Remember those gene expression profiles of CLL cells that were published in 2001(Klein et al; Rosenwald et al)? Both showed that the mRNA encoding the PTK receptor Ror1 (it stands for receptor tyrosine kinase-like orphan receptor) is overexpressed by CLL cells. Nine years later it was demonstrated that Ror1 protein was expressed by CLL cells but not by normal T or B lymphocytes nor by the majority of adult tissues. There seems to be a link with both Tom Kipps' gene therapy approach and with lenalidomide treatment.
Ror1 levels were remarkably uniform in cells from CLL patients and were independent of IGHV mutation status. Ror1 is engaged by Wnt5a, an interaction that induces NF-κB activity. Wnt5a augments survival of CLL cells and this protection was abolished by anti-Ror1 antisera. These observations, together with the uniform expression of Ror1 in CLL, suggest that it may be a promising candidate for therapeutic targeting. T cells engineered to express chimeric antigen receptors against Ror1 have been constructed. These cells target primary CLL cells in vitro, including rare drug-resistant clones.
Transfection of CD154 into CLL cells ex vivo followed by reinfusion of the transfected cells into patients results in the generation of anti-Ror1 antibodies, suggesting that ectopic expression of CD154 corrects the immune dysfunction characteristic of CLL, thereby facilitates immune responses against Ror1. Treatment of CLL patients with lenalidomide also results in CD154 upregulation. The consequent generation of anti-Ror1 antibodies by a lenalidomide-treated patient may underlie the therapeutic activity of this drug in CLL.
5 comments:
Do you think lenalidomide is worth trying as a single agent, first line therapy for younger patients to try to delay the need for FCR. Would there be any harm, at least, in trying it?
There are already trials of this.
I have been told this trial is on hold!
If you are talking about the single agent lenalidomide trial at Roswell Park, the reason for putting a hold on recruiting new patients could be because Dr. Asher Chanan-Khan is moving from Roswell Park. In the next month or so he will move to the Mayo Clinic, Florida. They have not decided who is going to take over responsibility for the clinical trials that Dr. Chanan-Khan was supervising.
No it is the trial in the UK. I had an appointment with Dr. Devereux soon to be Professor Devereux and asked him about the RESPECT trial, he told me this was suspended because of second malignancies in patients with myeloma, treated with this drug.
Post a Comment