The CLL Global Research Foundation (CLL Global) has funded 31 individual, peer-reviewed grants over the last four years, totaling $5.3 mil. All of these grants have produced new information and insights; many have led to further grant support from other agencies. The grant recipients prominently acknowledged the Foundation’s support at the International Workshop on CLL in London in 2007. Our grant support will help two new drugs enter the clinic in 2008.
8-chloroadenosine is being developed by Dr. William Wierda in conjunction with Dr. Varsha Gandhi, both at MD Anderson Cancer Center. The Phase I trial at MD Anderson will be the first human study in the United States. Some patients in China have already received the drug but for a variety of other malignancies. In addition, Dr. Peng Huang is now ready to put PEITC (an extract of vegetables) in capsules. PEITC shows promise as an active agent against the most aggressive forms of CLL including those with abnormalities in chromosome 17.
After a period of time it is always useful for an organization to evaluate the success of its programs. We have funded excellent grants; however, the weakness of this mechanism is that research is performed in silos rather than in an integrated fashion. I presented an initiative to integrate research on the five big ideas in CLL research to my mentor and member of the Board of Directors, Dr. Emil J Freireich.
He stated that “while patients who are donating funds for the research would love for us to understand CLL, they would like for the understanding to come after curative treatment has been developed.” Being a quick learner, I decided to change the initiative to the five big treatment concepts in CLL. Thus, the U.S./European Alliance for the Therapy of CLL (Alliance) was born. The five thematic areas are:
- Gene and Vaccine Therapy
- Transplantation or cellular immunotherapy and reconstitution of the immune system
- New drugs
- Antibody development and measurement of minimal residual disease
- Understanding the supporting stroma of CLL
Twenty-five experts were asked to participate in one of the five working groups. Each of the groups convened, under the leadership of a working group leader, to identify areas ripe for exploration and integration. In this first year, four out of the five leaders have come from the MD Anderson Cancer Center because of ease of administration. Dr. John Gribben, a long-time collaborator, from the United Kingdom is leading the fifth group in conjunction with MD Anderson colleagues. Twenty projects have been evaluated and funded (totaling $2.98 mil.) and the dispersal of the funds is ongoing at this time.
There is a close interaction among all of the different grants with overlapping areas of interest. The Alliance structure provides an opportunity to integrate research which will accelerate research and our understanding of how to treat this disease.
The U.S. members of the Alliance met in January 2008 and, with great enthusiasm, shared the concepts which have been developed by investigators receiving the awards. We also have established an oversight committee comprised of major figures in hematologic research.
Themes 1 and 2 – These two themes are intimately interrelated.
Theme 1- Gene and Vaccine Therapy
Some years ago at the University of California San Diego, Drs. Thomas Kipps and William Wierda initiated a clinical trial of gene therapy with a CD40 ligand gene (CD154) in which a virus was used to carry the gene into the CLL cells and turn it into a cellular vaccine. This was successful but was associated with the development of antibodies as the virus was mouse-derived.
The human construct, ISF35, has now been developed and is being evaluated in clinical trials at MD Anderson. The phase I part of this gene therapy study (using a single infusion) completed with clear evidence of effective transduction of the cells to create the vaccine. The results show tolerance of the vaccine and good biologic response. The phase II part of the study, to be activated later this year, will use multiple doses. There is great enthusiasm for this approach. The expectation is to enter 20 patients to get an idea of the tolerance and efficacy of the approach.
A second project is being spearheaded by Dr. Thomas Kipps. During the original studies with the mouse CD40 ligand, CD154, it was noted that there were antibodies formed against a fetal protein called ROR1. Further exploration demonstrated that this protein was present on CLL cells but not on other normal cells in the body. It appears that this protein is commonly available in CLL and, therefore, a great target for a general vaccine. Dr. Kipps is developing a DNA vaccine which may be able to be injected into the skin or muscle to manufacture ROR1 and attempt to induce antibodies and immune T-cells to work against the leukemia. (ROR1 is also being explored by members of the New Antibody section and represents an opportunity for collaboration.)
Dr. Clemens Wendtner from Cologne, Germany will be doing a similar gene therapy study to that developed by Dr. Wierda with a different transduction system and will be making available assays to measure the success of this approach. Thus, there may be both protein antigens and cellular vaccines that will be available to stimulate the patient’s own immune cells.
Theme 2 – Transplantation and Immune Reconstitution
The studies in Theme 1 lead directly into the elements of Theme 2. Dr. Gribben (St. Bartholomew’s Hospital at Barts and the London School of Medicine) has become aware over a number of years that there is a block in the immune response of the T-lymphocytes in CLL. Dr. Carl June at the University of Pennsylvania has developed a methodology to activate and expand a patient’s own immune cells 100 to 1,000-fold by incubating them with beads that have stimulatory molecules, CD3 and CD28. In collaboration with Dr. June, Drs. Chitra Hosing and Elizabeth Shpall (both at MD Anderson) and Dr. Gribben are exploring this methodology in a multi-faceted grant sponsored by the Alliance. Three elements of this research are very important.
- After many different treatments including alemtuzumab (Campath), there is a persistent prolonged deficiency of T-lymphocytes. This predisposes patients to unusual infections. The first protocol (under this grant) will endeavor to rebuild the immune system by having these cells stored before the immune suppressing treatment is given. Subsequently, the cells will be expanded for infusion into the patients to see if we can rebuild the immune system.
- We are attempting to increase the use of cord blood transplants. However, there are very few T-lymphocytes in cord blood collection to give to patients for donor-lymphocyte infusions if they have a less than complete response to mini-transplantation (non-ablative stem cell transplantation, NST). Dr. Shpall and Dr. Hosing will be separating 20% of the cord blood cells to expand up the T-lymphocytes. These cells will be frozen so that a donor-lymphocyte infusion can be given, similar to transplantation from siblings or unrelated adult donors.
- There is great enthusiasm for the concept of developing an autologous transplantation program. Cells which are activated by gene therapy can be used to simulate the expanded T-lymphocytes of patients. This would lead to the possibility of doing autologous immune therapy with T-cells developed from the patient’s own cells. This would take away the risk of graft vs. host disease and is a key element in trying to prevent recurrence of the disease.
Dr. Michael Caligiuri and Dr. Don Benson from Ohio State University have been actively exploring the activity of natural killer cells in CLL and in transplantation. They will closely integrate their studies together with those of the previous investigators to further refine the use of transplantation and immune therapy in CLL. Dr. Emili Montserrat (Hospital Clinic of Barcelona) is a leader in the use of autologous and allogeneic transplant in CLL and lymphoma in Europe. He and his group will be monitoring the reconstitution of the immune system in patients who are having transplantation so that application of the above investigations can be applied more broadly.
Theme 3- New Drugs
Many patients do not like chemotherapy. Despite that feeling, chemotherapy drugs have been responsible for major treatment advances in cancer. Chemotherapy has become much more palatable as the side effects are able to be modified. Dr. William Plunkett and his group of major collaborators at MD Anderson, Dr. Varsha Gandhi, Dr. Peng Huang, and Dr. Deepa Sampath are major investigators in the development of new drugs for CLL.
Dr. Plunkett is developing compounds that will initiate apoptosis specifically in CLL. The lead compound is currently in clinical trial sponsored by Sunesis Pharmaceuticals, Inc. In addition, he is working on a concealed nucleoside drug conceptualized by Gilead Sciences that is carried into the CLL cells in an inactive form. Activation then occurs specifically in lymphoid cells including the CLL cells.
Dr. Gandhi is exploring agents that may reverse the immortalization of CLL cells. The Bcl-2 family of proteins is important in protecting CLL cells from dying; she is studying agents which can block this family. Dr. Huang is looking at how CLL cells are kept alive through the interaction of stromal cells and soluble chemicals. Without these interactions, CLL cells would die quite rapidly. He is developing a system to test a number of new drugs by manipulating the cellular environment.
Dr. Michael Hallek from Cologne, Germany, is also looking to make screening mechanisms for new drug combinations more efficient. Dr. Sampath is using a group of drugs called histone deacetylase (HDAC) inhibitors to re-sensitize CLL cells to the activity of other agents. She is also finding that gene therapy-modified cells also regain sensitivity. This is a very vibrant group of investigators which promises to lead to a number of new and exciting compounds in CLL.
Theme 4- Antibody Development and Measurement of Minimal Residual Disease
Major advances have occurred over the last ten years with the introduction of the monoclonal antibodies, rituximab and alemtuzumab in CLL. Dr. Constantine Tam will be working with Dr. Susan O’Brien and me (both at MD Anderson) to study plasma to see if DNA and soluble proteins can be used to measure the total burden of CLL in the body. This is a very important element for monitoring the success of minimal residual disease after effective treatment. The chemicals which they will be measuring will be the DNA of the heavy chain immunoglobulin gene which is the fingerprint gene of CLL cells together with surface antigens such as CD20, CD52, and CD23 (the targets for rituximab, alemtuzumab, and a new monoclonal antibody called lumiliximab).
Drs. Peter Hillmen and Andy Rawstron lead a very important investigator group from Leeds Hospitals in the United Kingdom in developing minimal residual disease. They are looking to identify new potential targets for the diagnosis and treatment of CLL. They are exploring the ROR1 protein mentioned previously. Drs. Håkan Mellstedt and Anders Osterborg at the Karolinska Institute, Stockholm will also explore the activity of ROR1 as a potential target for monoclonal antibody therapy. We hope that the Alliance will provide a forum for these three research groups to collaborate on the study of ROR1.
Dr. Stephan Stilgenbauer (University of Ulm) will actively explore the mechanisms preventing alemtuzumab from killing CLL cells. While we are always happy that monoclonal antibodies kill cells, we know that certain cells are resistant to this destruction. The resistant cells tend to recur. By better understanding the mechanism of resistance, we may be able to manipulate the mechanism and/or improve therapies.
Theme 5 – Stroma CLL Interaction
This concept may prove difficult to fully explain. All CLL cells exist in a matrix of different tissues. There are supporting cells, blood vessel cells, fat cells, and very specific cells which maintain the integrity and survival of the CLL cells. This complex interaction is the reason why CLL cells will last for 100 days in the body but will die in 3 – 6 days when taken out of the body. A number of separate approaches will be used to evaluate how we can modify this matrix to improve CLL therapy.
Dr. Jan Burger (MD Anderson) identified nurse-like cells which can sustain the survival of CLL cells over long periods of time. He will continue to explore the CLL cells microenvironment and develop standardized assays to measure the support of the CLL cells and its impact on treatment resistance. Dr. Federico Caligaris-Cappio, from Milan, Italy, will be identifying a number of the pathways which allow the interaction between these stromal cells and the CLL cells to keep the CLL cells alive.
Dr. Neil Kay (Mayo Clinic) has been very involved in exploring elements of the stromal system, including the substance coming from blood vessels and other supporting cells. Dr. Andreas Rosenwald is a noted molecular pathologist and histopathologist from Wuerzburg in Germany. He will be doing sophisticated analysis of the structure of lymph nodes and bone marrow so that we can understand the dialogue which occurs between these cells. Dr. Zeev Estrov (MD Anderson) will examine the proliferation and growth proteins in the STAT3 pathway which are universally switched on in CLL patients. A number of drugs are being developed which could potentially inhibit the support of CLL survival by this STAT3 pathway.
This is an extremely ambitious program. We have invited and received acceptance from most of the major CLL investigators in the world who are committed to working together to eradicate CLL. We will have our first U.S./European joint meeting in Italy this summer. At that time, we will develop interactive ideas that can be explored during the grant period.
If two to three new ideas come from this activity that are truly novel and lead to new therapies of CLL, the Alliance will be a success. We hope to decrease the amount of disease, to prevent recurrence by treating minimal residual disease and activating the immune system, to expand the use of transplantation and to enhance our understanding of the CLL microenvironment. We will work to rapidly disseminate the information to other members of the CLL research community and the public at large.
We look forward to sharing with you additional information on the Alliance as we make progress in accelerating CLL research. The Alliance represents a surge in our efforts to accelerate CLL research. Combining our Alliance and individual peer-review grants, we have awarded almost $9 mil. in grants in the last four years. We hope this funding will provide momentum to succeed in the battle against CLL.