Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05921123 |
| Other study ID # |
29BRC22.0219 (TADIG-R) |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
November 25, 2023 |
| Est. completion date |
November 25, 2024 |
Study information
| Verified date |
January 2024 |
| Source |
University Hospital, Brest |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Immune checkpoint inhibitors (ICI) have dramatically changed the management of some types of
metastatic cancer, with indications for their use continuing to expand. Despite the hope
brought by these new anti-cancer molecules, the response to ICI in these poorly
prognosticated cancers is heterogeneous, with a benefit observed in 20 to 30% of patients,
with the combination with chemotherapy or targeted therapies offering new perspectives. By
inhibiting natural checkpoints of the immune system, ICI increase the anti-tumor response,
but are also responsible for immune-related adverse events (irAEs), which can be severe.
There are many hypothesized mechanisms for these immune-related adverse events, but no one
has ever characterized in detail the immune infiltrate within the irAEs targeted tissues.
In-depth identification of cell subpopulations within the tumor microenvironment, as well as
the infiltrate within the irAEs targeted tissues, would allow the identification of new
predictive factors of response and toxicity, which could be used in clinical practice at the
time of diagnosis. A better understanding of immuno-mediated toxicities would allow to adapt
their management, which is currently based on the inflammatory diseases they mimic. The
Hyperion technology is an innovative mass cytometry imaging system, allowing the simultaneous
analysis of nearly 40 markers within a tissue.
Description:
Treatment by ICI opens two important fields of investigation: the first concerns the
prediction of the efficacy of these treatments, an important public health issue, as they are
costly and not without toxicity; and the second concerns the understanding and therefore the
management of specific immuno-mediated toxicities, which may be limiting. This project will
bring together several investigations, carried out by different investigators and coordinated
within the B Lymphocytes, Autoimmunity and Immunotherapies (LBAI), research unit (UMR 1227)
in Brest, in order to characterize the tissue actors involved in the response and the
immuno-induced toxicities, in order to establish predictive factors.
1. Tissue players involved in the anti-tumour response to ICI. Predicting the response to
ICI, both before the start of treatment and during the first few months, remains a real
challenge, particularly in view of the possibility of pseudo-progression during the
first few weeks of treatment. This question is nevertheless of vital importance, as the
indications for these molecules continue to expand, with new prospects for their
combination with chemotherapies or targeted therapies. The correlation between the
tumour immune microenvironment and response to ICI is relatively little studied in
digestive cancers, such as gastric cancer, where contradictory data exist, particularly
on the prognostic value of intra-tumour lymphocytes (TILs), which may be intra-tumour or
present in the stroma. Intratumoral regulatory T cells may have a negative effect on
responses to ICI, in contrast to intratumoral CD8+ T cells, with a possible prognostic
impact of the regulatory T cells/T cell CD8+ ratio. In contrast, the stromal infiltrate
of regulatory T cells could have a positive effect. A high infiltrate of anti-tumour M2
macrophages has been associated with poorer survival in several solid cancers, in
contrast to M1 macrophages in gastric cancer. In hepatocellular carcinoma, PDL1
expression by tumour cells is low and heterogeneous, but PDL1 expression by host cells,
such as innate immune cells, can inhibit the cytotoxic activity of CD8+ T cells. The
role of M1 macrophages remains unclear.
2. Tissue players involved in immune-mediated toxicities. By inhibiting the immune system's
natural checkpoints, ICI increase the anti-tumour response, but this also leads to a
loss of peripheral tolerance mechanisms and therefore to the appearance of
immuno-induced side-effects (irAEs), which can affect all organs and mimic genuine
autoimmune diseases. Depending on the ICI used, the type and frequency of irAEs differ,
with a frequency of up to 70% for anti-PD-(L)-1 and up to 90% for anti-CTLA-4. The
digestive tract is the second most frequently affected organ after the skin, with the
occurrence of immuno-induced diarrhoea and colitis, sharing macroscopic features with
Crohn's disease. Approximately 6% of patients may present with rheumatological
involvement, with a variety of phenotypes, most often mimicking polyarthritis,
polymyalgia rheumatica (PMR) or oligoarthritis of the large joints. Several hypotheses
have been put forward to explain the appearance of irAEs, most of which are based on the
T cell effector due to the mechanism of action of ICI. The hypothesis of
cross-reactivity between a tumour antigen and a self antigen has been put forward to
explain the occurrence of irAEs, as for example in cases of vitiligo occurring under
immunotherapy in metastatic melanomas, with antigens shared between tumour and
non-tumour melanocytes. The role of regulatory T cells (Tregs) has also been suggested.
The level of circulating IL17 at the initiation of ICI has also been associated with the
risk of colitis. Two recent studies have investigated synovial biopsies from
immune-induced arthritis using immunohistochemistry and flow cytometry techniques after
disaggregation. The first revealed the presence of memory T cells and macrophages, and
demonstrated the production of TNF alpha. The other found T cells, with CD4 slightly
over-represented compared with CD8, and B cells in equivalent proportion, as well as
macrophages. However, no study has ever accurately characterised the inflammatory
infiltrate, either within the articular synovium or within the digestive mucosa, via the
simultaneous study of numerous markers, with a spatial dimension. Nor has this been done
in the skin in the case of cutaneous toxicity of ICI, or in the salivary glands in the
case of immuno-induced dry syndrome, for example.
3. Hyperion technology. The Hyperion imaging technology is an innovative technology within
the LBAI research unit (UMR1227) in Brest, enabling the expression of 37 markers to be
assessed on a tissue slide, and thus the sub-populations of immune cells within a tissue
to be quantified precisely, at cellular and sub-cellular level with a resolution of 1
µm2.
