John Anderson

γδ T cells for cancer immunotherapy: A systematic review of clinical trials

γδ T cells contribute to the front line of lymphoid antitumor surveillance and bridge the gap between innate and adaptive immunity. They can be readily expanded to high numbers in vivo and in vitro, starting from the blood of cancer patients, and a number of Phase I trials have demonstrated that these cells can be employed in cancer immunotherapy. Sufficient patients have received γδ T cell-based immunotherapies in the context of clinical trials to evaluate their utility, and to inform the direction of new trials. A systematic approach was used to identify Phase I, Phase II, and feasibility studies testing γδ T cell-based immunotherapy in cancer patients. Studies were excluded from further analysis if they did not provide patient-specific data. Data were compiled to evaluate efficacy, with stratification by treatment approach. When possible, comparisons were made with the efficacy of second-line conventional therapeutic approaches for the same malignancy. Twelve eligible studies were identified, providing information on 157 patients who had received γδ T cell-based immunotherapy. The comparison of objective response data suggests that γδ T cell-based immunotherapy is superior to current second-line therapies for advanced renal cell carcinoma and prostate cancer, but not for non-small cell lung carcinoma. An evaluation of pooled data from 132 published in vitro experiments shows a consistent improvement in the cytotoxicity of γδ T cells in the presence of antitumor antibodies. Immunotherapy using γδ T cells alone shows promising clinical activity, but there is a strong preclinical rationale for combining this treatment modality with cancer-targeting antibodies to augment its efficacy.

New Strategies in Neuroblastoma: Therapeutic Targeting of MYCN and ALK

Clinical outcome remains poor in patients with high-risk neuroblastoma, in which chemoresistant relapse is common following high-intensity conventional multimodal therapy. Novel treatment approaches are required. Although recent genomic profiling initiatives have not revealed a high frequency of mutations in any significant number of therapeutically targeted genes, two exceptions, amplification of the MYCN oncogene and somatically acquired tyrosine kinase domain point mutations in anaplastic lymphoma kinase (ALK), present exciting possibilities for targeted therapy. In contrast with the situation with ALK, in which a robust pipeline of pharmacologic agents is available from early clinical use in adult malignancy, therapeutic targeting of MYCN (and MYC oncoproteins in general) represents a significant medicinal chemistry challenge that has remained unsolved for two decades. We review the latest approaches envisioned for blockade of ALK activity in neuroblastoma, present a classification of potential approaches for therapeutic targeting of MYCN, and discuss how recent developments in targeting of MYC proteins seem to make therapeutic inhibition of MYCN a reality in the clinic. Clin Cancer Res; 19(21); 5814–21. ©2013 AACR.

Clinical and pathological features of paediatric malignant rhabdoid tumours

Malignant rhabdoid tumours (MRT) and their central nervous system (CNS) counterparts atypical teratoid/rhabdoid tumours (ATRT) are rare, highly aggressive malignant neoplasms of childhood. Although there are isolated reports of long‐term survival with intensive, multimodal therapy, outcomes are generally poor.

Polyphenol E Enhances the Antitumor Immune Response in Neuroblastoma by Inactivating Myeloid Suppressor Cells

Purpose: Neuroblastoma is a rare childhood cancer whose high risk, metastatic form has a dismal outcome in spite of aggressive therapeutic interventions. The toxicity of drug treatments is a major problem in this pediatric setting. In this study, we investigated whether Polyphenon E, a clinical grade mixture of green tea catechins under evaluation in multiple clinical cancer trials run by the National Cancer Institute (Bethesda, MD), has anticancer activity in mouse models of neuroblastoma. Experimental Design: We used three neuroblastoma models: (i) transgenic TH-MYCN mouse developing spontaneous neuroblastomas; (ii) nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice xenotransplanted with human SHSY5Y cells; and (iii) A/J mice transplanted with syngeneic Neuro 2A cells. Mice were randomized in control and Polyphenon E–drinking groups. Blood from patients with neuroblastoma and normal controls was used to assess the phenotype and function of myeloid cells. Results: Polyphenon E reduced the number of tumor-infiltrating myeloid cells, and inhibited the development of spontaneous neuroblastomas in TH-MYCN transgenic mice. In therapeutic models of neuroblastoma in A/J, but not in immunodeficient NOD/SCID mice, Polyphenon E inhibited tumor growth by acting on myeloid-derived suppressor cells (MDSC) and CD8 T cells. In vitro, Polyphenon E impaired the development and motility of MDSCs and promoted differentiation to more neutrophilic forms through the 67 kDa laminin receptor signaling and induction of granulocyte colony-stimulating factor. The proliferation of T cells infiltrating a patient metastasis was reactivated by Polyphenon E. Conclusions: These findings suggest that the neuroblastoma-promoting activity of MDSCs can be manipulated pharmacologically in vivo and that green tea catechins operate, at least in part, through this mechanism. Clin Cancer Res; 19(5); 1116–25. ©2012 AACR.

Measuring disparities in sanitation access: does the measure matter?

Initiatives to monitor progress in health interventions like sanitation are increasingly focused on disparities in access. We explored three methodological challenges to monitoring changes in sanitation coverage across socio‐economic and demographic determinants: (i) confounding by wealth indices including water and sanitation assets, (ii) use of individual urban and rural settings versus national wealth indices and (iii) child‐level versus household‐level analyses.

Estimated impact and cost-effectiveness of rotavirus vaccination in India: Effects of geographic and economic disparities

India accounts for 23% of global rotavirus mortality in under-five children, with more than 100,000 deaths from rotavirus annually. Introduction of a vaccine in India is considered to be the most effective intervention for preventing rotavirus mortality. Recent research suggests that there is considerable variation in rotavirus mortality burden across regional, gender and socio-economic subpopulations within India. In addition, there is potential variability in who would likely receive rotavirus vaccine if introduced. We use available household data to estimate heterogeneity in rotavirus mortality risk, vaccination benefits, and cost-effectiveness across geographic and socio-economic groups within India. We account for heterogeneity by modeling estimated three-dose routine vaccinations as a proxy for a generalized rotavirus vaccine, and mortality for subpopulations of children aggregated by region and state, socio-economic status and sex, separately. Results are presented for six geographic regions and for Bihar, Uttar Pradesh, and Madhya Pradesh, three high mortality states accounting for 56% of national mortality estimates. Impact estimates accounting for disparities predict rotavirus vaccine introduction will prevent 35,000 deaths at an average cost of

Characterisation and Validation of Insertions and Deletions in 173 Patient Exomes

118/DALY averted (7292 INR/DALY averted). Rotavirus vaccines are most cost-effective for the poor living in high mortality regions and states. Reductions in geographic and socio-economic disparities based on regional estimates could prevent an additional 9400 deaths annually, while reductions in socio-economic disparities in the three highest morality states alone could prevent an additional 10,600 deaths annually. Understanding the impact of heterogeneity can help improve strategies to maximize the benefits of rotavirus vaccination introduction, leading to fewer lives lost as a result of rotavirus disease.

The immune environment of paediatric solid malignancies: evidence from an immunohistochemical study of clinical cases

Recent advances in genomics technologies have spurred unprecedented efforts in genome and exome re-sequencing aiming to unravel the genetic component of rare and complex disorders. While in rare disorders this allowed the identification of novel causal genes, the missing heritability paradox in complex diseases remains so far elusive. Despite rapid advances of next-generation sequencing, both the technology and the analysis of the data it produces are in its infancy. At present there is abundant knowledge pertaining to the role of rare single nucleotide variants (SNVs) in rare disorders and of common SNVs in common disorders. Although the 1,000 genome project has clearly highlighted the prevalence of rare variants and more complex variants (e.g. insertions, deletions), their role in disease is as yet far from elucidated. We set out to analyse the properties of sequence variants identified in a comprehensive collection of exome re-sequencing studies performed on samples from patients affected by a broad range of complex and rare diseases (N = 173). Given the known potential for Loss of Function (LoF) variants to be false positive, we performed an extensive validation of the common, rare and private LoF variants identified, which indicated that most of the private and rare variants identified were indeed true, while common novel variants had a significantly higher false positive rate. Our results indicated a strong enrichment of very low-frequency insertion/deletion variants, so far under-investigated, which might be difficult to capture with low coverage and imputation approaches and for which most of study designs would be under-powered. These insertions and deletions might play a significant role in disease genetics, contributing specifically to the underlining rare and private variation predicted to be discovered through next generation sequencing.

A novel small-molecule inhibitor of IL-6 signalling

Childhood malignancies are relatively poorly studied in terms of tumour/host interaction. Using tissue arrays of childhood cancers, we analysed immunohistochemical staining for CD68, CD3 and FOXP3 to evaluate infiltration of myeloid cells, lymphocytes and regulatory T cells. Staining for phosphorylated STAT3 was performed in a subset. The majority of paediatric tumours demonstrated a marked infiltration of CD68+ myeloid cells but, with the exception of neuroblastoma, most showed only sparse infiltration of CD3+/ FOXP3- cells. There was evidence for activation of STAT3 in pPNET (50%), ependymoma (45%) and undifferentiated sarcoma (38%), but it was rarely activated in other tumours.

Non-V delta 2 gamma delta T lymphocytes as effectors of cancer immunotherapy

A small library of pyrrolidinesulphonylaryl molecules has been synthesized via an efficient 4-step route, and members evaluated for their ability to inhibit IL-6 signalling. One molecule (6a) was found to have promising activity against IL-6/STAT3 signalling at the low micromolar level, and to selectively inhibit phosphorylation of STAT3 (but not STAT1) in IL-6 stimulated MDA-MB-231 breast cancer and HeLa cell lines. It was also selectively cytostatic in MDA-MB-231 (STAT3-dependent) versus A4 (STAT3-null) cells suggesting STAT3-specific inhibitory properties.