Nicholas P. Restifo, M.D.
Building 10 - Hatfield CRC, Room 3-5762
Bethesda, MD 20892
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In new work from our laboratory (Roychoudhuri R, et al., Nature, in press) as well as unpublished experiments, we have identified several candidate transcription factors that are differentially expressed in naive and stem cell-like T cells and have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:
- Generation of iPSC from tumor-specific T cells
- Redifferentiation of iPSC into mature naive or Tscm cells
- Safety and efficacy testing of reprogrammed human T cells in humanized mouse models
- 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.
Dr. Nicholas Restifo is a pioneer in the field of cancer immunotherapy. He was recruited from Memorial Sloan Kettering Cancer Center where he was inspired by Lloyd Old and Murray Brennan. Since joining the NCI in 1989, his research has focused entirely on T lymphocytes because they are at the heart of anti-tumor immunity.
He is an honors graduate from The Johns Hopkins University and obtained his MD from New York University. He became a principal investigator in 1993 and has authored or co-authored more than 300 papers and book chapters on cancer immunotherapy. His most recent efforts include a focus on how elements – literally from the periodic table – influence cancer immunity. These include work on how oxygen can inhibit anti-tumor immunity and how potassium ions from dying cancer cells can shut down the anti-tumor response.
Successful treatment of patients with cancer is the goal of his laboratory, and his therapeutic approaches employ adoptive T cell transfer, gene modification and cellular reprogramming. Basic aspects of tumor and T cell immunology inform novel therapeutic interventions in the clinic.
Clever D, Roychoudhuri R, Constantinides MG, Askenase MH, Sukumar M, Klebanoff CA, Eil RL, Hickman HD, Yu Z, Pan JH, Palmer DC, Phan AT, Goulding J, Gattinoni L, Goldrath AW, Belkaid Y, Restifo NP. Oxygen Sensing by T Cells Establishes an Immunologically Tolerant Metastatic Niche. Cell. 2016;166(5):1117-1131.e14.
Eil R, Vodnala SK, Clever D, Klebanoff CA, Sukumar M, Pan JH, Palmer DC, Gros A, Yamamoto TN, Patel SJ, Guittard GC, Yu Z, Carbonaro V, Okkenhaug K, Schrump DS, Linehan WM, Roychoudhuri R, Restifo NP. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature. 2016;537(7621):539-543.
Klebanoff CA, Restifo NP. Customizing Functionality and Payload Delivery for Receptor-Engineered T Cells. Cell. 2016;167(2):304-306.
Roychoudhuri R, Clever D, Li P, Wakabayashi Y, Quinn KM, Klebanoff CA, Ji Y, Sukumar M, Eil RL, Yu Z, Spolski R, Palmer DC, Pan JH, Patel SJ, Macallan DC, Fabozzi G, Shih HY, Kanno Y, Muto A, Zhu J, Gattinoni L, O'Shea JJ, Okkenhaug K, Igarashi K, Leonard WJ, Restifo NP. BACH2 regulates CD8(+) T cell differentiation by controlling access of AP-1 factors to enhancers. Nat Immunol. 2016;17(7):851-860.
Sukumar M, Liu J, Mehta GU, Patel SJ, Roychoudhuri R, Crompton JG, Klebanoff CA, Ji Y, Li P, Yu Z, Whitehill GD, Clever D, Eil RL, Palmer DC, Mitra S, Rao M, Keyvanfar K, Schrump DS, Wang E, Marincola FM, Gattinoni L, Leonard WJ, Muranski P, Finkel T, Restifo NP. Mitochondrial Membrane Potential Identifies Cells with Enhanced Stemness for Cellular Therapy. Cell Metab. 2016;23(1):63-76.
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This page was last updated on May 1st, 2019