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Research Interests

Research efforts of the Laboratory of Tumor Immunology and Biology involve the development of novel cancer immunotherapy strategies, with emphasis being placed on the development of recombinant vaccines. Studies include identification of the appropriate gene product target, appropriate vectors to enhance immunogenicity, and the use of cytokines and co-stimulatory molecules to enhance T-cell activation. Studies are ongoing in a multidimensional approach to design and develop recombinant vaccines to both point-mutated and overexpressed tumor-associated gene products. Analyses of patients' immune responses to first generation recombinant vaccines are being employed to design more potent second and third generation vaccines and to develop strategies to enhance T-cell responses. Some ongoing studies include:

Design of Recombinant Vaccines to Tumor Associated Antigens
Three gene products that are overexpressed in human carcinomas are being evaluated as targets for recombinant vaccines. These are: (1) carcinoembryonic antigen (CEA), which is overexpressed in gastrointestinal, breast, and lung carcinomas; (2) prostate specific antigen (PSA); and (3) the breast cancer mucin muc-1, which is also overexpressed in lung and pancreatic carcinomas. Phase I clinical trials have recently been completed employing a recombinant vaccinia virus (rV) and a recombinant avipox containing the CEA gene. Vaccination was shown to elicit T-cell responses in carcinoma patients specific for CEA. A Phase I clinical trial has also been completed employing rV-PSA as immunogen, and T-cell responses specific for PSA were induced. The immunodominant epitopes to which these CEA- and PSA-specific T-cell responses were directed have been identified. A T-cell receptor enhancer agonist epitope has also been identified for CEA. Studies are currently in progress in the design and analysis of second and third generation vaccines.

The ras proto-oncogene is mutated at codon 12 in a range of human tumors. Studies are ongoing to define if specific epitopes can be identified within oncogene products that are capable of eliciting human T-cell responses. A clinical trial has now shown that advanced carcinoma patients can be vaccinated with peptides reflecting the ras mutation found in their tumor; both ras-specific CD4+ T-helper and CD8+ CTL responses have been observed and are currently being studied.

T-Cell Costimulation
Studies on the design and use of recombinant pox viruses to present T-cell costimulatory signals are under way. This approach is potentially useful in both gene therapy and recombinant vaccine development. Recent studies have shown that the admixture of a recombinant vaccinia virus (rV) containing the B7-1, ICAM-1, or other costimulatory molecules with one of several recombinant vaccines containing a tumor antigen gene leads to enhanced T-cell responses and anti-tumor activity. Studies are ongoing to design novel vaccines containing multiple costimulatory molecules to better define the principles of optimal costimulation.

Cytokines as Biological Adjuvants
Recent research interests have broadened to include the investigation of different cytokines that may augment a T-cell response to a defined tumor antigen. To date, studies have focused on cytokines that enhance T-cell proliferation (i.e., IL-2) and cytokines that act on antigen presentation to T cells (i.e., GM-CSF). For example, IL-2 administration can augment the anti-tumor efficacy of a recombinant vaccinia virus expressing human CEA. Concomitant GM-CSF administration with an antigen having poor immunogenic properties can enhance the antigen-specific T-cell response. The use of poxvirus recombinants to express cytokines is also being evaluated.

Novel Recombinant Immunoglobulin Forms for Cancer Therapy and Diagnosis
The overall goal of ongoing research is the design and characterization of recombinant immunoglobulin (Ig) forms for use in both therapeutic and diagnostic applications for a range of human cancers. Emphasis is being placed on the design and translational research of CDR-grafted and CDR-modified forms, domain-deleted Ig forms, and single-chain fusion molecules. Studies are ongoing in experimental models to define metabolic and pharmacokinetic properties, as well as tumor targeting of these recombinant Igs. Studies are also being conducted in which chimeric single-chain anti-tumor Ig genes and the zeta chain of the T-cell receptor are being introduced into T lymphocytes to develop specific, redirected anti-tumor human T-cell populations.

Selected Publications Top

Zhu MZ, Terasawa H, Gulley J, Panicali D, Arlen P, Schlom J, and Tsang KY. Enhanced activation of human T cells via avipox vector-mediated hyperexpression of a triad of costimulatory molecules in human dendritic cells. Cancer Res. 61: 3725-3734, 2001.

Grosenbach DW, Barrientos JC, Schlom J, and Hodge JW. Synergy of vaccine strategies to amplify antigen-specific immune responses and anti-tumor effects. Cancer Res. 61: 4497-4505, 2001.

Sabzevari H, Kantor J, Jaigirdar A, Tagaya Y, Naramura M, Hodge JW, Bernon J, and Schlom J. Acquisition of CD 80 (B7-1) by T cells. J. Immunol. 166: 2505-2513, 2001.

Marshall JL, Hoyer RJ, Toomey MA, Faraguna K, Chang P, Richmond E, Pedicano JE, Gehan E, Peck RA, Arlen P, Tsang KY, and Schlom J. Phase I study in cancer patients of a diversified prime and boost vaccination protocol using recombinant vaccinia virus and recombinant nonreplicating avipox virus to elicit anti-carcinoembryonic antigen immune responses. J. Clin. Oncol. 18:3964-3973 (2000).

Hodge JW, Rad AN, Grosenbach DW, Sabzevari H, Yafal AG, Gritz L, and Schlom J. Enhanced activation of T cells by dendritic cells engineered to hyperexpress a triad of costimulatory molecules. J. Natl. Cancer Inst. 92:1228-1239 (2000).

Salazar E, Zaremba S, Tsang KY, Arlen P, and Schlom J. Agonist peptide from a cytotoxic T lymphocyte epitope of human carcinoembryonic antigen stimulates production of Tc1-type cytokines and increases tyrosine phosphorylation more efficiently than cognate antigen. Int. J. Cancer 86:829-838 (2000).

Hodge JW, Sabzevari H, Lorenz MGO, Yafal AG, Gritz L, and Schlom J. A triad of costimulatory molecules synergize to amplify T-cell activation. Cancer Res. 59:2800-2807 (1999).

Kass E, Schlom J, Thompson J, Guadagni F, and Greiner JW. Induction of protective host immunity to carcinoembryonic antigen (CEA), a self-antigen in CEA transgenic mice, by immunizing with a recombinant vaccinia-CEA virus. Cancer Res. 59:676-683 (1999).

Contact Information Top

Other Information Top

Chief, Laboratory of Tumor Immunology and Biology
Center for Cancer Research
National Cancer Institute
National Institutes of Health
Bethesda, MD
http://rex.nci.nih.gov/research/basic/ltib/ltibpage.htm