Immune checkpoint inhibitors in Wilms' tumor and Neuroblastoma : What now?
Valind, Anders LU
and Gisselsson, David
LU
(2021)
In Cancer Reports
4(6).
- 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:... (More)
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.
(Less)
- author
- Valind, Anders
LU
and Gisselsson, David
LU
- organization
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- immune checkpoint inhibition, neoantigens, neuroblastoma, Wilms' tumor
- in
- Cancer Reports
- volume
- 4
- issue
- 6
- article number
- e1397
- publisher
- John Wiley & Sons Inc.
- external identifiers
-
- scopus:85105177455
- pmid:33932141
- ISSN
- 2573-8348
- DOI
- 10.1002/cnr2.1397
- language
- English
- LU publication?
- yes
- id
- aa9bdb87-f33c-417b-a444-af2c82a204b5
- date added to LUP
- 2021-05-31 13:24:22
- date last changed
- 2024-04-20 06:51:34
@article{aa9bdb87-f33c-417b-a444-af2c82a204b5,
abstract = {{<p>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.</p>}},
author = {{Valind, Anders and Gisselsson, David}},
issn = {{2573-8348}},
keywords = {{immune checkpoint inhibition; neoantigens; neuroblastoma; Wilms' tumor}},
language = {{eng}},
number = {{6}},
publisher = {{John Wiley & Sons Inc.}},
series = {{Cancer Reports}},
title = {{Immune checkpoint inhibitors in Wilms' tumor and Neuroblastoma : What now?}},
url = {{http://dx.doi.org/10.1002/cnr2.1397}},
doi = {{10.1002/cnr2.1397}},
volume = {{4}},
year = {{2021}},
}