NBL) is the most common extracranial solid tumor that occurs in children. The addition of the monoclonal antibody (moAb) dinutuximab (which targets the NBL-associated antigen GD2), interleukin-2 (IL-2) and granulocyte-monocyte colony stimulating factor (GM-CSF) improved event-free and overall survival [2], but is not curative for the majority of patients who will relapse and die. Another treatment approach is needed that can potentially improve survival further and lead to a long-term cure. Because of both preclinical evidence [10, 11] and case reports suggesting some clinical benefit of allogeneic HSCT in NBL, in the haploidentical setting [12, 13], the objective of this preclinical study was to incorporate haploidentical HSCT as a platform for a combined immunotherapy regimen to enhance the GVT effect against NBL
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