A new tumor necrosis factor for CLL immune therapy?

May 15, 2001

Enhanced Immunogenicity of CLL Cells Transduced with

Herpes Simplex Amplicons Encoding Light.

Khaled A. Tolba, et.al. Hematology-Oncology Unit,

University of Rochester, Rochester, NY.

Several members of the TNF superfamily play a key role

in immune modulation and T-cell activation

(CD40/CD40L, 4-1-BB/4-1BBL). LIGHT, (TNFSF14) a

recently cloned member of the TNF superfamily binds

HVEM and lymphotoxin [beta] receptor (LT[beta]R) and

activates T-cells through an NF-[kappa]B dependent

pathway. LIGHT is expressed on immature dendritic

cells.

We have cloned the cDNA for human LIGHT by RT-PCR from

dendritic cell RNA. LIGHT cDNA was subcloned into an

HSV amplicon plasmid and packaged using a helper

virus-free BAC (bacterial artificial chromosome)

method. The packaged vector, hf-HSV-LIGHT, was used to

transduce primary chronic lymphocytic leukemia (CLL)

cells. Transduced CLL cells expressing LIGHT were

compared to CLL cells expressing CD40L following

transduction with an hf-HSV-CD40L amplicon vector.

Both CD40L and LIGHT transduction induced expression

of B7.1 and B7.2 on CLL cells. This was associated

with enhanced stimulatory capacity of the transduced

CLL cells in an allogeneic MLTR.

Transduced CLL cells successfully stimulated the

generation of specific autologous cytotoxic

T-lymphocyte activity following in vitro priming. CTL

activity was blocked by the anti-MHC-I antibody W6-32.

Our data suggests that LIGHT is a candidate molecule

for enhancing immunogenicity of B-cell CLL and

deserves further consideration for CLL immune therapy.

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