When I attend a committee that awards grants to researchers, I am of course sworn to secrecy about what goes on there, but I can blog about the general themes that researchers are pursuing without referring to specific grant proposals. On Thursday it was clear CLL is very much a focus for new research.
Following the German trial that everyone knows will be reported at ASH, that will show FCR to be superior to FC, there seems no doubt that FCR is the treatment of choice for patients under the age of 70 and possibly those under 65. Even so, around 5% will be resistant to this regime and what to do for them is still a difficult decision. Alemtuzumab (Campath) is clearly one of the drugs that should be used, but it penetrates large tumor masses poorly and needs to be combined with something else. Most is known about teh high dose steroid + Campath combination, but workers are taking a close look at Fludarabine and Campath. This combination seems to work in patients with del 17p and large nodes. There are several ways of using this drug combination and trials are being conducted with several different schedules.
Revlimid is another drug that works in del 17p patients, though it does not seem to be as effective as either Campath or high dose steroids. There are several trials and proposed trials which are seeking to further evaluate this drug. One possible way of using it is in poor risk symptomless early stage disease. The aim here is to avoid chemotherapy which would damage normal bone marrow and possible select for more malignant clones or even trigger disease progression. Revlimid seems to have no direct effect on the tumor, but works in CLL by limiting the help to tumor growth provided by the stroma in bone marrow and lymph nodes. It may be that this is the best way to use the drug.
Other experimental drugs that I have already written about are also reaching clinical trials. A correspondent let it be known that he was the second patient to start on a Nutlin trial. Nutlin is an MDM-2 inhibitor that allows p53 to accumulate. The PARP-1 inhibitor AZD2281 is also close to clinical trial in CLL. AZD2281 is an inhibitor of DNA repair. It is effective in vitro in cells that have a defect of homologous recombination, such as breast cancer cells that lack BRCA-1 or CLL cells that lack ATM. Trials in breast cancer have already begun.
Means of enhancing immunity to tumors is very much a current interest. Stem cell allograft is the principle current means of such immunotherapy, but it is hard to separate GVHL from GVHD. One means of lessening the GVHD effect without reducing the GVL effect is the infusion of regulatory T cells. This is ready to be scaled up from mice to men. The same effect might also be achieved by depleting donor lymphocyte infusions of CD8 positive T cells.
Vaccination of the donor before harvest of donor lymphocyte infusion is another approach, making use of donor altruism. HA-1 is a minor histocompatability antigen which is lacking in 30% of donors, but present on 70% of tumors. There are lots of new ways of vaccinating, one of which, DNA vaccination is very much a thing of the moment. With my GTAC hat on, I frequently see DNA vaccines against HIV, TB and malaria. One of the most effective methods is so called prime boost, where the immune system is primed by a DNA vaccine and then boosted by a genetic vaccine, where the foreign gene is contained within a virus. Modified vaccinia Ankara is the safest choice.
Another potential antigen for DNA vaccines is WT-1, a tumor antigen represented on myeloid malignancies. Electroporation (passing a small electric shock through the vaccination site) enhances the effect of DNA vaccines and was recently successfully employed in a prostate cancer trial.