Journal
FRONTIERS IN IMMUNOLOGY
Volume 10, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2019.02213
Keywords
cutaneous melanoma; CSF-470 vaccine; vaccination site; cutaneous metastasis; tumor infiltrating lymphocytes; TCR beta repertoire
Categories
Funding
- CONICET
- Instituto Nacional del Cancer-Ministerio de Salud de la Nacion Argentina (INC-MSal) INC III [IS001946]
- Fundacion Sales
- Fundacion Cancer
- Fundacion Pedro F. Mosoteguy, Argentina
- Laboratorio Pablo Cassara S.R.L.
Ask authors/readers for more resources
The CSF-470 cellular vaccine plus BCG and rhGM-CSF increased distant metastases-free survival in cutaneous melanoma patients stages IIB-IIC-III relative to medium dose IFN-alpha 2b (CASVAC-0401 study). Patient-045 developed a mature vaccination site (VAC-SITE) and a regional cutaneous metastasis (C-MTS), which were excised during the protocol, remaining disease-free 36 months from vaccination start. CDR3-TCR beta repertoire sequencing in PBMC and tissue samples, along with skin-DTH score and IFN-gamma ELISPOT assay, were performed to analyze the T-cell immune response dynamics throughout the immunization protocol. Histopathological analysis of the VAC-SITE revealed a highly-inflamed granulomatous structure encircled by CD11c(+) nested-clusters, brisk CD8(+) and scarce FOXP3(+), lymphocytes with numerous Langhans multinucleated-giant-cells and macrophages. A large tumor-regression area fulfilled the C-MTS with brisk lymphocyte infiltration, mainly composed of CD8(+)PD1(+) T-cells, CD20(+) B-cells, and scarce FOXP3(+) cells. Increasing DTH score and IFN-gamma ELISPOT assay signal against the CSF-470 vaccine-lysate was evidenced throughout immunization. TCR beta repertoire analysis revealed for the first time the presence of common clonotypes between a VAC-SITE and a C-MTS; most of them persisted in blood by the end of the immunization protocol. In vitro boost with vaccine-lysate revealed the expansion of persistent clones that infiltrated the VAC-SITE and/or the C-MTS; other persistent clones expanded in the patient's blood as well. We propose that expansion of such persistent clonotypes might derive from two different although complementary mechanisms: the proliferation of specific clones as well as the expansion of redundant clones, which increased the number of nucleotide rearrangements per clonotype, suggesting a functional antigenic selection. In this patient, immunization with the CSF-470 vaccine plus BCG and rhGM-CSF induced a T-cell repertoire at the VAC-SITE that was able to infiltrate an emerging C-MTS, which resulted in the expansion of a T-cell repertoire that persisted in blood by the end of the 2-year treatment.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available