Expansion of infiltrating T lymphocytes in hepatocarcinoma and study of their antigenic specificity. Implication in adoptive cell therapy (HepaTIL).

Project information

Immunotherapy has emerged as a promising therapeutic approach for several malignancies, including hepatocarcinoma (HCC). Treatments with immune-checkpoint blockers have shown encouraging objective response rates and increased overall survival in patients with advanced HCC. However, approximately 30% of these patients do not respond to immune-checkpoint inhibitors, so there is a need to develop more effective treatments, or new combinations of treatments, for these patients.

Adoptive cell transfer (ACT) of tumor-infiltrating T lymphocytes (TILs) has achieved high response rates in advanced melanoma and recent studies suggest that it could become an excellent salvage treatment for those patients refractory to immune-checkpoint inhibitor therapy.

A problem in extending TIL therapy to tumors other than melanoma is the lower degree of lymphocyte infiltration that is generally present in other tumors, which makes it difficult to obtain tumor-reactive TIL end products. In melanoma and ovarian cancer it has been shown that the use of certain biomarkers, such as PD-1, allows the selection of tumor-specific T lymphocytes.

Recently our group has demonstrated that the selection and expansion of PD-1+ TILs allows obtaining highly tumor-specific TILs end product that improve the efficacy of ACT in various murine models of cancer. In HCC, 50% of TILs express PD-1. It is not yet known whether PD-1+ TILs from HCC are tumor reactive. If they are, the selection and subsequent expansion of this population would facilitate the application of ACT-TILs to the treatment of HCC.

There is increasing evidence that tumor regression from immunotherapy treatments, including ACT-TIL, is mediated by recognition of antigens (Ag) resulting from non-synonymous mutations, so-called neoantigens (NeoAgs). NeoAg-specific TILs have been detected in tumors with high mutational rate (10 mutations/Mb), such as melanoma and lung, but also in tumors with medium mutational rate (1 mutation/Mb), such as cholangiocarcinoma and breast cancer. Treatment with single neoAg-specific TIls has been able to mediate tumor regression and metastasis stabilization in a patient with cholangiocarcinoma, indicating the high potential of therapy with neoAg-specific TILs.

To date no work has addressed the antigenic specificity of HCC TILs, and whether they are able to recognize mutations present in this type of tumor. The mutation rate in HCC is 2 mutations/Mb, with a median of 45 non-synonymous mutations (range 2-381), so it is expected that neoAgs specific TILs can be detected in these tumors.

In this proposal, we propose to study the possibility of generating and expanding TILs under acceptable conditions and at acceptable levels for future clinical use by ACT, and (ii) to identify the antigenic specificity of the expanded TILs by analyzing the neoAgs they recognize. This approach will serve as a basis for developing therapeutic strategies for HCC based on ACT-TILs. In addition, it would allow the identification and validation of neoAgs with which to subsequently develop personalized vaccines for HCC.

The project is funded by the Government of Navarra Department of Health and co-financed by the European Regional Development Fund (ERDF) 2014-2020 of Navarra “A way of doing Europe”.

• Convocation: Proyectos de Investigación en Ciencias de la Salud 2017. Gobierno de Navarra Dtpo. Salud
• Reference: 45/2017
• Duration: 3 años
• Start date: December 15, 2017
• End date: December 14, 2020
• Funders: Gobierno de Navarra / Departamento de Salud, Comisión Europea
• Grant: 75.900,88 €
• Nature of project: European