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Going back to class I: MHC and immunotherapies for childhood cancer.

ABSTRACT: After decades of unfulfilled promise, immunotherapies for cancer have reached a tipping point, with several FDA approved products now on the market and many more showing promise in both adult and pediatric clinical trials. Tumor cell expression of MHC class I has emerged as a potential determinant of the therapeutic success of many immunotherapy approaches. Here we review current knowledge regarding MHC class I expression in pediatric cancers including a discussion of prognostic significance, the opposing influence of MHC on T-cell versus NK-mediated therapies, and strategies to reverse or circumvent MHC down-regulation.

SUBMITTER: Haworth KB

PROVIDER: S-EPMC4339346 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Going back to class I: MHC and immunotherapies for childhood cancer.

Haworth Kellie B KB Leddon Jennifer L JL Chen Chun-Yu CY Horwitz Edwin M EM Mackall Crystal L CL Cripe Timothy P TP

Pediatric blood & cancer 20141218 4

After decades of unfulfilled promise, immunotherapies for cancer have reached a tipping point, with several FDA approved products now on the market and many more showing promise in both adult and pediatric clinical trials. Tumor cell expression of MHC class I has emerged as a potential determinant of the therapeutic success of many immunotherapy approaches. Here we review current knowledge regarding MHC class I expression in pediatric cancers including a discussion of prognostic significance, th ...[more]

PMID: 25524394

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Project description:BackgroundA cancer diagnosis during childhood or adolescence causes nursery and school absences to various degrees. Attending school and meeting classmates gives many children and adolescents some normality back. Nevertheless, it can cause fears and concerns among the teachers. We are currently lacking information about the fears and needs of teachers having a child or adolescent diagnosed with cancer or with a cancer history in their classes. With this study, we aim to close this knowledge gap and assess the teachers' fears, worries and information needs having a child or adolescent diagnosed with cancer in the class to develop a suitable information tool (flyer).MethodsWe performed an online survey including teachers covering all grades from nursery to vocational school within the catchment area of our hospital. The survey included separate questions for experience with students still receiving active treatment and those in follow-up care. Answer options included tick boxes and open-ended questions, which we grouped thematically. We used descriptive analysis to describe the survey findings, resulting in a newly developed flyer.ResultsIn total 358 teachers participated in the survey, 80% were female, 63% worked in nursery or primary school. One quarter (26%) had experience with a student diagnosed with cancer. Most teachers with (81%) and without (85%) experience reported at least one concern. The top three concerns reported were: (1) how to inform the class, (2) the resilience of the student and (3) how to deal with the student and his or her family. The teachers preferred oral information by physicians or parents and written information equally. Information on resilience, guidelines with an emergency situation, and the need for cancer-specific information were considered important by about 75-94% of the teachers.ConclusionMost teachers reported concerns, which we cover in a newly developed information flyer. However, such a flyer cannot replace individual communication between health care professionals and teachers. The identified concerns are likely to be transferable to other school systems and countries.

Project description:Tumour-specific mutations are ideal targets for cancer immunotherapy as they lack expression in healthy tissues and can potentially be recognized as neo-antigens by the mature T-cell repertoire. Their systematic targeting by vaccine approaches, however, has been hampered by the fact that every patient's tumour possesses a unique set of mutations ('the mutanome') that must first be identified. Recently, we proposed a personalized immunotherapy approach to target the full spectrum of a patient's individual tumour-specific mutations. Here we show in three independent murine tumour models that a considerable fraction of non-synonymous cancer mutations is immunogenic and that, unexpectedly, the majority of the immunogenic mutanome is recognized by CD4(+) T cells. Vaccination with such CD4(+) immunogenic mutations confers strong antitumour activity. Encouraged by these findings, we established a process by which mutations identified by exome sequencing could be selected as vaccine targets solely through bioinformatic prioritization on the basis of their expression levels and major histocompatibility complex (MHC) class II-binding capacity for rapid production as synthetic poly-neo-epitope messenger RNA vaccines. We show that vaccination with such polytope mRNA vaccines induces potent tumour control and complete rejection of established aggressively growing tumours in mice. Moreover, we demonstrate that CD4(+) T cell neo-epitope vaccination reshapes the tumour microenvironment and induces cytotoxic T lymphocyte responses against an independent immunodominant antigen in mice, indicating orchestration of antigen spread. Finally, we demonstrate an abundance of mutations predicted to bind to MHC class II in human cancers as well by employing the same predictive algorithm on corresponding human cancer types. Thus, the tailored immunotherapy approach introduced here may be regarded as a universally applicable blueprint for comprehensive exploitation of the substantial neo-epitope target repertoire of cancers, enabling the effective targeting of every patient's tumour with vaccines produced 'just in time'.

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Going back to class I: MHC and immunotherapies for childhood cancer.

Publications

Going back to class I: MHC and immunotherapies for childhood cancer.

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