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Trial Title:
Understanding and Anticipating Therapeutic Response And Immuno-meDIated Adverse Events in Anti-cancer Immune-checkpoint Inhibition: a Tissue Biopsy Based imaGing Study
NCT ID:
NCT05921123
Condition:
Cancer
Study type:
Observational
Overall status:
Recruiting
Study design:
Time perspective:
Retrospective
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.
Detailed 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.
Criteria for eligibility:
Study pop:
All patients with tumors treated by immunotherapy with Immune Checkpoint Inhibitors
(ICI).
Sampling method:
Non-Probability Sample
Criteria:
Inclusion Criteria:
Age ≥ 18 years old
- Treated by Immune checkpoint inhibitor (ICI) for an advanced cancer
- Treated at Brest University-Hospital, Morlaix Hospital, Quimper Hospital, Clinique
Pasteur in Brest or Bordeaux University Hospital
- With a tumor or tissue biopsy (organ target of irAEs) archived in sufficient
quantity for Hyperion analysis
- For the control group: patient with an inflammatory disease (autoimmune,
autoinflammatory) who had a biopsy at diagnosis
Exclusion Criteria:
- Subject of guardianship (tutorship, curatorship)
- Refusal to participate
- Patient not meeting inclusion criteria for each point
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Brest University Hospital
Address:
City:
Brest
Zip:
29200
Country:
France
Status:
Recruiting
Contact:
Last name:
Pierre-Guillaume Poureau
Phone:
+332 98 22 37 40
Email:
pierre-guillaume.poureau@chu-brest.fr
Start date:
November 25, 2023
Completion date:
November 25, 2024
Lead sponsor:
Agency:
University Hospital, Brest
Agency class:
Other
Source:
University Hospital, Brest
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05921123