Comparison of two CD40-ligand/interleukin-2 vaccines in patients with chronic lymphocytic leukemia

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BlankComparison of two CD40-ligand/interleukin-2 vaccines in patients with

chronic lymphocytic leukemia.

FV Okur, E Yvon, E Biagi, G Dotti, G Carrum, H Heslop, MP Mims, JC Fratantoni,

MV Peshwa, L Li, and MK Brenner

Cytotherapy, July 12, 2011; .

Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist

Hospital and Texas Children's Hospital , Houston, Texas , USA.

Abstract Background aims. Several studies have demonstrated that the

immunogenicity of chronic lymphocytic leukemia (CLL) cells can be increased by

manipulation of the CD40/CD40-ligand (CD40L) pathway. Although immunologic, and

perhaps clinical, benefits have been obtained with an autologous CLL tumor

vaccine obtained by transgenic expression of CD40L and interleukin (IL)-2, there

is little information about the optimal gene transfer strategies. Methods. We

compared two different CLL vaccines prepared by adenoviral gene transfer and

plasmid electroporation, analyzing their phenotype and immunostimulatory

activity. Results. We found that higher expression of transgenic CD40L was

mediated by adenoviral gene transfer than by plasmid transduction, and that

adenoviral transfer of CD40L was associated with up-regulation of the

co-stimulatory molecules CD80 and CD86 and adhesion molecule CD54. In contrast,

transgenic IL-2 secretion was greater following plasmid transduction. These

phenotypic differences in the vaccines were associated with different

functionality, both ex vivo and following administration to patients. Thus

adenoviral vaccines induced greater activation of leukemia-reactive T cells ex

vivo than plasmid vaccines. In treated patients, specific T-cell (T helper 1

(Th1) and T helper 2 (Th2)) and humoral anti-leukemia responses were detected

following administration of the adenoviral vaccine (n = 15), while recipients of

the plasmid vaccine (n = 9) manifested only a low-level Th2 response.

Progression-free survival at 2 years was 46.7% in the adenoviral vaccine

recipients, versus 11.1 % in those receiving plasmid vaccine. Conclusions. CLL

vaccines expressing the same transgenes but produced by distinct methods of gene

transfer may differ in the polarity of the immune response they induce in

patients.

PMID: 21745159