Ira Pastan, M.D.
NIH Distinguished Investigator
Laboratory of Molecular Biology
Building 37, Room 5106
Bethesda, MD 20892
Immunotoxin Therapy of Cancer
1.2 million Americans develop cancer each year and about 500,000 die from the disease. To improve the therapy of cancer new approaches and drugs with new mechanisms of action are needed. We are developing a treatment that incorporates both these principles. We employ genetic engineering to modify a potent bacterial toxin, which is designed to kill many different types of cells, to an agent that kills cancer cells.
Pseudomonas exotoxin A (PE)
is a three-domain protein composed of 613 amino acids. We have produced anti-cancer agents by deleting the binding domain of PE (aa 1-252), and replacing it with the Fv portion of an antibody that directs the toxin to a target on cancer cells. These agents are termed "recombinant immunotoxins" (RITs). They kill cells by arresting protein synthesis, a mechanism not employed by other anti-cancer agents.
Several different recombinant immunotoxins have been developed in our laboratory and we are now conducting clinical trials with 2 of them. Moxetumomab pasudotox (HA22) targets CD22 on B cell malignancies and LMB-100 targets mesothelin present on mesothelioma and many other epithelial cancers (pancreas, ovary, lung, bile duct and triple negative breast cancer).
Moxetumomab pasudotox has produced complete remissions in many patients with drug-resistant Hairy Cell Leukemia (HCL) and has also shown anti-tumor activity in childhood acute lymphoblastic leukemia (ALL). Moxetumomab pasudotox is licensed to AsraZeneca who has just completed a phase 3 trial in drug resistant Hairy Cell Leukemia.
SS1P is an anti-mesothelin immunotoxin that was evaluated in patients with advanced drug-resistant mesothelioma. When given alone SS1P had limited anti-cancer activity because of its high immunogenicity in patients with normal immune systems, but when combined with cytoxan and Pentostatin to suppress the formation of ADAs to the bacterial toxin, several striking and long term remissions were observed. To allow us to give more treatment cycles and achieve better anti-tumor activity without using immuno-suppressive drugs to prevent anti-drug antibody (ADA) formation, we have designed and produced a new RIT, LMB-100 (RG7787) in which the major B cell epitopes and T cell epitopes in the toxin have been identified and silenced. LMB-100 is now being evaluated in patients with mesothelioma and pancreatic cancer.
Current laboratory efforts are focused on
- Investigating the use of rapamycin containing nano-particles to prevent ADAs to LMB-100 and to induce specific immune tolerance to LMB-100 so many treatment cycles can be given,
- Using protein engineering to extend the half-life of immunotoxins in the blood and to decrease their non-specific side effect so higher doses can be given,
- Determining how to effectively combine immunotoxins with other anti-cancer agents (Abraxane, actinomycin D) and check point inhibitors to increase their efficacy.
- To identify new targets for immunotoxin based therapies.
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.
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
Hassan R, Thomas A, Alewine C, Le DT, Jaffee EM, Pastan I. Mesothelin Immunotherapy for Cancer: Ready for Prime Time? J Clin Oncol. 2016;34(34):4171-4179.
Liu XF, Xiang L, Zhou Q, Carralot JP, Prunotto M, Niederfellner G, Pastan I. Actinomycin D enhances killing of cancer cells by immunotoxin RG7787 through activation of the extrinsic pathway of apoptosis. Proc Natl Acad Sci U S A. 2016;113(38):10666-71.
Mazor R, Onda M, Park D, Addissie S, Xiang L, Zhang J, Hassan R, Pastan I. Dual B- and T-cell de-immunization of recombinant immunotoxin targeting mesothelin with high cytotoxic activity. Oncotarget. 2016;7(21):29916-26.
Hollevoet K, Mason-Osann E, Liu XF, Imhof-Jung S, Niederfellner G, Pastan I. In vitro and in vivo activity of the low-immunogenic antimesothelin immunotoxin RG7787 in pancreatic cancer. Mol Cancer Ther. 2014;13(8):2040-9.
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.