In the fight against cancer, immunotherapy – which aims to boost the body’s natural defences against cancer - is experiencing remarkable growth. Most of these treatments are based on CD8 T lymphocytes, ‘‘killer cells’’ able to eliminate diseased cells. A team from the University of Geneva (UNIGE) has explored an alternative approach involving CD4 T lymphocytes. Long considered mere auxiliary cells, their therapeutic potential has been considered of secondary importance. But the scientists have discovered that they also have strong killing capacity, while continuing to support other immune cells. Using cell engineering technologies, the team reprogrammed the cells to target a tumour marker found in many cancers, both in adults and children. These results, published in the journal Science Advances, offer hope for a faster therapeutic strategy that could benefit a greater number of patients.

Traditionally considered as auxiliary cells, CD4 T cells produce molecules to support the action of other immune cells by facilitating their functions, migration or proliferation in the organism. Recent work by Camilla Jandus, Assistant Professor in the Department of Pathology and Immunology, in the Centre for Inflammation Research and in the Translational Research Centre in Onco-haematology at the UNIGE Faculty of Medicine, shows that they have been vastly underestimated.

In collaboration with the CHUV-UNIL Oncology Department and the Lausanne Branch of the Ludwig Institute for Cancer Research, UNIGE scientists studied the molecular characteristics of CD4 T lymphocytes isolated from melanoma patients (a skin cancer). They identified that a unique subset of these cells bears a T cell receptor (TCR) capable of efficiently recognising an antigen specific to tumour cells: NY-ESO-1. This TCR was then isolated and artificially expressed in other CD4 T cells.

‘‘We then evaluated the effectiveness of these engineered cells against cancer cells, both in vitro and in animal models,’’ explains Camilla Jandus. ‘‘The results are impressive: they effectively target not only melanoma, but also lung, ovarian, sarcoma and brain cancers, while sparing healthy cells. This demonstrates that TCR-modified CD4 T cells can attack tumours directly, in addition to their auxiliary role’’.

The major advantage of a widespread allele

The HLA system is a set of genes responsible for immune recognition. Everyone inherits different versions of these genes, known as alleles. ‘‘They code for cell surface proteins, HLA molecules, which enable the T cells to distinguish healthy cells from pathogen infected or malignant cells,’’ explains Camilla Jandus. ‘‘The effectiveness of T cell-based therapies depends on whether the patient carries the specific HLA allele that presents the tumour antigen. The NY-ESO-1 antigen, recognised by our TCR, is presented by a widespread allele, found in about half the Caucasian population, compared to only 10 to 15% for other HLA alleles. This dramatically expands the pool of patients who could benefit, especially since the targeted antigen is expressed in many types of cancer”.

Hope for adults and children with cancers

Camilla Jandus’ team is currently preparing a clinical trial of TCR-engineered CD4-based cell therapy. The trial will include different types of cancer expressing NY-ESO-1. First, a HLA test will verify the presence of the appropriate HLA allele, and then tumours will be analysed to confirm expression of NY-ESO-1. The CD4 T cells will then be harvested, modified in the laboratory to express the TCR, multiplied and reinjected into the patient.

But Camilla Jandus envisages a further step: the creation of a bank of ready-to-use TCR engineered immune cells from healthy donors, matched to avoid rejection, which would save precious time, especially in the case of aggressive cancers. This strategy could also pave the way for treatments for cancers that are currently incurable, particularly in children. The first in vitro tests on paediatric neuroblastomas are indeed promising.

This research was supported by the ISREC Foundation, as part of the ISREC Tandem programme and the Fondazione San Salvatore.