Effective combination treatment of GD2-expressing neuroblastoma and Ewing's sarcoma using anti-GD2 ch14.18/CHO antibody with Vγ9Vδ2+ γδT cells.

Gamma delta T lymphocytes (γδT cells) have pleiotropic properties including innate cytotoxicity, which make them attractive effectors for cancer immunotherapy. Combination treatment with zoledronic acid and IL-2 can activate and expand the most common subset of blood γδT, which express the Vγ9Vδ2 T cell receptor (TCR) (Vδ2 T cells). Vγ9Vδ2 T cells are equipped for antibody-dependent cell-mediated cytotoxicity (ADCC) through expression of the low-affinity FcγR CD16. GD2 is a highly ranked tumor associated antigen for immunotherapy due to bright expression on the cell surface, absent expression on normal tissues and availability of therapeutic antibodies with known efficacy in neuroblastoma. To explore the hypothesis that zoledronic acid, IL-2 and anti-GD2 antibodies will synergize in a therapeutic combination, we evaluated in vitro cytotoxicity and tumor growth inhibition in the GD2 expressing cancers neuroblastoma and Ewing's sarcoma. Vδ2 T cells exert ADCC against GD2-expressing Ewing's sarcoma and neuroblastoma cell lines, an effect which correlates with the brightness of GD2 expression. In an immunodeficient mouse model of small established GD2-expressing Ewing's sarcoma or neuroblastoma tumors, the combination of adoptively transferred Vδ2+ T cells, expanded in vitro with zoledronic acid and IL-2, with anti-GD2 antibody ch14.18/CHO, and with systemic zoledronic acid, significantly suppressed tumor growth compared to antibody or γδT cell-free controls. Combination treatment using ch14.18/CHO, zoledronic acid and IL-2 is more effective than their use in isolation. The already-established safety profiles of these agents make testing of the combination in GD2 positive cancers such as neuroblastoma or Ewing's sarcoma both rational and feasible.

Neuroblastoma killing properties of Vδ2 and Vδ2-negative γδT cells following expansion by artificial antigen-presenting cells.

PURPOSE: The majority of circulating human γδT lymphocytes are of the Vγ9Vδ2 lineage, and have T-cell receptor (TCR) specificity for nonpeptide phosphoantigens. Previous attempts to stimulate and expand these cells have therefore focused on stimulation using ligands of the Vγ9Vδ2 receptor, whereas relatively little is known about variant blood γδT subsets and their potential role in cancer immunotherapy. EXPERIMENTAL DESIGN: To expand the full repertoire of γδT without bias toward specific TCRs, we made use of artificial antigen-presenting cells loaded with an anti γδTCR antibody that promoted unbiased expansion of the γδT repertoire. Expanded cells from adult blood donors were sorted into 3 populations expressing respectively Vδ2 TCR chains (Vδ2(+)), Vδ1 chains (Vδ1(+)), and TCR of other δ chain subtypes (Vδ1(neg)Vδ2(neg)). RESULTS: Both freshly isolated and expanded cells showed heterogeneity of differentiation markers, with a less differentiated phenotype in the Vδ1 and Vδ1(neg)Vδ2(neg) populations. Expanded cells were largely of an effector memory phenotype, although there were higher numbers of less differentiated cells in the Vδ1(+) and Vδ1(neg)Vδ2(neg) populations. Using neuroblastoma tumor cells and the anti-GD2 therapeutic mAb ch14.18 as a model system, all three populations showed clinically relevant cytotoxicity. Although killing by expanded Vδ2 cells was predominantly antibody dependent and proportionate to upregulated CD16, Vδ1 cells killed by antibody-independent mechanisms. CONCLUSIONS: In conclusion, we have demonstrated that polyclonal-expanded populations of γδT cells are capable of both antibody-dependent and -independent effector functions in neuroblastoma.

Regeneration of stalled immune responses to transformed and infected cells using γδ T cells.

Manipulation of the human immune system is becoming more of a therapeutic focus as a treatment option or complement. Prominent examples are the increasing use of monoclonal antibodies in combating malignant tumours, and the numerous adoptive immunotherapy trials underway. One important aspect of any use of the human immune system in this regard is to harness the power of professional antigen-presenting cells (pAPC), that is, dendritic cells (DC), to direct immune responses. Here, we review how recent findings regarding the biology of γδT cells have revealed that they, surprisingly, could serve as convenient tools for this purpose, in that they combine innate cytotoxic cell and pAPC functions in one cell type, with potential benefits in cancer immunotherapy and infectious disease.

Neonatal neuroblastoma.

Neuroblastoma, an embryonal tumour arising from the sympathetic nervous system, is the most common neonatal malignancy accounting for >20% of neonatal cancers. It may present as an antenatal adrenal mass or more commonly with localised or metastatic (4s/Ms) disease, which is usually low risk with a very good clinical outcome. Around 20% of neonatal neuroblastoma presents with spinal cord compression requiring prompt diagnosis and treatment with steroids and chemotherapy to relieve the cord compression. Patients with stage Ms disease without life- or organ-threatening symptoms or adverse genetic features (MYCN amplification or segmental chromosomal abnormalities) can be safely observed for spontaneous regression which may also occur with other localised neonatal neuroblastomas. Universal mass screening for neuroblastoma is not indicated but targeted screening of infants at risk of hereditary neuroblastoma with germline ALK or PHOX2B mutations is appropriate. Future studies will be aimed at observing more patients without adverse genetics or life-threatening features.

Preventing varicella in children with malignancies: what is the evidence?

PURPOSE OF REVIEW: The prevention of varicella in children with cancer is generally agreed to be an important goal, because of their elevated risk of varicella zoster virus (VZV)-associated morbidity and mortality. However, there is a lack of consensus on the best means of achieving this. Here, we review the existing evidence in relation to postexposure prophylaxis against varicella in this group and summarize data regarding the role of active vaccination. RECENT FINDINGS: Death from varicella during treatment for cancer is now rare, but VZV disease and its prevention remain significant problems in paediatric oncology practice. Measures to reduce VZV exposure amongst seronegative individuals are often neglected. When exposure is known to have occurred, early administration of varicella zoster immune globulin (VZIG) is generally protective against severe and complicated varicella. However, many centres in the UK and Japan use an oral antiviral agent, aciclovir, in place of VZIG. Published evidence for the efficacy of aciclovir as postexposure prophylaxis (PEP) relates mostly to healthy children, with no controlled studies in the immunocompromised. SUMMARY: Good evidence already supports the administration of varicella vaccine to healthy susceptible family contacts of children with malignancy, but not to patients themselves. Further data are urgently needed to inform the choice of PEP against VZV in the immunocompromised.