I recently returned from a meeting of the U.S./European Alliance for the Therapy of CLL in Spain. As most of you are aware, CLL Global organizes the Alliance to bring together leading CLL experts. We convened outside of Barcelona for two days in June to evaluate the progress made to date. As you will see from the photos, we occasionally enjoyed the beautiful surroundings; however, the majority of time was spent inside listening to the latest in CLL research.
As discussed previously, our major new initiative has been the development of a genetics component in the Alliance. Drs. Carlo Croce and George Calin have been the fathers of microRNA technology in CLL, bringing forth much of our understanding of the role of these genes in CLL growth and survival. They each presented how we can use these genes from a diagnosis, prognosis and monitoring point of view, as well as a potential therapy by replacing missing microRNAs. Dr. Stephan Stilgenbauer presented very interesting information on the genetic material that is lost in association with various genetic abnormalities. Dr. Stilgenbauer and I will co-direct the genetics program.
Ultimately, we hope to understand how the biology of CLL and its genetic variants affect patients’ outcome. We hope to have a full genetic fingerprint of each patient to allow for a more personalized treatment program. For example, Dr. Bill Plunkett, the working group leader of the drug development theme, is examining a new agent, sapacitabine, which may be specific for the management of 11q abnormalities in combination with other drugs. Laboratory studies are currently being conducted with a goal of moving to a clinical trial.
Dr. Deepa Sampath is looking at the processes of acetylation (silencing activated genes) and deacetylation (activating silenced genes). This intervention of genetic activity has the possibility of altering the genetic defects that influence CLL. This includes p53 mutation which is associated with the group of patients having an abnormality on chromosome 17 . Clinical trials are being developed to evaluate this strategy with agents called histone deacetylase inhibitors (HDAC inhibitors).
Another new agent that will be tested in a clinical trial soon is PEITC, a natural product derived from cruciferous vegetables such as watercress, broccoli and cauliflower. Dr. Peng Huang continues to evaluate PEITC which shows consistently high activity against CLL alone and in conjunction with other drugs. The drug is currently being manufactured and should move into clinical trials in the near future.
Work on PEITC led to Dr. Huang’s development of another agent, selecticine. This simple chemical has shown substantial results. Of note, selecticine is highly potent against CLL cells in the presence of stroma, the environment surrounding CLL cells. Stroma has always been a major obstacle for drug treatments because it inhibits drugs from being fully effective. This preliminary research is promising and something we are all excited about.
A major struggle with current therapies is that CLL cells hide in the body’s lymph nodes, spleen, etc. This allows the CLL cells to be protected and prevents the CLL cells from being killed by drug treatments. Dr. Jan Burger is working on ways to shake the CLL cells out of their hiding places and into the peripheral blood where they are more vulnerable to treatment.
During the meeting, I asked members of the transplantation/immune reconstitution group to “dream” of new strategies. This led to a very vibrant discussion of different options that are on the brink of being available. There is a possibility of immunizing transplant donor cells to grow immune cells which work specifically against leukemic cells. This is a very encouraging prospect.
Participants from Baylor College of Medicine introduced us to novel technologies. Dr. Helen Heslop presented on the prospective role of viruses to potentially control leukemic cells. Dr. Catherine Bollard presented on the use of potential cellular therapies after transplant to prevent CLL relapse. Dr. Gianpietro Dotti, also of Baylor, is collaborating with Alliance members to teach immune cells to recognize and kill CLL cells. This is being done with the use of chimeric antigen receptors (CARs).
CARs provide a link between CLL cells and immune cells. When a CAR is introduced, the immune cells are able to recognize CLL cells as a foreign object in the body. Subsequently, immune cells destroy the CLL cells. Later this year, a CAR which utilizes a surface protein on CLL cells called CD19 should be available in a clinical trial. A CAR is also being developed to target ROR1, a gene which is relatively specific to CLL. This is being conducted by Drs. Laurence Cooper, William Wierda and Tom Kipps, members of the gene/vaccine therapy group. It should be available next year.
A different approach is also being taken to target ROR1, as it is a lucrative target to eliminate CLL cells. Dr. Håkan Mellstedt from the Karolinska Institute in Stockholm is developing monoclonal antibodies to target ROR1. He is also investigating small molecules which have the potential to be given orally to block the protein activity of the ROR1 protein. Another CLL specific protein called TOSO has been explored by Drs. Gribben from the UK and Clemens Wendtner from Germany. Like ROR1, TOSO is a very attractive target for new antibody development and also the development of CARs.
This recent Alliance meeting was certainly exciting. It was clear from the presentations that several promising technologies are on the horizon. We look forward to informing you of subsequent developments. Your investment in the cure of CLL has allowed us to advance CLL research on multiple fronts.
