Nicholas P. Restifo, M.D.
Nicholas P. Restifo, M.D.
Senior Investigator

Dr. Restifo pioneered the use of molecularly defined T cell-based immunotherapies by developing mouse models with predictive value for human clinical trials. The Restifo group was amongst the first to identify myeloid-derived cell subsets that impair anti-tumor T cell responses. His work on immunoablation underlies many of the current generation of cellular therapies in the clinic. Dr. Restifo’s group was the first to discover a novel subset of long-lived human T memory stem cells in humans. These fundamental discoveries are aimed at improving the treatment of adults and children with metastatic cancer.

Areas of Expertise
1) immunotherapy 2) immunoablation 3) adoptive cell therapy 4) novel mouse tumor models 5) T cell development 6) T memory stem cells

Contact Info

Nicholas P. Restifo, M.D.
Center for Cancer Research
National Cancer Institute
Building 10 - Hatfield CRC, Room 3-5762
Bethesda, MD 20892
301-496-4904
restifo@nih.gov

Designing Potent New Cancer Immunotherapies

Our goal is to design new immunotherapies for patients with advanced cancer. Our strategy is based on the use of animal models and human in vitro assays to test hypotheses. We then translate the most promising of these therapies into human clinical trials, which often generate new questions to be tested experimentally. The process is an iterative one that involves close collaboration with basic researchers, biotech scientists and experimental clinicians.

Our work focuses on immunotherapy based on the adoptive transfer of naturally-occurring and gene-engineered tumor-specific T cells. We explore the signals that T cells receive within tumor masses, and what T cells must do to trigger the eradication of tumor cells.

Current efforts are focused on the use of stem cell-like anti-tumor T cells to induce curative responses patients with metastatic cancer who have failed other available forms of therapy. These efforts are aimed at reprogramming the exhausted and senescent T cells that are characteristic of the immune response to growing tumors. We currently treat about 120 patients per year with naturally-occurring or gene-engineered adoptively transferred T cells.

Effectiveness of T cell-based immunotherapies. T cell-based immunotherapy using naturally-occurring and genetically-engineered T cells is demonstrably capable of inducing complete and probably curative responses in some patients with advanced metastatic cancer. Significant evidence indicates that less-differentiated T cells, including those that have longer telomeres and higher levels of CD27, are associated with a greater likelihood of objective response in adoptive T cell therapy (ACT). These findings are corroborated in our tumor-specific T-cell receptor transgenic murine model (Pmel-1) in which there is a progressive loss of anti-tumor function as T-cells mature towards terminal differentiation. The robust clinical response associated with less-differentiated phenotypes of anti-tumor T cells suggests that the efficacy of ACT may be improved with transfer of less-differentiated cells.

In new work from our laboratory (Roychoudhuri R, et al., Nature, in press) as well as unpublished experiments, we have identified several candidate transcription factors that are differentially expressed in naive and stem cell-like T cells and have preliminary evidence that a retroviral transduction of these transcription factors results in successful reprogramming. We are exploring the possibilities that lineage reprogramming of terminally differentiated T cells could significantly improve the effectiveness of ACT in treating patients with metastatic cancer. Alternatively, nuclear reprogramming through iPSC intermediates is capable of achieving the same goal.

Despite years of investigational use, cellular immunotherapy remains an experimental treatment, only available at a very few centers world-wide. Patients with metastatic cancer who have failed available forms of treatment in the community need the option for curative therapy. Studies support the existence of cancer stem cells (CSC) resistant to current forms of therapy. We thus seek to restore multipotency and stemness to anti-tumor T cells. This strategy is akin to fighting fire with fire.

Evidence for the existence of a stem cell-like state in lymphocytes has been developed in our laboratory and elsewhere. Extensive data in mice and in humans supports the concept that younger anti-tumor T cells, such as human T memory stem cells (Tscm) described by our laboratory, are logs more effective than the cells employed in current clinical trials. An increasingly sophisticated understanding of the ontogeny of peripheral T cells has now led to the possibility of inducing plasticity in T cells to modulate pluripotency and expand the pool of multipotent tumor-specific T cells with the aim of enhancing the immune destruction of metastatic cancer.

Current projects in the laboratory include:

  1. Generation of iPSC from tumor-specific T cells
  2. Redifferentiation of iPSC into mature naive or Tscm cells
  3. Safety and efficacy testing of reprogrammed human T cells in humanized mouse models
  4. Development and conduct of early phase clinical trials using the adoptive transfer of younger, less-differentiated anti-tumor T cells to patients with metastatic cancers.
Scientific Focus Areas:
Cancer Biology, Chromosome Biology, Clinical Research, Immunology, Stem Cell Biology

View Dr. Restifo's PubMed Summary.

Selected Recent Publications
  1. Abate-Daga D, Lagisetty KH, Tran E, Zheng Z, Gattinoni L, Yu Z, Burns WR, Miermont AM, Teper Y, Rudloff U, Restifo NP, Feldman SA, Rosenberg SA, Morgan RA.
    Hum Gene Ther. 25: 1003-12, 2014. [ Journal Article ]
  2. Farber DL, Yudanin NA, Restifo NP.
    Nat Rev Immunol. 14: 24-35, 2014. [ Journal Article ]
  3. Crompton JG, Clever D, Vizcardo R, Rao M, Restifo NP.
    Trends Immunol. 35: 178-85, 2014. [ Journal Article ]
  4. Church SE, Jensen SM, Antony PA, Restifo NP, Fox BA.
    Eur J Immunol. 44: 69-79, 2014. [ Journal Article ]
  5. Crompton JG, Sukumar M, Restifo NP.
    Immunol Rev. 257: 264-76, 2014. [ Journal Article ]

Dr. Restifo, a 1983 honors graduate from Johns Hopkins University, obtained his M.D. in 1987 from New York University. He did post-doctoral training at the Memorial Sloan-Kettering Cancer Center and the NCI before becoming a principal investigator in 1993. He has authored or co-authored more than 250 papers and book chapters on cancer immunotherapy. His work focuses on the iterative development of T cell-based adoptive immunotherapies by simultaneously exploring novel aspects of mouse and human T cell immunobiology.

Position Number of Positions Contact E-mail Contact Name Contact Phone
Postdoctoral Fellow 1

restifo@nih.gov

Nicholas P. Restifo, M.D. 301-496-4904
Name Position
David Clever Guest Researcher
Kira Finkel Summer Student
Luca Gattinoni M.D. Investigator
Yun Ji Ph.D. Research Fellow
Sidharth Kerkar M.D. Clinical Fellow
Douglas Palmer Research Biologist
Rahul Roychoudhuri Postdoctoral Fellow (Visiting)
Madusudhanan Sukumar Postdoctoral Fellow (Visiting)
Tori Yamamoto Special Volunteer

Research

Designing Potent New Cancer Immunotherapies

Our goal is to design new immunotherapies for patients with advanced cancer. Our strategy is based on the use of animal models and human in vitro assays to test hypotheses. We then translate the most promising of these therapies into human clinical trials, which often generate new questions to be tested experimentally. The process is an iterative one that involves close collaboration with basic researchers, biotech scientists and experimental clinicians.

Our work focuses on immunotherapy based on the adoptive transfer of naturally-occurring and gene-engineered tumor-specific T cells. We explore the signals that T cells receive within tumor masses, and what T cells must do to trigger the eradication of tumor cells.

Current efforts are focused on the use of stem cell-like anti-tumor T cells to induce curative responses patients with metastatic cancer who have failed other available forms of therapy. These efforts are aimed at reprogramming the exhausted and senescent T cells that are characteristic of the immune response to growing tumors. We currently treat about 120 patients per year with naturally-occurring or gene-engineered adoptively transferred T cells.

Effectiveness of T cell-based immunotherapies. T cell-based immunotherapy using naturally-occurring and genetically-engineered T cells is demonstrably capable of inducing complete and probably curative responses in some patients with advanced metastatic cancer. Significant evidence indicates that less-differentiated T cells, including those that have longer telomeres and higher levels of CD27, are associated with a greater likelihood of objective response in adoptive T cell therapy (ACT). These findings are corroborated in our tumor-specific T-cell receptor transgenic murine model (Pmel-1) in which there is a progressive loss of anti-tumor function as T-cells mature towards terminal differentiation. The robust clinical response associated with less-differentiated phenotypes of anti-tumor T cells suggests that the efficacy of ACT may be improved with transfer of less-differentiated cells.

In new work from our laboratory (Roychoudhuri R, et al., Nature, in press) as well as unpublished experiments, we have identified several candidate transcription factors that are differentially expressed in naive and stem cell-like T cells and have preliminary evidence that a retroviral transduction of these transcription factors results in successful reprogramming. We are exploring the possibilities that lineage reprogramming of terminally differentiated T cells could significantly improve the effectiveness of ACT in treating patients with metastatic cancer. Alternatively, nuclear reprogramming through iPSC intermediates is capable of achieving the same goal.

Despite years of investigational use, cellular immunotherapy remains an experimental treatment, only available at a very few centers world-wide. Patients with metastatic cancer who have failed available forms of treatment in the community need the option for curative therapy. Studies support the existence of cancer stem cells (CSC) resistant to current forms of therapy. We thus seek to restore multipotency and stemness to anti-tumor T cells. This strategy is akin to fighting fire with fire.

Evidence for the existence of a stem cell-like state in lymphocytes has been developed in our laboratory and elsewhere. Extensive data in mice and in humans supports the concept that younger anti-tumor T cells, such as human T memory stem cells (Tscm) described by our laboratory, are logs more effective than the cells employed in current clinical trials. An increasingly sophisticated understanding of the ontogeny of peripheral T cells has now led to the possibility of inducing plasticity in T cells to modulate pluripotency and expand the pool of multipotent tumor-specific T cells with the aim of enhancing the immune destruction of metastatic cancer.

Current projects in the laboratory include:

  1. Generation of iPSC from tumor-specific T cells
  2. Redifferentiation of iPSC into mature naive or Tscm cells
  3. Safety and efficacy testing of reprogrammed human T cells in humanized mouse models
  4. Development and conduct of early phase clinical trials using the adoptive transfer of younger, less-differentiated anti-tumor T cells to patients with metastatic cancers.
Scientific Focus Areas:
Cancer Biology, Chromosome Biology, Clinical Research, Immunology, Stem Cell Biology

Publications

View Dr. Restifo's PubMed Summary.

Selected Recent Publications
  1. Abate-Daga D, Lagisetty KH, Tran E, Zheng Z, Gattinoni L, Yu Z, Burns WR, Miermont AM, Teper Y, Rudloff U, Restifo NP, Feldman SA, Rosenberg SA, Morgan RA.
    Hum Gene Ther. 25: 1003-12, 2014. [ Journal Article ]
  2. Farber DL, Yudanin NA, Restifo NP.
    Nat Rev Immunol. 14: 24-35, 2014. [ Journal Article ]
  3. Crompton JG, Clever D, Vizcardo R, Rao M, Restifo NP.
    Trends Immunol. 35: 178-85, 2014. [ Journal Article ]
  4. Church SE, Jensen SM, Antony PA, Restifo NP, Fox BA.
    Eur J Immunol. 44: 69-79, 2014. [ Journal Article ]
  5. Crompton JG, Sukumar M, Restifo NP.
    Immunol Rev. 257: 264-76, 2014. [ Journal Article ]

Biography

Dr. Restifo, a 1983 honors graduate from Johns Hopkins University, obtained his M.D. in 1987 from New York University. He did post-doctoral training at the Memorial Sloan-Kettering Cancer Center and the NCI before becoming a principal investigator in 1993. He has authored or co-authored more than 250 papers and book chapters on cancer immunotherapy. His work focuses on the iterative development of T cell-based adoptive immunotherapies by simultaneously exploring novel aspects of mouse and human T cell immunobiology.

Positions

Position Number of Positions Contact E-mail Contact Name Contact Phone
Postdoctoral Fellow 1

restifo@nih.gov

Nicholas P. Restifo, M.D. 301-496-4904

Team

Name Position
David Clever Guest Researcher
Kira Finkel Summer Student
Luca Gattinoni M.D. Investigator
Yun Ji Ph.D. Research Fellow
Sidharth Kerkar M.D. Clinical Fellow
Douglas Palmer Research Biologist
Rahul Roychoudhuri Postdoctoral Fellow (Visiting)
Madusudhanan Sukumar Postdoctoral Fellow (Visiting)
Tori Yamamoto Special Volunteer