Wednesday, June 01, 2011

Gene therapy for CLL

Although monoclonal antibodies have proved reasonably successful in treating CLL, the arm of the immune system that ought to kill CLL cells better is the cellular immune response, particularly T cells. T cells recognize their targets through peptides that are placed within the groove of the major histocompatability complex. WE are quite unsure what might be a reasonable target for T cells in CLL and this approach has not borne any fruit.

Many groups have had the idea of redirecting T cells from their primary target by using an antibody target (like CD20) and linking this to the attack mechanism of T cells. One such attempt is reported in the May 2011 Blood.

This makes use of gene therapy technology to express in T cells a chimeric antigen receptor (CAR). The target chosen was CD23, a molecule found on almost all CLL cells but not on normal B cells. A CAR was constructed comprising a single chain variable fragment (scFv) coupled to the zeta chain of the T-cell receptor complex. This receptor was cloned into T cells from healthy donors.

Incubation of these T cells showed effective killing of CD23+ cell lines and of primary CLL cells. It also released large amounts of inflammatory cytokines (TNF alpha and beta, gamma interferon and IL-2). In a xenograft mouse model there was also effective immunotherapy.

An important element of the CAR is the incorporation of the CD28 costimulatory endodomain within the construct which allows the production of IL-2 which sustains the expansion of the adoptedly transferred T cells in response to primary tumors.


Anonymous said...

Off the cuff, how practical do you suppose it would be to move such technology from mice to men and how long might the necessary work take to reach a level of clinical practicality, assuming that no unforseen major issues arise in such work?

Thanks, Rick

Terry Hamblin said...

There are several of these gene therapy programs underway with CAR. I think that they could be rolled out within 5 years.

Wayne said...


The CD23 mAb Lumiliximab was pretty unimpressive in clinical trials and I do not remember if a reason for its lack of more efficient cell lysis was ever given.

CAR development appears more sophisticated than mAb technology but still uses CD23 as a target. Is efficacy with CAR wishful thinking or do you believe the problems in effective targeting of CD23 are accurately understood?

Does the CD28 costimulatory factor affect the binding or killing mechanism of the CAR complex?



Terry Hamblin said...

Lumiliximab was not a particularly good monoclonal and I didn't think it was worth commiting patients to that trial when I was practising. I was proved right.

CAR technology just needs a target confined to CLL cells; it doesn't matter how the antibody performed.

There are some pretty good results with other examples of CAR technology and I am impressed by the possibilities. The CD28 is there to activate the T cells and keep them proliferting.