Ira Pastan, M.D.
Ira  Pastan, M.D.
Co-Chief
Head, Molecular Biology Section

To improve the therapy of cancer, new approaches and drugs with new mechanisms of action are needed. Dr. Pastan and his team are developing a treatment that incorporates both these principles. They employ genetic engineering to modify a potent bacterial toxin, which is designed to kill many different types of cells, to one that kills cancer cells.

Pseudomonas exotoxin A (PE)
 is a three-domain protein composed of 613 amino acids. Dr. Pastan and his colleagues 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 Dr. Pastan's laboratory and his clinical team is conducting clinical trials with 3 of them.

Areas of Expertise
1) recombinant immunotoxins, 2) genetic engineering

Contact Info

Ira Pastan, M.D.
Center for Cancer Research
National Cancer Institute
Building 37, Room 5106
Bethesda, MD 20892
301-496-4797
pastani@mail.nih.gov

New Approaches to Cancer Treatment: Recombinant Immunotoxins

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 one 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 conducting clinical trials with 3 of them. Moxetumomab pasudotox (HA22) targets CD22 on B cell malignancies, LMB2 targets CD25 on T cell malignancies, and SS1P 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 MedImmune LLC and they are sponsoring clinical trials in leukemias and lymphomas expressing CD22. Recently a phase 3 trial has opened in patients with drug-resistant Hairy Cell Leukemia.

SS1P is being evaluated in clinical trials in mesothelioma, where it is combined with chemotherapy. Recently we found that some patients with advanced drug-resistant mesothelioma had profound and prolonged remissions when SS1P was combined with cytoxan and pentostatin.

Because the toxin portion of RITs is a foreign protein, patients with solid tumors who have normal immune function usually make antibodies to the RITs and inactivate them, limiting their efficacy. To allow us to give more treatment cycles and achieve better anti-tumor activity, we have designed and produced new RITs in which the major B cell epitopes and T cell epitopes in the toxin have been identified and silenced. These new agents are being developed for clinical trials.

Scientific Focus Areas:
Cancer Biology, Immunology

View Dr. Pastan's PubMed Summary.

Selected Key Publications
  1. Hassan R, Miller AC, Sharon E, Thomas A, Reynolds JC, Ling A, Kreitman RJ, Miettinen MM, Steinberg SM, Fowler DH, Pastan I.
    Sci. Transl. Med. 5: 208ra147, 2013. [ Journal Article ]
  2. Kreitman RJ, Tallman MS, Robak T, Coutre S, Wilson WH, Stetler-Stevenson M, Fitzgerald DJ, Lechleider R, Pastan I.
    J. Clin. Oncol. 30: 1822-8, 2012. [ Journal Article ]
  3. Chaudhary VK, Queen C, Junghans RP, Waldmann TA, FitzGerald DJ, Pastan I.
    Nature. 339: 394-7, 1989. [ Journal Article ]
  4. Chang K, Pastan I.
    Proc. Natl. Acad. Sci. U.S.A. 93: 136-40, 1996. [ Journal Article ]
  5. Liu W, Onda M, Kim C, Xiang L, Weldon JE, Lee B, Pastan I.
    Protein Eng. Des. Sel. 25: 41645, 2012. [ Journal Article ]

Dr. Pastan is co-chief of the Laboratory of Molecular Biology, Center for Cancer Research. He obtained his M.D. from Tufts University, received his medical training at Yale University and research training at the NIH. He established the Laboratory of Molecular Biology in 1970.

Name Position
Joan Aaron R.N. Nurse Specialist
Selamawit Addissie Postdoctoral Fellow (CRTA)
Fatima Ali-Rahmani Postdoctoral Fellow (Visiting)
Prince Awuah Postbaccalaureate Fellow
Richard Beers Research Biologist
Tapan Bera Ph.D Associate Scientist
Guilhem Combet Special Volunteer
Tyler Cunningham Postbaccalaureate Fellow
Messan Folivi Summer Student
Youjin Jang Postbaccalaureate Fellow
Gilad Kaplan Ph.D. Postdoctoral Fellow (Visiting)
Jasmin Leshem Postdoctoral Fellow (Visiting)
Xiu-Fen Liu Ph.D. Research Biologist
Alexander Lopez Summer Student
Michael Manning Postdoctoral Fellow (CRTA)
Emily Mason-Osann Postbaccalaureate Fellow
Ronit Mazor Postdoctoral Fellow (CRTA)
Timothy McNickle Laboratory Technician (Contr)
Fabian Muller Postdoctoral Fellow (Visiting)
Masanori Onda M.D., Ph.D. Staff Scientist
DongWoon Park Postdoctoral Fellow (Visiting)
Naini Shiswawala Summer Student
David Waters Ph.D. Staff Scientist (Contr)
Laiman Xiang Research Biologist

Research

New Approaches to Cancer Treatment: Recombinant Immunotoxins

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 one 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 conducting clinical trials with 3 of them. Moxetumomab pasudotox (HA22) targets CD22 on B cell malignancies, LMB2 targets CD25 on T cell malignancies, and SS1P 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 MedImmune LLC and they are sponsoring clinical trials in leukemias and lymphomas expressing CD22. Recently a phase 3 trial has opened in patients with drug-resistant Hairy Cell Leukemia.

SS1P is being evaluated in clinical trials in mesothelioma, where it is combined with chemotherapy. Recently we found that some patients with advanced drug-resistant mesothelioma had profound and prolonged remissions when SS1P was combined with cytoxan and pentostatin.

Because the toxin portion of RITs is a foreign protein, patients with solid tumors who have normal immune function usually make antibodies to the RITs and inactivate them, limiting their efficacy. To allow us to give more treatment cycles and achieve better anti-tumor activity, we have designed and produced new RITs in which the major B cell epitopes and T cell epitopes in the toxin have been identified and silenced. These new agents are being developed for clinical trials.

Scientific Focus Areas:
Cancer Biology, Immunology

Publications

View Dr. Pastan's PubMed Summary.

Selected Key Publications
  1. Hassan R, Miller AC, Sharon E, Thomas A, Reynolds JC, Ling A, Kreitman RJ, Miettinen MM, Steinberg SM, Fowler DH, Pastan I.
    Sci. Transl. Med. 5: 208ra147, 2013. [ Journal Article ]
  2. Kreitman RJ, Tallman MS, Robak T, Coutre S, Wilson WH, Stetler-Stevenson M, Fitzgerald DJ, Lechleider R, Pastan I.
    J. Clin. Oncol. 30: 1822-8, 2012. [ Journal Article ]
  3. Chaudhary VK, Queen C, Junghans RP, Waldmann TA, FitzGerald DJ, Pastan I.
    Nature. 339: 394-7, 1989. [ Journal Article ]
  4. Chang K, Pastan I.
    Proc. Natl. Acad. Sci. U.S.A. 93: 136-40, 1996. [ Journal Article ]
  5. Liu W, Onda M, Kim C, Xiang L, Weldon JE, Lee B, Pastan I.
    Protein Eng. Des. Sel. 25: 41645, 2012. [ Journal Article ]

Biography

Dr. Pastan is co-chief of the Laboratory of Molecular Biology, Center for Cancer Research. He obtained his M.D. from Tufts University, received his medical training at Yale University and research training at the NIH. He established the Laboratory of Molecular Biology in 1970.

Team

Name Position
Joan Aaron R.N. Nurse Specialist
Selamawit Addissie Postdoctoral Fellow (CRTA)
Fatima Ali-Rahmani Postdoctoral Fellow (Visiting)
Prince Awuah Postbaccalaureate Fellow
Richard Beers Research Biologist
Tapan Bera Ph.D Associate Scientist
Guilhem Combet Special Volunteer
Tyler Cunningham Postbaccalaureate Fellow
Messan Folivi Summer Student
Youjin Jang Postbaccalaureate Fellow
Gilad Kaplan Ph.D. Postdoctoral Fellow (Visiting)
Jasmin Leshem Postdoctoral Fellow (Visiting)
Xiu-Fen Liu Ph.D. Research Biologist
Alexander Lopez Summer Student
Michael Manning Postdoctoral Fellow (CRTA)
Emily Mason-Osann Postbaccalaureate Fellow
Ronit Mazor Postdoctoral Fellow (CRTA)
Timothy McNickle Laboratory Technician (Contr)
Fabian Muller Postdoctoral Fellow (Visiting)
Masanori Onda M.D., Ph.D. Staff Scientist
DongWoon Park Postdoctoral Fellow (Visiting)
Naini Shiswawala Summer Student
David Waters Ph.D. Staff Scientist (Contr)
Laiman Xiang Research Biologist