Research Topics
Mesothelin as a Target for Cancer Therapy by CAR-T cells and Bispecific Antibodies
To improve the therapy of cancer new approaches and drugs with unique mechanisms of action are needed. Mesothelin is a popular target on solid tumors. It was discovered by Ira Pastan and Mark Willingham in LMB, NCI. It is a lineage restricted cell surface protein that is highly expressed by many cancers, and only a few non-essential tissues. The specificity of mesothelin expression makes it a popular target for antibody-based therapies, but shed mesothelin has been found to be a major barrier to these therapies. To overcome the shedding problem, Pastan and collaborators developed Mab 15B6 that binds to a juxta-membrane region of mesothelin and does not bind to shed mesothelin. Mab 15B6 was used to make CAR T cells and bispecific (T cell engagers that have high anti-tumor activity in mice. An improved CAR-T cell variant is being prepared for clinical trials in human with mesothelin expressing cancers.
Biography
Dr. Ira Pastan was educated at the Boston Public Latin School, Tufts College, and Tufts Medical School. He did his residency at the Yale School of Medicine (1957-1959) and came to NIH in 1959. In 1970, he founded the Laboratory of Molecular Biology in the NCI.
Major honors
Van Meter Prize, 1971
G. Burroughs Mider Lectureship, National Institutes of Health, 1973
Membership, National Academy of Sciences, 1982
American Academy of Arts and Sciences, 1997
Fellow, American Academy of Microbiology, 1997
Fellow, American Association for the Advancement of Science, 1997
International Feltrinelli Prize for Medicine, 2009
Nathan Davis Award of the AMA for Government Service, 2010
Membership, Institute of Medicine of the National Academies, 2010
AACR Team Science Award, 2014
Humbert Humphrey Award, DHHS, 2019
Selected Publications
- Hassan R, Miller AC, Sharon E, Thomas A, Reynolds JC, Ling A, Kreitman RJ, Miettinen MM, Steinberg SM, Fowler DH, Pastan I. Major cancer regressions in mesothelioma after treatment with an anti-mesothelin immunotoxin and immune suppression. Sci Transl Med. 2013;5(208):208ra147.
- Liu W, Onda M, Kim C, Xiang L, Weldon JE, Lee B, Pastan I. A recombinant immunotoxin engineered for increased stability by adding a disulfide bond has decreased immunogenicity. Protein Eng Des Sel. 2012;25(1):1-6.
- Kreitman RJ, Tallman MS, Robak T, Coutre S, Wilson WH, Stetler-Stevenson M, Fitzgerald DJ, Lechleider R, Pastan I. Phase I trial of anti-CD22 recombinant immunotoxin moxetumomab pasudotox (CAT-8015 or HA22) in patients with hairy cell leukemia. J Clin Oncol. 2012;30(15):1822-8.
- Chang K, Pastan I. Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers. Proc Natl Acad Sci U S A. 1996;93(1):136-40.
- Chaudhary VK, Queen C, Junghans RP, Waldmann TA, FitzGerald DJ, Pastan I. A recombinant immunotoxin consisting of two antibody variable domains fused to Pseudomonas exotoxin. Nature. 1989;339(6223):394-7.
Related Scientific Focus Areas
Biomedical Engineering and Biophysics
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Molecular Biology and Biochemistry
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This page was last updated on Wednesday, October 23, 2024