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Fig. 1. Ad-CD154 activation of CLL B-cells. Leukemia B-cells are modified via transduction with an adenovirus vector encoding a recombinant CD40- ligand (Ad-CD154). This induces or enhances the expression of important immune accessory molecules, such as CD80 and CD54, which allow these cells to crosslink specific ligands on the T-cell surface that are required for T-cell activation. These accessory molecules are important in cognate intercellular immune interactions that lead to T-cell immunity. In addition, CD40 ligation downmodulates the expression of molecules, such as CD27, that can inhibit such interactions. The end result is to convert the resting leukemia cells into active antigen-presenting cells that are able to induce an immune response to leukemia-associated antigens. LFA, leukocyte factor-associated antigen.

Fig. 1. Ad-CD154 activation of CLL B-cells. Leukemia B-cells are modified via transduction with an adenovirus vector encoding a recombinant CD40- ligand (Ad-CD154). This induces or enhances the expression of important immune accessory molecules, such as CD80 and CD54, which allow these cells to crosslink specific ligands on the T-cell surface that are required for T-cell activation. These accessory molecules are important in cognate intercellular immune interactions that lead to T-cell immunity. In addition, CD40 ligation downmodulates the expression of molecules, such as CD27, that can inhibit such interactions. The end result is to convert the resting leukemia cells into active antigen-presenting cells that are able to induce an immune response to leukemia-associated antigens. LFA, leukocyte factor-associated antigen.

several hours after the infusion. Less common clinical side effects included nausea, myalgia, arthralgia, and diarrhea. Laboratory abnormalities consisted primarily of minor elevations in hepatic transaminases and thrombocytopenia. Nevertheless, the clinical and laboratory abnormalities were transient and resolved within a few days after treatment. None of the patients experienced any dose-limiting toxicity.

The biological effects of this treatment were encouraging. Within 24-48 h of receiving the modified cells, virtually all the patients in groups 1, 2, and 3 had measurable increases in plasma cytokines, such as IL-12, IFN-y, and/or IL-6. All the CLL B-cells in the blood of the treated patients started expressing low levels of immune costimulatory molecules, similar to what we had observed with the bystander effect noted in vitro. This was noted 1-2 d after treatment, when circulating Ad-CD154-infected cells could no longer be detected, and lasted for several days, if not longer. Such immune costimulatory molecules were not induced on any infected CLL B-cells that were incubated in plasma from the treated patients, indicating that a soluble factor was not responsible for this effect.

The clinical effects of this treatment were encouraging. Most of the patients in groups 1, 2, and 3 experienced acute falls in the blood leukemia cell count within the first few days after treatment. Subsequently the lymphocyte count tended to return to approximately 60% of pre-treatment levels. However, not all the blood lymphocytes that returned to such levels were CLL B-cells. In nearly all treated patients we noted significant increases in the absolute numbers of both CD4 T-cells and CD8 T-cells at 1 wk after treatment, sometimes to more than four times that of pretreatment levels. After the first week or two, many patients experienced stabilization in absolute lymphocyte counts. The CLL B-cell counts of many of the treated patients remained at or below treatment levels for several weeks, if not longer. One to two weeks after gene therapy, nearly all the treated patients experienced reductions, some significant, in lymph node size lasting for more than several weeks. Finally, several of the patients have not required additional therapy for their disease more than 2 yr after receiving gene therapy. Thus, this strategy may have activity even in patients who have advanced disease with high leukemia cell counts and diffuse adenopathy. More pronounced clinical effects are anticipated with repeat dosing, which is currently being examined in a phase II clinical study conducted at the University of California, San Diego and the Dana Farber Cancer Institute. Conceivably, we may soon experience effective gene therapy for patients with this disease.

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