Our Science – Restifo Website
Nicholas P. Restifo, M.D.
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.
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 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In new work from our laboratory (Roychoudhuri, R, et al, Nature, in press) as well as unpublished experiments, we have identified several candidate transcription factors that are differentially expressed in naïve and stem cell-like T cells and have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 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.
This page was last updated on 6/10/2014.