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John C. Morris, M.D.

Metabolism Branch Cytokine Immunology and Immunotherapy Section Staff Clinician Metabolism Branch, Center for Cancer Research, National Cancer Institute Mark O. Hatfield Clinical Research Center, Room 4-5330 10 Center Drive Bethesda, MD 20892-1547 Phone:   301-402-2912, 301-496-7417 Fax:   301-402-1001 E-Mail:   jmorris@mail.nih.gov

Biography

Dr. Morris received his baccalaureate with honors in biology from Queens College, City University of New York in 1978, and his M.D. degree in 1982 from the Upstate Medical Center College of Medicine, State University of New York in Syracuse, NY. He completed his residency in Internal Medicine and a fellowship in Medical Oncology at the Mount Sinai Medical Center in New York City. He served as Chief Medical Resident and subsequently as Assistant Professor of Medicine and Neoplastic Diseases at Mount Sinai Medical Center. Dr. Morris then did a post-doctoral fellowship in the Blaese Laboratory of Clinical Gene Therapy Branch of the National Human Genome Research Institute from 1995 to 1999. In 1999, he moved to the National Cancer Institute and joined the Metabolism Branch as Co-Director of Clinical Trials where he has focused on tumor vaccines, cytokine and monoclonal antibody therapy of cancer. Dr. Morris is board-certified in Internal Medicine and Medical Oncology.

Research

View Dr. Morris' Current Clinical Trials

Clinical Trials Evaluating Cytokine-Directed Therapy, Antitumor Vaccines and Gene Therapy of Cancer.

The goals of the Metabolism Branch Cancer Gene Therapy Section are to develop new and innovative gene transfer approaches for the treatment of cancer. Gene therapy strategies for cancer treatment include the replacement of defective tumor suppressor genes, use of antisense to block the expression of dominant oncogenes, the transfer of immune stimulatory molecules and cytokines into tumors, and the transfer of genes encoding enzymes that locally activate nontoxic drugs into cytotoxic agents in tumors. Despite initial optimism, few responses have been reported clinical trials. Reasons for this are many, but include the low efficiency of gene transfer in vivo achieved by current vectors as well as the fact that most gene transfer approaches to cancer represent local therapies. Initial safety considerations required the use of viral gene transfer vectors that were replication-defective and therefore unable to infect tumor cells much beyond the initial site of vector inoculation. Even if successful distant or occult sites of tumor were left untreated. In attempt to address these issues, our research efforts have focused on: (1) antitumor vaccination using dendritic cells modified by adenoviral-mediated gene transfer of non-functioning tumor antigens, immunostimulatory cytokines and their receptors; and (2) development of the cotton rat model to study replicating (oncolytic) human adenoviruses.

We are studying the induction of antitumor immunity using adenoviral-mediated transfer of non-functioning tumor antigen genes such as truncated mutant K-ras or non-signaling HER-2/neu into bone marrow-derived dendritic cells (DCs) and transferring these cells to mice bearing tumors. DCs play a pivotal role in generating, sustaining and directing the immune response. There is mounting evidence that the inability of the immune system to eradicate tumors may be due to ineffective presentation of tumor antigens by DCs as well as attenuation of DC co-stimulatory signals. Clinical trials using autologous DCs pulsed with peptide sequences of tumor-specific antigens are undergoing evaluation in the Branch as a cancer vaccine strategy. A limitation of the peptide-loading approach is the requirement for prior knowledge of the binding affinity of the antigen-derived peptide epitopes for various MHC molecules and the weak affinity many of these epitopes for the MHC molecule. Using recombinant adenoviral vectors to introduce tumor antigens into DCs offers an alternative. An advantage of this approach is that DCs can process the intracellular expressed antigens, and in theory, present an optimal epitope sequence regardless of the specific MHC. In addition, expression of the antigen gene provides a continuous source of peptide expression. The infection of DC's with adenoviruses increases the expression of several markers of DC maturation including CD80 (B7.1), CD86 (B7.2) and the expression of MHC classes I and II, as well as enhancing the ability of DC's to stimulate the proliferation of lymphocytes. Using a transgenic mouse model (BALB-neuT) of HER-2/neu-induced spontaneous breast cancer, we demonstrated that vaccination with bone marrow-derived DC's infected with an adenovirus expressing a truncated non-signaling neu oncoprotein prevented or significantly delay the onset of spontaneous breast tumors in these mice and reduced the numbers of breast cancers per mouse. The mechanism of protection appears to be the induction of anti-neu antibody rather than the generation of a specific cytolytic T lymphocyte response. Depletion of CD8+ T cells and NK cells using monoclonal antibodies did not inhibit the vaccine's effect, whereas depletion of CD4+ T cells abrogated its effectiveness. In collaboration with the Immunogenetics and Vaccine Research Section of the Cancer Vaccine Branch the important role of anti-neu antibody was confirmed in this model in a series of knockout mouse and serum transfer experiments. An important finding was that while the effectiveness of direct antitumor vaccination with our neu expressing adenoviral vector (Ad.Neu) was inhibited by pre-existing immunity to adenovirus in the mice, the vaccination approach using DCs modified ex vivo by adenovirus remained effective. We believe that genetically modified DCs using adenoviral gene transfer vectors offer a significant potential as antitumor vaccines.

Our other area of interest has been on the development of a transplantable cotton rat tumor model for the evaluation of replicating (oncolytic) human adenoviruses. In collaboration with Virion Systems, Inc (Gaithersburg, MD) a number of transplantable cotton rat tumor cell lines have been isolated from spontaneous tumors that appear to support the independent replication of human adenoviruses on 'burst' assay. If confirmed, this would likely be the first non-human cell lines that can be transplanted between immunocompetent hosts that could be used to study wild type or other engineered replicating adenoviral vectors.

DCs play a pivotal role in the immune response including generation of antitumor immunity. The inability of the immune system to eradicate tumors may be due to ineffective tumor antigen presentation by DCs as well as attenuation of DC costimulatory signals. Clinical trials using autologous DCs pulsed with peptide sequences of tumor-specific antigens are undergoing evaluation in the Metabolism Branch as a cancer vaccine strategy. A limitation of this approach is the requirement to have prior knowledge of the binding affinity of different antigen-derived peptides for various MHC molecules. Using recombinant adenoviral vectors to introduce tumor antigens into DCs offers a potential alternative. An advantage of this approach is that DCs can process the intracellular expressed antigens and present an optimal sequence regardless of specific MHC. We studied the efficiency of adenoviral-mediated gene transfer into murine bone marrow-derived DCs and the phenotypic changes that it induced. Other studies are in progress examining the ability of this approach to induce specific antitumor immunity.

This page was last updated on 9/25/2008.