Immune checkpoint inhibitors in Wilms' tumor and Neuroblastoma: What now?

Abstract

Background: Therapeutic activation of tumor-infiltrating lymphocytes using monoclonal antibodies targeting PD1 or PD-L1 (immune checkpoint inhibitors-ICIs) has revolutionized treatment of specific solid tumors in adult cancer patients, and much hope has been placed on a similar effect in relapsed or refractory solid pediatric tumors. Recent clinical trials have disappointingly shown an almost nonexistent response rate, while case reports have demonstrated that some pediatric patients do achieve durable responses when treated with this type of drug.Aim: To elucidate this paradox, we mapped the landscape of expressed neoantigens as well as the levels of immune cell infiltration in the two most common extracranial solid pediatric tumors: Wilms tumor and neuroblastoma using state-of-the-art in silico analysis of a large cohort of patients with these tumors. Methods: By integration of whole exome sequencing and RNA-sequencing, we mapped the landscape of neoantigens in the TARGET cohorts for these diagnoses and correlated these findings with known genetic prognostic markers.Results: Our analysis shows that these tumors typically have much lower levels of expressed neoantigens than commonly seen in adult cancers, but we also identify subgroups with significantly higher levels of neoantigens. For neuroblastomas, the cases with higher levels of neoantigens were confined to the group without MYCN-amplification and for Wilms tumor restricted to the TP53-mutated cases. Furthermore, we demonstrate that neuroblastomas have an unexpectedly high level of CD8+ tumor-infiltrating lymphocytes, even when compared to adult tumor types where ICI is an approved treatment. Conclusion:These results could be important to consider when designing future clinical trials of ICI treatment in pediatric patients with relapsed or refractory solid tumors.

A Novel Inflammation-Related Gene Signature for Overall Survival Prediction and Comprehensive Analysis in Pediatric Patients with Wilms Tumor

“…We further postulate that appropriate reactivation and enhancement of immune function may be beneficial for pediatric WT therapy. Furthermore, no significant treatment efficacy was observed with the use of an immune checkpoint inhibitor targeting PD-L1 for pediatric tumors, including WT patients [ 47 ]. We found that NK cells were enriched higher in high-risk patients with WT.…”

Spontaneous xenogeneicGvHDin Wilms' tumorPatient‐Derivedxenograft models and potential solutions

“… 15 The occurrence of such an unwanted event (xGvHD) in “melanoma PDX models” is quite expectable given that the melanoma is classified among the highly immunogenic tumors with high TIL density, 17 and a proper candidate for immune checkpoint inhibitor treatments. 18 , 19 However, for WT, which is not listed among lymphocyte‐predominant solid tumors, 3 , 20 the incidence of xGvHD in PDX models has been unexpected and not been reported elsewhere. Not only in xenografting of the solid tumors, but also in hematologic malignancies, the presence of cotransplanted lymphocytes can 1 mask the engraftment of the original tumor, 2 develop posttransplant lymphoproliferative disorder, or 3 cause xGvHD.…”

Checkpoint Immunotherapy in Pediatric Oncology: Will We Say Checkmate Soon?

“…Their analysis showed that non-MYCN amplified NB patients have a high neo-antigen burden. This group was, however, found to have less PD-1 and PD-L1 expression compared to adult tumors but a degree of CD8+ tumor infiltrating lymphocytes (TIL) that was comparable to adult malignancies [ 51 ]. Preclinical NB murine models have demonstrated modest response to PD-1/PD-L1 and CTLA-4 blockade [ 52 , 53 ].…”

“…This group also performed a nested case-control study and established that favorable histology patients with more than 60% expression for PD-L1 were at a high risk of treatment failure of initial therapy [ 59 ]. In a landscape paper by Valind et al, a higher neo-antigen burden was detected in TP53 -mutated WT, and this subgroup of WT patients may potentially benefit from ICI therapy [ 51 ].…”