Christian M. Capitini

Modulating T-cell homeostasis with IL-7: preclinical and clinical studies

Interleukin‐7 (IL‐7) is required for the development and survival of T cells and plays a critical role in modulating T‐cell homeostasis. This review will address current understanding of IL‐7 biology, review recent clinical experiences and discuss potential future clinical applications of IL‐7, or IL‐7 blockade, in the setting of disease.

Bone marrow deficient in IFN-γ signaling selectively reverses GVHD-associated immunosuppression and enhances a tumor-specific GVT effect

Vaccine-based expansion of T cells is one approach to enhance the graft-versus-tumor effect of allogeneic bone marrow transplantation (BMT), but the complex immunobiology of the allogeneic environment on responses to tumor vaccines has not been well characterized. We hypothesized that subclinical graft-versus-host disease (GVHD) impairs immunity, but modulation of gamma interferon (IFN-gamma) signaling could reverse this effect. Dendritic cell vaccines and donor lymphocyte infusions (DLIs) were incorporated into a minor histocompatibility antigen-mismatched, T cell-depleted, allogeneic BMT mouse model. Animals were then challenged with H-Y expressing tumors. CD4(+) and CD8(+) responses to H-Y were diminished in vaccinated allogeneic versus syngeneic BMT recipients with DLI doses below the threshold for clinical GVHD, especially in thymectomized hosts. IFN-gamma receptor 1-deficient (IFN-gammaR1(-/-)) T cells cannot cause GVHD but also have diminished vaccine responses. Remarkably, IFN-gammaR1(-/-) bone marrow abrogates GVHD, allowing higher DLI doses to be tolerated, but improves vaccine responses and tumor protection. We conclude that tumor vaccines administered after allogeneic BMT can augment graft-versus-tumor if GVHD is avoided and that prevention of IFN-gamma signaling on donor bone marrow is an effective approach to preventing GVHD while preserving immunocompetence.

Extracorporeal Photopheresis Attenuates Murine Graft-versus-Host Disease via Bone Marrow–Derived Interleukin-10 and Preserves Responses to Dendritic Cell Vaccination

Extracorporeal photopheresis (ECP) is emerging as a therapy for graft-versus-host-disease (GVHD), but the full mechanism of action and the impact on immunity have not been fully established. After murine minor histocompatibility antigen-mismatched bone marrow (BM) transplantation (allo-BMT), coinfusion of ECP-treated splenocytes with T cell-replete BM attenuated GVHD irrespective of the donor strain of the ECP-treated splenocytes, and was associated with increased numbers of regulatory T cells. Coculture of myeloid dendritic cells (DCs) with ECP-treated splenocytes resulted in increased interleukin (IL)-10 production after submaximal stimulation with lipopolysaccharide. Furthermore, male myeloid DCs exposed to ECP-treated splenocytes were less potent at inducing CD8(+) HY responses when used as a vaccine in vivo. The efficacy of ECP-treated splenocytes was enhanced when administered just before delayed donor lymphocyte infusion following T cell-depleted allo-BMT, allowing for the administration of sufficient numbers of T cells to respond to myeloid DC vaccination in the absence of a thymus. Finally, the therapeutic effect of ECP-treated splenocytes was lost in recipients of IL-10-deficient BM. We demonstrate that ECP-treated splenocytes attenuate GVHD irrespective of the source of ECP-treated cells via a mechanism that likely involves modulation of DCs and requires IL-10 produced by BM-derived cells. Importantly, the attenuation of GVHD by ECP-treated splenocytes permits donor lymphocyte infusion-dependent responses to DC vaccines after allo-BMT.

Highlights of the Second International Conference on “Immunotherapy in Pediatric Oncology”

The Second International Conference on Immunotherapy in Pediatric Oncology was held in Houston, Texas, USA, October 11–12, 2010, to discuss the progress and challenges that have occurred in cutting edge immunotherapeutic strategies currently being developed for pediatric oncology. Major topics included immune targeting of acute lymphoblastic leukemia and pediatric solid tumors, chimeric antigen receptors (CARs) for hematologic malignancies and solid tumors, enhancing graft-versus-leukemia for pediatric cancers, overcoming hurdles of immunotherapy, strategies to active the innate immune system, and moving immunotherapy beyond phase I studies. Significant progress has been made in the last 2 years both in the development of novel immunobiologics such as CARs, and in establishing survival benefits of an anti-GD2 monoclonal antibody in randomized studies. Although there is much excitement going forward, a great deal of laboratory and regulatory challenges lie ahead in improving the efficacy of each of these modalities as well as getting them to patients in a timely and cost-effective fashion. The resulting discussions will hopefully lead to new collaborations and insight for further translational and clinical studies.

Highlights of the first international "immunotherapy in pediatric oncology: Progress and challenges" meeting

The first annual conference on immunotherapy in pediatric oncology was held in Bethesda, MD, from September 9 to 10, 2008 to discuss the state-of-the-art of immunotherapeutic strategies currently being explored in pediatric oncology. Major topics included targeting cell surface receptors, understanding and improving T-cell-based therapies, augmenting innate immune strategies, and enhancing graft-versus-leukemia for pediatric malignancies. As can be seen in the summaries of the individual presentations, significant progress has been made in developing preclinical models of pediatric tumors and a variety of novel immunobiologic therapies are approaching, or already in, the clinic. Although there is much excitement about the potential utility of these agents, a great deal of challenges lie ahead in improving the efficacy of each of these modalities and getting them to patients in a timely fashion. The resulting discussions will hopefully lead to new collaborations and insight for further translational and clinical studies.