TIGIT in Patients With Chronic Myeloid Leukemia

Chronic Myeloid Leukemia Clinical Trial

Official title:

Expression of TIGIT in NK Cells in Patients With Chronic Myeloid Leukemia

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04818619
• Other study ID #: chronic myeloid leukemia
• Status: Not yet recruiting
• Start date: April 2021
• Est. completion date: December 2022

Study information

• Verified date: March 2021
• Source: Assiut University
• Contact: Ola Abdelkarem, M.B.B.Ch
• Phone: 00201066088250
• Email: olaabdelkarem1994[@]gmail.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

To expresse TIGIT in NK Cells in Patients with Chronic Myeloid Leukemia

Description:

Chronic myeloid leukemia (CML) is also known as chronic myelogenous leukemia. It's a type of cancer that starts in certain blood-forming cells of the bone marrow.

In CML, a genetic change takes place in an early (immature) version of myeloid cells that make red blood cells, platelets, and most types of white blood cells (except lymphocytes). This change forms an abnormal gene called BCR-ABL, which turns the cell into a CML cell. The leukemia cells grow and divide, building up in the bone marrow and spilling over into the blood. In time, the cells can also settle in other parts of the body, including the spleen. CML is a fairly slow growing leukemia, but it can change into a fast-growing acute leukemia that's hard to treat.

CML occurs mostly in adults, but very rarely it occurs in children, too. In general, their treatment is the same as for adults.

Chronic myeloid leukemia (CML) is characterized by the expression of the BCR/ABL1 fusion gene and the presence of the Philadelphia chromosome (Ph). The product of this fusion gene is a protein with deregulated tyrosine kinase activity, resulting in a malignant clonal disorder of the hematopoietic stem cells in the bone marrow (BM) and the accumulation of immature myeloid cells in peripheral blood (PB).

The use of tyrosine kinase inhibitors (TKIs) leads to a complete remission rate reaching 83%; however, mutation in the ABL kinase domain results in certain treatment failure. Furthermore, long-lasting side effects of treatment and the cost of TKIs remain a problem Therefore, the development of new TKI agents and combination therapies is urgently needed for CML patients .

Natural killer (NK) cells serve an important role in eliminating malignant cells. The cytotoxic effects of NK cells were first identified against leukemia cells, and it is now hypothesized that they may have a critical role in leukemia therapy.

The cellular functions of NK cells are mediated by their cell surface receptors, which recognize ligands on cancer cells. The role of NK cells is specifically regulated by the activating or inhibitory killer cell immunoglobulin like receptors (KIRs) on their surface, which bind to the human leukocyte antigen (HLA) class I ligands present on the target cells.

There is an abundance of evidence that NK cells can exhibit potent antitumor activity against CML, However, disease-associated mechanisms often inhibit the proper functions of endogenous NK cells, leading to inadequate tumor control and risk for disease progression.

As it is well known, the function of NK cells is precisely regulated by inhibitory and activating receptors.

Recently, T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine -based inhibitory motif (ITIM domain) (TIGIT) has been identified as a novel NK inhibitory receptor that can lead to NK cell exhaustion and dysfunction.

Targeting TIGIT is believed to restore 4 key function :Restoration of NK function, Depletion of T reg, Increase antigen-specific CD8 memory response and Induction of new antigen-specific CD8 T cells.

TIGIT was first identified as an inhibitory receptor expressed by activated CD4 Tcells , tregs and NK cells. However , direct evidence supporting a clinical role for TIGIT in AML.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 65
• Est. completion date: December 2022
• Est. primary completion date: April 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• CML patients

• Healthy individuals

Exclusion Criteria:

• Patients who have current or recent acute infection

• Patients who have autoimmune disease

• Patients who have diabetes mellitus disease

Related Conditions & MeSH terms

• Chronic Myeloid Leukemia
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid

Intervention

Diagnostic Test:
• flow cytometry test
Blood samples will be stained with TIGIT by flow cytometry test

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Assiut University

References & Publications (8)

Carlsten M, Järås M. Natural Killer Cells in Myeloid Malignancies: Immune Surveillance, NK Cell Dysfunction, and Pharmacological Opportunities to Bolster the Endogenous NK Cells. Front Immunol. 2019 Oct 11;10:2357. doi: 10.3389/fimmu.2019.02357. eCollection 2019. Review. — View Citation

Faderl S, Talpaz M, Estrov Z, O'Brien S, Kurzrock R, Kantarjian HM. The biology of chronic myeloid leukemia. N Engl J Med. 1999 Jul 15;341(3):164-72. Review. — View Citation

Heaney NB, Holyoake TL. Therapeutic targets in chronic myeloid leukaemia. Hematol Oncol. 2007 Jun;25(2):66-75. Review. — View Citation

Hughes A, Clarson J, Tang C, Vidovic L, White DL, Hughes TP, Yong AS. CML patients with deep molecular responses to TKI have restored immune effectors and decreased PD-1 and immune suppressors. Blood. 2017 Mar 2;129(9):1166-1176. doi: 10.1182/blood-2016-10-745992. Epub 2017 Jan 3. — View Citation

Kiladjian JJ, Bourgeois E, Lobe I, Braun T, Visentin G, Bourhis JH, Fenaux P, Chouaib S, Caignard A. Cytolytic function and survival of natural killer cells are severely altered in myelodysplastic syndromes. Leukemia. 2006 Mar;20(3):463-70. — View Citation

Lee HR, Baek KH. Role of natural killer cells for immunotherapy in chronic myeloid leukemia (Review). Oncol Rep. 2019 May;41(5):2625-2635. doi: 10.3892/or.2019.7059. Epub 2019 Mar 13. Review. — View Citation

O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J, Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Druker BJ; IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003 Mar 13;348(11):994-1004. — View Citation

Pizzolo G, Trentin L, Vinante F, Agostini C, Zambello R, Masciarelli M, Feruglio C, Dazzi F, Todeschini G, Chilosi M, et al. Natural killer cell function and lymphoid subpopulations in acute non-lymphoblastic leukaemia in complete remission. Br J Cancer. 1988 Sep;58(3):368-72. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	TIGIT expression frequency on NK cells	In this study, we will assay the TIGIT expression frequency on NK cells in the peripheral blood of CML patients	18 month