Cellular Immune Response to AD-CD154 Gene Therapy

Thomas J. Kipps, M.D., Ph.D.

University of California, San Diego

Funded in June, 2002: $300000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY . SELECTED PUBLICATIONS .

LAY SUMMARY

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Are Immune B Cells Activated in Leukemia Through Experimental Gene Therapy?

Chronic lymphocytic leukemia (CLL) is a malignancy of immune B cells. Under ordinary circumstances these adaptive immune system cells learn to recognize and attack a specific invader. But in CLL, these malignant B cells are rendered unable to detect leukemia-associated antigens. Instead, they accumulate in patients' blood, marrow, and lymphoid tissue, while leukemia antigens go unscathed. The investigators propose to measure the extent to which an experimental gene therapy can activate immune B cells to display the leukemia antigen's "code" and teach immune T cells to recognize and kill off the leukemia antigens.

Using immunologic assays on treated patients, the investigators will assess whether T cells proliferate and produce interferon that attacks the leukemia antigens. Specifically, they will determine whether leukemia cells undergo apoptosis (literally growing themselves to death), thus "clearing out" the accumulated infected B cells residing in marrow, blood, and lymph tissue. This measurement study will be conducted as part of a Phase II study(safety and efficacy in a small number of patients) to be conducted at UCSD and Dana-Farber.

ABSTRACT

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Cellular Immune Response to AD-CD154 Gene Therapy

Chronic lymphocytic leukemia (CLL) cells can be made to express recombinant CD40-ligand (CD154) by transduction with a replication-defective adenovirus vector (Ad-CD154). Ad-CD154-transduced and bystander leukemia cells become highly effective antigen-presenting cells that can induce CLL-specific autologous cytotoxic T lymphocytes in vitro. We investigated the immunologic and clinical responses to infusion of autologous Ad-CD154 CLL cells in patients with CLL. Following a one-time bolus infusion of autologous, Ad-CD154-transduced leukemia cells, there was increased or de novo expression of immune accessory molecules on bystander, non-infected CLL cells in vivo. Treated patients also developed high plasma-levels of interleukin-12 and interferon-gamma, the magnitudes of which corresponded to absolute blood CD4+ T cell counts prior to therapy. On average, patients experienced a greater than 240% increase in absolute blood T cell counts within 1 - 4 weeks of treatment. Moreover, treatment increased the numbers of leukemia-specific T cells, demonstrated by autologous ELISPOT assay and mixed lymphocyte reactions. These biologic effects were associated with reductions in leukemia cell counts and lymph node size. Treatment did not induce autoimmune thrombocytopenia or hemolytic anemia and no dose-limiting toxicity was observed. This approach may provide a novel and effective form of gene therapy for patients with this disease.

INVESTIGATOR BIOGRAPHIES

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Thomas J. Kipps, M.D., Ph.D.

Thomas J. Kipps, M.D., Ph.D., is Professor of Medicine and Head of Hematology/ Oncology at the University of California, San Diego's (UCSD) Department of Medicine. Dr. Kipps also serves as Deputy Director of Research Operations for the NCI-designated Comprehensive Cancer Center at UCSD. He graduated summa cum laude from Columbia University (Biochemistry), and magna cum laude from Harvard with an M.D. and a Ph.D. in immunology. After training in Internal Medicine, he completed fellowships in Hematology, Immunology, and Genetics at Stanford University.

Dr. Kipps served on the faculty at the Scripps Research Institute from 1985 to 1990, when he moved to UCSD. There he oversees a molecular and cellular immunology research laboratory and conducts translational research in immunology and genetics. He established investigator-initiated Phase I and II trials, including the first gene therapy trial in human leukemia, based on discoveries made in his laboratory. This involves the capacity of CD40-ligation to induce expression of immune co-stimulatory molecules that are critical for T cell activation, in response to presented tumor-associated antigen.

Dr. Kipps also leads the chronic lymphocytic leukemia (CLL) research consortium (CRC), a national consortium of basic and clinical investigators who are conducting research on adult leukemia. He has received numerous research awards, authored more than 210 peer-reviewed scientific articles and book chapters, and serves on several scientific journal editorial boards, the Progress Review Group, and other scientific advisory committees for public and private research funding and for industry.

SELECTED PUBLICATIONS

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Dicker F., Kater A.P., Fukuda T., and Kipps T.J.  Fas-ligand (CD178) and TRAIL synergistically induce apoptosis of CD40-activated chronic lymphocytic leukemia B cells. Blood. 2005 Apr 15;105(8):3193-8.

Messmer D. and Kipps T.J.  Treatment of solid tumors with immunotoxins.  Breast Cancer Res. 2005;7(5):184-6.

Rieger R., Cantwell M.J., Rassenti L.Z., Prussak C.E., and Kipps T.J.  CpG oligodeoxynucleotides enhance the capacity of adenovirus-mediated CD154 gene transfer to generate effective B-cell lymphoma vaccines.  Cancer Res. 2003 Jul 15;63(14):4128-35.