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Purpose: Checkpoint-inhibitors have limited efficacy for children with unselected solid and brain tumors. We report the first prospective pediatric trial (NCT02992964) using nivolumab exclusively for refractory non-hematological cancers harboring tumor mutation burden (TMB) ≥5 mutations/megabase (mut/Mb) and/or mismatch-repair deficiency (MMRD). Patients and methods: Twenty patients were screened, and ten ultimately included in the response cohort of whom nine had TMB >10mut/Mb (three initially eligible based on MMRD) and one patient had TMB between 5-10 mut/Mb. Results: Delayed immune responses contributed to best overall response of 50%, improving on initial objective responses (20%) and leading to 2-year overall survival (OS) of 50% (95% CI; 27, 93). Four children, including three with refractory malignant gliomas are in complete remission at a median follow-up of 37-months (range: 32.4-60), culminating in 2-year OS of 43% (95% CI; 18.2, 100). Biomarker analyses confirmed benefit in children with germline MMRD, microsatellite instability, higher activated and lower regulatory circulating T-cells. Stochastic mutation accumulation driven by underlying germline MMRD impacted the tumor microenvironment, contributing to delayed responses. No benefit was observed in the single patient with a MMR-proficient tumour and TMB 7.4 mut/Mb. Conclusions: Nivolumab resulted in durable responses and prolonged survival for the first time in a pediatric trial of refractory hypermutated cancers including malignant gliomas. Novel biomarkers identified here need to be translated rapidly to clinical care to identify children who can benefit from checkpoint-inhibitors, including for upfront management of their cancers.

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy., Hypermutation and microsatellite burden determine responses and long-term survival following PD-1 blockade in children and young adults with refractory cancers resulting from germline DNA replication repair deficiency.

Supplemental digital content is available in the text., Background Kidney transplant recipients (KTRs) receiving the mammalian target of rapamycin inhibitor sirolimus may display a reduced risk of skin cancer development compared to KTRs receiving calcineurin inhibitors. Despite studies investigating the effects of these 2 drug classes on T cells in patient blood, the effect these drugs may have in patient skin is not yet known. Methods Fifteen patients with chronic kidney disease (not recipients of immunosuppressive drugs), and 30 KTRs (15 receiving a calcineurin inhibitor, and 15 receiving sirolimus) provided matched samples of blood, sun exposed (SE) and non-SE skin. The abundance of total CD8+ and CD4+ T cells, memory CD8+ and CD4+ T cells, and regulatory T (Treg) cells in each sample was then assessed by flow cytometry. Results Sirolimus treatment significantly increased absolute numbers of CD4+ T cells, memory CD8+- and CD4+ T cells, and Treg cells in SE skin versus paired samples of non-SE skin. No differences were found in the absolute number of any T cell subset in the blood. Correlation analysis revealed that the percentage of T cell subsets in the blood does not always accurately reflect the percentage of T-cell subsets in the skin of KTRs. Furthermore, sirolimus significantly disrupts the balance of memory CD4+ T cells in the skin after chronic sun exposure. Conclusions This study demonstrated that immunosuppressive drug class and sun exposure modify the abundance of multiple T-cell subsets in the skin of KTRs. Correlation analysis revealed that the prevalence of Treg cells in KTR blood does not accurately reflect the prevalence of Treg cells in KTR skin.