Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): a multicentre, open-label, single-arm, phase 1–2 trial

Davis, Kara L.; Fox, Elizabeth; Merchant, Melinda S.; Reid, Joel M.; Kudgus, Rachel A.; Liu, Xiaowei; Minard, Charles G.; Voss, Stephan D.; Berg, Stacey L.; Weigel, Brenda; Mackall, Crystal L.

doi:10.1016/s1470-2045(20)30023-1

Cited by 230 publications

(247 citation statements)

References 33 publications

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“…Most pediatric solid malignancies, and some cancers of adults, are non-T cell-inflamed tumors. They are associated with low mutational burden, low numbers of neoantigens, an immunosuppressive microenvironment, and poor response rates to immune checkpoint blockade [1][2][3][4][5]. Pediatric sarcoma, in particular Ewing sarcoma (EwS), are aggressive malignancies of enigmatic histogenesis [6] with a high metastatic capacity.…”

Section: Introductionmentioning

confidence: 99%

MHC Class I-Restricted TCR-Transgenic CD4+ T Cells Against STEAP1 Mediate Local Tumor Control of Ewing Sarcoma In Vivo

Schober

Thiede

Gassmann

et al. 2020

Cells

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In this study we report the functional comparison of T cell receptor (TCR)-engineered major histocompatibility complex (MHC) class I-restricted CD4+ versus CD8+ T cells targeting a peptide from six transmembrane epithelial antigen of the prostate 1 (STEAP1) in the context of HLA-A*02:01. STEAP1 is a tumor-associated antigen, which is overexpressed in many cancers, including Ewing sarcoma (EwS). Based on previous observations, we postulated strong antitumor potential of tumor-redirected CD4+ T cells transduced with an HLA class I-restricted TCR against a STEAP1-derived peptide. We compared CD4+ T cell populations to their CD8+ counterparts in vitro using impedance-based xCELLigence and cytokine/granzyme release assays. We further compared antitumor activity of STEAP130-TCR transgenic (tg) CD4+ versus CD8+ T cells in tumor-bearing xenografted Rag2−/−γc−/− mice. TCR tgCD4+ T cells showed increased cytotoxic features over time with similar functional avidity compared to tgCD8+ cells after 5–6 weeks of culture. In vivo, local tumor control was equal. Assessing metastatic organotropism of intraveniously (i.v.) injected tumors, only tgCD8+ cells were associated with reduced metastases. In this analysis, EwS-redirected tgCD4+ T cells contribute to local tumor control, but fail to control metastatic outgrowth in a model of xenografted EwS.

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Section: Introductionmentioning

confidence: 99%

MHC Class I-Restricted TCR-Transgenic CD4+ T Cells Against STEAP1 Mediate Local Tumor Control of Ewing Sarcoma In Vivo

Schober

Thiede

Gassmann

et al. 2020

Cells

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“…The introduction of anti-GD2 immunotherapy to high-risk neuroblastoma treatment protocols has achieved some improvement in outcomes, but the number of other immunotherapies that have entered clinical trial in this disease is limited. New immunotherapies being investigated in neuroblastoma include checkpoint blockade 34 , T cell therapy 35 and NKT cell therapies 36 . Neuroblastoma is rare, with approximately 100 cases per year in the UK and therefore, in contrast to adult oncology, the number of clinical trials that can be conducted to assess new therapeutics is limited.…”

Section: Discussionmentioning

confidence: 99%

Immune characterization of pre-clinical murine models of neuroblastoma

Webb

Lanati

Wareham

et al. 2020

Sci Rep

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Immunotherapy offers a potentially less toxic, more tumor-specific treatment for neuroblastoma than conventional cytotoxic therapies. Accurate and reproducible immune competent preclinical models are key to understanding mechanisms of action, interactions with other therapies and mechanisms of resistance to immunotherapy. Here we characterized the tumor and splenic microenvironment of two syngeneic subcutaneous (NXS2 and 9464D), and a spontaneous transgenic (TH-MYCN) murine model of neuroblastoma, comparing histological features and immune infiltrates to previously published data on human neuroblastoma. Histological sections of frozen tissues were stained by immunohistochemistry and immunofluorescence for immune cell markers and tumor architecture. Tissues were dissociated by enzymatic digestion, stained with panels of antibodies to detect and quantify cancer cells, along with lymphocytic and myeloid infiltration by flow cytometry. Finally, we tested TH-MYCN mice as a feasible model for immunotherapy, using prior treatment with cyclophosphamide to create a therapeutic window of minimal residual disease to favor host immune development. Immune infiltration differed significantly between all the models. TH-MYCN tumors were found to resemble immune infiltration in human tumors more closely than the subcutaneous models, alongside similar GD2 and MHC class I expression. Finally, TH-MYCN transgenic mice were administered cyclophosphamide alone or in combination with an anti-GD2 or anti-4-1BB monoclonal antibody, which resulted in increase in survival in both combination therapies. The TH-MYCN transgenic mouse is a promising in vivo model for testing immunotherapy compounds and combination therapy in a preclinical setting.

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“…CPIs have been tested in early‐phase trials in pediatric solid tumours 61‐63 showing safety, tolerability and variable clinical efficacy. A single case of a 15‐year‐old with tRCC showed some response to fifth‐line nivolumab 64 .…”

Section: Treatmentsmentioning

confidence: 99%

Pediatric and young adult renal cell carcinoma

Ray

Jones

Pritchard‐Jones

et al. 2020

Pediatric Blood & Cancer

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Renal cell carcinoma (RCC) is rare in children but is the most common renal tumor in adults. Pediatric RCC has different clinical characteristics, histopathology, and treatment compared with adult disease. Databases were reviewed from inception to February 2020, identifying 32 publications pertaining to 350 patients under 27 years. Surgery is the cornerstone for cure in localized RCC. Lymph node dissection remains controversial. Conventional radiotherapy has no curative role in RCC; similarly, conventional chemotherapy has not proven to be effective in large cohorts. Pediatric metastatic RCC has a poor outlook. There are no published prospective studies demonstrating which adjuvant therapy could improve outcome. Sunitinib, a tyrosine kinase inhibitor, is recommended in this group despite limited evidence. This review provides an overview for pediatric RCC, including the evolving role of precision medicine. K E Y W O R D S pediatrics, renal cell carcinoma, targeted therapy, treatment 1 INTRODUCTION In Europe, around 1000 children are diagnosed with a malignant renal tumor annually. 1 Renal cell carcinomas (RCC) make up 1.9% to 6% of all kidney cancers in children. 2-5 The international incidence of childhood cancer volume 3 (IICC-3) shows that the annual incidence of pediatric RCC is increasing globally, almost doubling, in 0-to 19-year

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Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): a multicentre, open-label, single-arm, phase 1–2 trial

Cited by 230 publications

References 33 publications

MHC Class I-Restricted TCR-Transgenic CD4+ T Cells Against STEAP1 Mediate Local Tumor Control of Ewing Sarcoma In Vivo

MHC Class I-Restricted TCR-Transgenic CD4+ T Cells Against STEAP1 Mediate Local Tumor Control of Ewing Sarcoma In Vivo

Immune characterization of pre-clinical murine models of neuroblastoma

Pediatric and young adult renal cell carcinoma

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