Vla-4 clinical trials

This insight, together with valuable data gained from more systemic analyses that are possible in animal models, may reveal more functions of VLA-4 and further enhance its prognostic and predictive potential for B cell- and other malignancies in the future.

The integrin family of adhesion molecules. In I domain containing integrins e. B Schematic structure of the VLA-4 integrin and its domains.

Integrin signaling pathways in B cells. Affinity upregulation can be initiated by various cellular receptors, e. Affinity states of VLA Modes of VLA-4 activation. An overall increase in cellular adhesiveness can be achieved by either of the following processes: A affinity modulation of the ligand binding domain, leading to increased stability of receptor-ligand bonds B extension of the integrin molecule, leading to an increased accessibility of the ligand-binding site for surface-bound ligands or C clustering of integrins on the cell surface, leading to a local increase in the number of receptor—ligand bonds.

Cellular activation often involves a combination of two or three of these processes; however, they can also occur separately. Conceptualization, A. All authors have read and agreed to the published version of the manuscript. National Center for Biotechnology Information , U. Int J Mol Sci. Published online Mar Find articles by Antonella Zucchetto. Find articles by Valter Gattei. Author information Article notes Copyright and License information Disclaimer.

Received Feb 14; Accepted Mar This article has been cited by other articles in PMC. Abstract Lineage commitment and differentiation of hematopoietic cells takes place in well-defined microenvironmental surroundings. Integrins in the Hematopoietic System The communication between hematopoietic cells and their microenvironment in primary and secondary lymphoid organs is relevant for the functioning of immune cells, and disturbances in this communication are characteristic of hematologic neoplasia.

Lessons Learned from Natalizumab A therapeutic potential of VLA-4 inhibition in cancer could be most reasonable as a combination approach. Conclusion and Future Perspectives of VLA-4 as a Therapeutic Target VLA-4 has been known for a long time as an essential homing and retention factor of hematopoietic stem- and progenitor cells. Open in a separate window. Scheme 1.

Scheme 2. Scheme 3. Scheme 4. Author Contributions Conceptualization, A. Conflicts of Interest The authors declare no conflict of interest. References 1. Humphries J. Integrin Ligands at a Glance. Pt 19 J. Cell Sci. Bertoni A. Integrins in T Cell Physiology. Chigaev A. Huhtala M. Matrix Biol. Carrasco Y.

EMBO J. Chen C. Agents Actions Suppl. Hui T. Spessotto P. Pt 21 J. Verdone G. Imhof B. Adhesion Mechanisms Regulating the Migration of Monocytes. Arroyo A. Ryan D. Postigo A. Rossi B. Patrick C. Spiegel A. Harima A. Shalapour S. Hinterseer E.

Beck T. Pereira J. Tedford K. Camponeschi A. Heinig K. Cancer Discov. Stache V. Tian Y. Robles E. Chopin M. Manevich-Mendelson E. Ousman S. Immune Surveillance in the Central Nervous System. Stuve O. Parker Harp C.

Lehmann-Horn K. Spaargaren M. Zucchetto A. Benedetti D. Bulian P. Gattei V. Shanafelt T. Tissino E. Deaglio S. Lucas F. Target Oncol. Arana E. Szenes E. Moreno O. Alon R. Cell Biol. Patients with substantial tumor burden of non-measurable disease may not be good candidates for an immunotherapy and should be discussed with the Medical Monitor. ECOG performance status of Key Exclusion Criteria: Patients with tumors to be injected lying close to an airway, major blood vessel or spinal cord that, in the opinion of the Investigator, could cause occlusion or compression in the case of tumor swelling or erosion into a major vessel in the case of necrosis.

Patients with lesions in mucosal areas vulvar, anus, oral cavity, etc. Patients with active, known or suspected autoimmune disease except for autoimmune thyroiditis or vitiligo. Thyroiditis patients must be asymptomatic, on adequate thyroid replacement and have normal thyroid function tests. Patients with active colitis or immune-mediated colitis that has not resolved to grade 1 or less.

Patients with untreated brain metastases. Patients with treated brain metastases who are off corticosteroids for at least two weeks and who demonstrate control of brain metastases with follow-up imaging 4 or more weeks after initial therapy are eligible. Patients previously treated with CVA Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials. More Information. National Library of Medicine U. National Institutes of Health U. Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Phase 1. As a consequence, patients taking Tysabri are required to have regular liver function tests and treatment discontinued in any patient judged at risk. Tysabri natalizumab is a SAM inhibitor that works by binding to cell surface receptors known as alphabeta-1 VLA-4 and alphabeta-7 integrins.

Alpha-4 integrins are important in mediating the migration of leukocytes white blood cells from the bloodstream to sites of inflammation in the tissues. By binding to alpha-4 integrin receptor sites, Tysabri selectively blocks leukocyte adhesion to blood vessel walls and subsequent migration of these immune cells to sites of chronic inflammation, where they can exacerbate the inflammatory process.

Leukocytes are believed to mediate the damage to the protective myelin sheath of nerve cells seen in multiple sclerosis. Estimates suggest that worldwide around 2. After trauma, it is the second most common neurological disability to affect young and middle-aged adults. The clinical efficacy of Tysabri in MS is supported by data from a number of clinical trials, including the pivotal phase III AFFIRM natalizumab safety and efficacy in relapsing-remitting MS trial that was designed to assess the ability of Tysabri to slow the progression of disability primary endpoint as well as reduce the rate of clinical relapse.

Sustained and statistically significant reductions in brain lesion activity as measured by MRI were also seen in the Tysabri treatment arm. Results over two years showed that the addition of Tysabri to ongoing interferon beta-1a therapy had a significant effect on disability progression, relapse rate and brain MRI disease activity compared to interferon beta-1a therapy alone.