Ignite Creation Date:
2024-05-06 @ 7:11 PM
Last Modification Date:
2024-10-26 @ 3:02 PM
Study NCT ID:
NCT05921123
Status:
RECRUITING
Last Update Posted:
2024-01-26
First Post:
2023-06-09
Brief Title:
Understanding and Anticipating Therapeutic Response And Immuno-meDIated Adverse Events in Anti-cancer Immune-checkpoint Inhibition a Tissue Biopsy Based imaGing Study
Sponsor:
University Hospital Brest
Organization:
University Hospital Brest
Study Overview
Official Title:
Understanding and Anticipating Therapeutic Response And Immuno-meDIated Adverse Events in Anti-cancer Immune-checkpoint Inhibition a Tissue Biopsy Based imaGing Study
Status:
RECRUITING
Status Verified Date:
2024-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
TADIG-R
Brief 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
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 cellsT 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 systems 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 Crohns 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
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 cellsT 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 systems 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 Crohns 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None