Until recently, chemotherapy has been the cornerstone of treatment of chronic lymphocytic leukemia. Chemotherapy provides many benefits to patients, but it also suppresses the immune system. The immune system of CLL patients is already not functioning well. Adding chemotherapy generally further comprises the immune system of CLL patients. Activating the immune system to fight against CLL cells may be the missing link in the fight to control CLL.
The next five years will be a revolutionary time in the management of CLL. We are now exploring opportunities to enhance the immune system and potentially to educate a patient’s immune cells to recognize and attack CLL cells.
The “Holy Grail” of immunotherapy is to develop vaccines to control various infectious diseases. Of course, the great successes have been in situations like polio, where there was a well defined virus and the ability to administer a uniform vaccine to a broad population. However each patient with CLL has cells which are unique to them. Therefore, vaccines for CLL need to be specific for each individual. Two approaches, protein and cellular vaccines, are currently being evaluated.
The MyVax vaccine, developed by Genitope, is now in clinical trial for early stage patients who have the most intact immune systems and the least aggressive type of disease. The protein (which is unique to each individual) on the surface of the CLL cells is produced and connected to another protein called keyhole-lympet-hemocyanin. Patients will receive a series of vaccinations with this protein which takes approximately eight months to manufacture. The trial will evaluate whether a response can be generated within the immune system.
In addition to protein vaccines, cellular vaccines are now coming into prominence. Early work at University of California – San Diego by Dr. Tom Kipps and Dr. William Wierda used a mice gene encoding for the CD40 ligand (AD154) and introduced it to CLL cells. The cellular vaccine turned the membrane of the CLL cells from very dim and hard to recognize by the immune system to very bright so that it would easily be recognized as foreign. More recently ISF35, the human construct of the CD40 ligand, has been developed. ISF35 can be introduced into the CLL cells. An active gene therapy program is underway at MD Anderson Cancer Center being conducted by Dr. Wierda. A handful of patients have already been treated with good tolerance and transient suppression of their blood counts. Only a single infusion is possible at the present time but in the near future studies of multiple doses will be conducted. Using multiple doses is the optimal way to develop this cellular therapy. This is an area of great interest with the potential of generating immune responses against the whole CLL cell. Dr. Wierda hopes to reproduce the promising results obtained with the mice construct using the human construct, ISF35. (Read more about Dr. Wierda’s study in CLL Research Momentum.)
Beyond vaccines, we continue to look at antibodies and combinations of antibodies to enhance activity and to work against the CLL cell. The monoclonal antibody rituximab has modest activity by itself in generating predominantly partial responses in previously treated and untreated patients with CLL. Studies in follicular lymphoma have shown that rituximab in combination with leukine (GMCSF) has been associated with a higher complete remission rate than rituximab by itself. Based on these results, Dr. Alessandra Ferrajoli at MD Anderson is now studying this combination in CLL patients; rituximab + GMCSF is showing a promising increase in response rate in CLL patients. The combination is now the initial therapy being offered at MD Anderson to patients over the age of 70 as initial treatment for CLL.
A new human antibody against CD20 (the target of rituximab), HuMax-CD 20, is being developed by Genmab. The antibody is interesting in that it attacks a different site on the CD20 molecule than rituximab and has demonstrated pre-clinical activity in rituximab-resistant patients. A study of this antibody has been conducted in CLL with promising results. An international study of this agent in fludarabine and Campath-1H refractory patients is already underway with many centers in the United States and Europe participating. Two other antibodies in earlier stages of development are lumilixamab which targets a protein CD23 which is found in all CLL patients and Chiron 1212 which targets CD40 which is prominent on CLL patients. The proliferation of antibodies is promising in that there is already the suggestion that rituximab + alemtuzumab (Campath-1H) is showing evidence of additive or potentially synergistic activity against CLL.
Immune modulating drugs
A new agent called lenalidomide (Revlimid) is an immune modulating class of drugs. It has marked activity in myelodysplastic syndrome and multiple myeloma and is approved for these indications. Early studies from Asher Chanan-Khan at Roswell Park in Buffalo have demonstrated activity in CLL. MD Anderson has recently completed a study which confirms and expands the information on the usefulness of lenalidomide in CLL. This is of interest because it modulates the immune system rather than directly attacking the CLL cells. Combination studies of lenalidomide with antibodies are being planned at the present time.
The consequence of therapy of CLL with chemotherapy and alemtuzumab is suppression of the immune system. Early studies have demonstrated that by the use of small beads which have stimulating molecules on the surface, the T-cells of patients can be expanded 100 to 1,000 fold outside the body in bags and then re-infused back to reconstitute an element of the immune system. These studies will be amplified or expanded in the next 12 – 18 months to see how effective immune reconstitution is after a variety of different treatments. All of the monoclonal antibodies and vaccines will require T-cell function to be as good as possible for it to have its maximum effect. These studies are being developed by Dr. Wierda in conjunction with Dr. E.J. Schpall at MD Anderson. While transplants are not usually considered to be a form of immune therapy, it is clear now that the majority of the benefit of allogeneic bone marrow transplants is due to be the effect of the engrafted immune cells attacking the leukemia. This applies regardless of whether the donor is a relative or unrelated.
Reduced intensity conditioning transplants or mini-transplants utilize the cellular immune system of the donor to function as a form of immune killing of the leukemic cells. The technology is now becoming available not only to switch on the CLL cells, to make them better able to activate the immune system but potentially be cultured together with activated T-cells of the same patient. This may enable the development of an educated T-cell program which could function like an allogeneic transplant.
We are now in era of immune attack on CLL. Many questions remain to be answered. Yet, I am optimistic that this will provide a major new initiative leading to further improvements in the control of the disease.
Dr. Michael Keating, professor of medicine at MD Anderson Cancer Center, serves as president and CEO of the CLL Global Research Foundation. He is an internationally renowned CLL clinical scientist dedicated to patient care and to development of potentially curative CLL therapies.