To CLL Global Supporters:
We have come to the end of 2009 and the start of a new decade. I think it is appropriate that I send you a state of the union summary for chronic lymphocytic leukemia. The past few years have been a time of tremendous progress in CLL and much of this progress can be attributed to the initiation of the CLL Global Research Foundation.
Genetics & Immunology
Tremendous advances have been made in the areas of genetics and immunology. In genetics, researchers are looking at the major common genetic abnormalities in chromosomes 11, 12, 13, and 17. There are major new techniques to look at the entire chromosome pattern in CLL. These techniques include comparative genomic hybridization (CGH) and single nucleotide polymorphisms (SNPs). Using these techniques, we are gaining a clearer understanding of why some patients with a particular genetic abnormality are more or less likely to do well.
The immunology of CLL is a tremendously fertile field. We discovered that the administration of rituximab decreased the complication of graft versus host disease in patients receiving stem cell transplants from siblings or unrelated donors. A whole field of research in the role of B-lymphocytes in transplant has blossomed. The drug lenalidomide (Revlimid) demonstrates clear activity in enhancing the activity of the T- lymphocytes and in restoring antibody levels to normal in approximately a third of the cases, as well as having a direct anti-tumor effect.
What about CLL Global?
What about CLL Global, the organization in which you can play a major role in developing and sustaining? We award approximately five to six individual grants per year, each at $100,000 per year for two years. As a result of these grants, ideas have been developed which should move rapidly to the clinic. Many of the investigators have leveraged the initial CLL Global funding into grants three to five times our initial investment. These have been stand alone grants and not integrated into overall synergistic programs. Going forward, we will continue to identify five to six projects a year which are worthy of funding in a competitive environment and have been reviewed by our Scientific Advisory Board.
We also have great pride in the development of the CLL research consortiums in Australia and Israel. The Australians have converted our initial $100,000 per year grant into more than $3 million of funding for various CLL projects. This has enabled a coalition of individuals to work closely together and to develop somewhat original clinical trials. One of the Australian investigators, Dr. Stephen Mulligan, has identified that the decreased immunoglobulin (antibody levels) in CLL are not a strong predictor of the likelihood of patients getting infection, but deficiencies of subclasses of immunoglobulins are strongly predictive of the likelihood of patients getting infections. This is a major conceptual breakthrough that warrants further exploration and confirmation.
The Israeli group is studying the genetics of CLL to see if there are genes which predispose to CLL such as the breast cancer susceptibility genes discovered in Ashkenazi women. The striking difference between the incidence in Ashkenazi and Sephardic Jews in Israel has a real prospect of identifying susceptibility genes in CLL. They also have used the funding to establish a coalition of investigators. Based on the relationship and support, a number of very committed, hard-working scientists will now shift emphasis to CLL research. They have some tremendous fundamental research activities going on in Israel.
Creation of the Alliance
The U.S./European Alliance for the Therapy of CLL (Alliance) was established to form a cohesive research mechanism for twenty to thirty of the major CLL investigators in the world. The Alliance was developed with five themes:
1) stroma or the environment in which the CLL cells grow
2) new agents
3) evaluation of minimal residual disease and the role of antibodies
4) immunology and transplantation
5) vaccine and gene therapy
CLL Global provided grants under each of the five themes. Most grant recipients have submitted progress reports. Feel free to visit the Alliance section of our website for information on the specific projects. In general, I have been impressed by the collaborative relationships that have formed as a result of the Alliance. I have long believed the solving the CLL puzzle will require many participants. I remain hopeful that the Alliance is the appropriate mechanism for bringing the key pieces together.
Microenviroment and New Agents
It is clear that the microenvironment has a major impact on the likelihood of new treatments working. Dr. Jan Burger and his colleagues in the microenvironment group have set up a successful working relationship with the new agent group. This resulted in a major publication in Blood on the role of the microenvironment in CLL. (Burger, Blood, 15 October 2009, pp 3367-3375).
Dr. Peng Huang has made a conceptual breakthrough in the area of new agents and stroma. Dr. Huang has demonstrated an extract of watercress and broccoli (PEITC) has clear activity impacting the stroma. He has shown that there is a deficiency of the transporter of a key immuno-acid in CLL and an alternative pathway has to be developed by the stroma. This has lead to the development of a combination of two agents which is the most potent combination I ever studied in killing off a variety of CLL cells. In addition the stromal group has worked extensively with Dr. Varsha Gandhi to look at a number of agents which inhibit the survival proteins of the BCL-2 family.
Immunotherapy and Gene Therapy
We continue to work on the development of an “educated T-cell” program. Investigators at MD Anderson recently developed a collaboration with investigators from Baylor College of Medicine. Baylor has tremendous experience in the technology with very few CLL patients for which to apply their technology. MD Anderson has the patients and CLL Global is providing funding. Together, we have put in place the ability to switch on the CLL cells to make them into a vaccine, incubate them with expanded immune T-lymphocytes and facilitate the interaction with lenalidomide. This is a truly very exciting concept which can potentially lead to the cure of CLL. There are also collaborations on the development of chimeric antigen receptors (CARs) in conjunction with Baylor College of Medicine, Dr. Laurence Cooper (M.D. Anderson pediatrics department) and Dr. Tom Kipps (UCSD) who is supplying a construct for the ROR1 molecule.
Gene therapy development has been difficult. The owners of the technology have explored multiple development paths but progress has been slow. There are gene therapy studies under discussion in the U.S. and Europe. We will update you as more details develop. The gene therapy and immunotherapy groups are collaborating to develop promising strategies.
After one year of funding, we have determined that there is a lack of new technologies to evaluate minimal residual disease. Many of the monoclonal antibodies are under the control of the pharmaceutical companies, making it too difficult to develop innovative studies. The Alliance was developed to remain flexible and shift attention when new opportunities present themselves. Therefore, we are shifting our emphasis from MRD/antibodies to genetics.
Addition of Genetics to the Alliance
Genetics is the key area in CLL that is “under-investigated” at the present time. The technology expansion is explosive and holds much promise. We are enhancing our understanding of the roles of microRNA genes initially discovered in CLL by Dr. Carlo Croce (OSU) and Dr. George Calin (now at MD Anderson). We are now in a position to very rapidly expand this area of research and apply it not only to patient material at MD Anderson but also to that of the German CLL study group working in conjunction with Dr. Stephan Stilgenbauer.
Another important genetic advance is the discovery that the immunoglobulin genes in CLL cells of many patients are absolutely identical. This suggests that the cells are driven by a bacterial or viral stimulus. This is a rapidly expanding area and is being linked with some of the cytogenetic abnormalities. Using new technology, we now know that there are major common abnormalities present as well as multiple fascinating and intriguing smaller abnormalities. Many years ago I hypothesized that viruses play a major role in CLL. We now know that an unusual DNA virus, which silently resides in most of us, emerges with impaired immune response in Hodgkin’s disease. This JC virus is a potential cause of cytogenetic instability. This may explain why the disease in some patients with a relatively stable fashion can suddenly dramatically change behavior.
Opportunities for CLL Global in 2010
Now that so many patients experience prolonged remissions, we must increase our focus on to associated conditions such as skin cancer, secondary cancers, and infections. The efficacy of vaccinations will be involved.
I am extremely proud of what has been accomplished in a relatively short period of time in CLL. Of course, we could not have done it without the support that our donors provide. We are still able to run the foundation with a very low overhead of less than five percent. I commit to work diligently, wisely and well and to ensure frugal application of the resources. I hope to report on significant advances made in 2010 thanks to the generosity of CLL Global’s supporters.
Sincerely,[Keating’s signature] Michael J. Keating