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Immunotherapy opportunities in uveal melanoma

SIRIC team
01/23/2019
Partager
Identifying tumor markers recognized by the immune system to develop vaccines
Mélanome uvéal - perte d'un chromosome 3

Response and resistance to immune checkpoints

O Lantz, S Piperno-Neumann, M Rodrigues, E Romano and R Barnhill

Background: Uveal melanoma is a very poorly mutated tumor that expresses few specific antigens but CD4 and CD8 effector T cells are found in the blood of approximately half of the number of patients. This indicates that there is an immune response to the presence of the tumor but it is ineffective since spontaneous regression never occurs.

Hypothesis: Identifying target tumor antigens of this inefficient tumor response and analyzing the T cell functionalities with the objective of stimulating them to obtain an efficient immune response could constitute an interesting therapeutic approach.

Objectives: Characterizing the specific tumor antigens and the differentiation program of CD4 and CD8 T cell effectors.

Neo-epitope prediction and SF3B1 mutations

O Lantz and MH Stern

Background: Splicing is a process by which RNA transcribed from genomic DNA is cut/ligated at different possible places leading to the elimination of different possible regions in the final RNA and as such the formation of different proteins. The protein coded by the SF3B1 gene is an essential factor in this splicing process.

In uveal melanoma SF3B1 is mutated for 20% of patients. These mutations lead to splicing anomalies and, consequently, the formation of new transcribed RNA sequences which then provoke the apparition of new peptides (neo-epitopes) recognized by the immune system via T cells. With bioinformatics analysis it is possible to predict these neo-epitopes and their antigenicity.

Hypothesis: Observe an immune response directed against neo-epitopes could enable the validation of antigenicity predictions and possibly open the way to vaccine development.

Objectives: Determine whether SF3B1 mutated patients have developed an immune response directed against these neo-epitopes and follow this response at different stages of the disease.

Tumor-infiltrating lymphocytes (TILs)

R Barnhill, N Cassoux, S Gardrat, O Lantz, P Mariani and E Romano

Background: It’s acknowledged that the microenvironment plays an important role in tumor development particularly because of the presence of immune cells.

Hypothesis: Comparing T cell populations present in tumor/metastatic pairs and comparing metastatic lymphoid infiltrate with healthy tissue or blood should provide important insights into the disease. This information is a prerequisite for monitoring the immune response during immunotherapy.

Objectives: Identifying on the various T cell subtypes the number of naïve effectors, CD4 and CD8 memory T cells, mucosal associated invariant T cells (MAIT) and natural killer cells (NK) as well as the expression of ICOS and PD1.

Neo-epitopes and vaccines

O Lantz, E Piaggio and C Sedlik

Background: The specific NA-17:HLA1-A2 tumor epitope is coded by an RNA messenger constantly and specifically expressed in uveal melanoma.

Hypothesis: Given the low number of mutations in uveal melanoma contrasting with the presence of an immune response observed in numerous patients, vaccination could be a promising therapeutic pathway.

Préparation d'un vaccin

Objectives: Develop a “long peptide” vaccination approach by associating the NA-17 neo epitope with an Epstein Barr virus epitope for which the memory T cells Th1 CD4 are present in the majority of individuals. Memory T cells Th1 CD4 seem to be the best cells helpze cells the tumor-specific CD8 T cells.

Projects of the uveal melanoma program