Development of Highly Active Anti-Leukemia Stem Cell Therapy (HALT)

Development of Highly Active Anti-Leukemia Stem Cell Therapy (HALT)

Funding Type: 
Disease Team Research I
Grant Number: 
DR1-01430
Award Value: 
$19,999,826
Disease Focus: 
Blood Cancer
Cancer
Collaborative Funder: 
Canada
Stem Cell Use: 
Cancer Stem Cell
Status: 
Active
Public Abstract: 
Leukemias are cancers of the blood forming cells that afflict both children and adults. Many drugs have been developed to treat leukemias and related diseases. These drugs are often effective when first given, but in many cases of adult leukemia, the disease returns in a form that is not curable, causing disability and eventual death. During the last few years, scientists have discovered that some leukemia cells possess stem cell properties that make them more potent in promoting leukemia growth and resistance to common types of treatment. These are called leukemia stem cells (LSC). More than in other cancers, scientists also understand the exact molecular changes in the blood forming cells that cause leukemias, but it has been very difficult to translate the scientific results into new and effective treatments. The main difficulty has been the failure of existing drugs to eliminate the small numbers of LSC that persist in patients, despite therapy, and that continue to grow, spread, invade and kill normal cells. In fact, the models used for drug development in the pharmaceutical industry have not been designed to detect drugs or drug combinations capable of destroying the LSC. Drugs against LSC may already exist, or could be simple to make, but there has not been an easy way to identify these drugs. Recently, physicians and scientists at universities and research institutes have developed tools to isolate and to analyze LSC donated by patients. By studying the LSC, the physicians and scientists have identified the molecules that these cells need to survive. The experimental results strongly suggest that it will eventually be possible to destroy LSC with drugs or drug combinations, with minimal damage to most normal cells. Now we need to translate the new knowledge into practical treatments. The CIRM Leukemia Team is composed of highly experienced scientists and physicians who first discovered LSC for many types of leukemia and who have developed the LSC systems to test drugs. The investigators in the Team have identified drug candidates from the vigorous California pharmaceutical industry, who have already performed expensive pharmacology and toxicology studies, but who lack the cells and model systems to assess a drug’s ability to eliminate leukemia stem cells. This Team includes experts in drug development, who have previously been successful in quickly bringing a new leukemia drug to clinical trials. The supported interactive group of physicians and scientists in California and the Collaborative Funding Partner country has the resources to introduce into the clinic, within four years, new drugs for leukemias that may also represent more effective therapies for other cancers for the benefit of our citizens.
Statement of Benefit to California: 
Thousands of adults and children in California are afflicted with leukemia and related diseases. Although tremendous gains have been made in the treatment of childhood leukemia, 50% of adults diagnosed with leukemia will die of their disease. Current therapies can cost tens of thousands of dollars per year per patient, and do not cure the disease. For the health of the citizens of California, both physical and financial, we need to find a cure for these devastating illnesses. What has held up progress toward a cure? Compelling evidence indicates that the leukemias are not curable because available drugs do not destroy small numbers of multi-drug resistant leukemia stem cells. A team approach is necessary to find a cure for leukemia, which leverages the expertise in academia and industry. Pharmaceutical and biotech companies have developed drugs that inhibit pathways known to be involved in leukemia stem cell survival and growth, but are using them for unrelated indications. In addition, they do not have the expertise to determine whether the inhibitors will kill leukemia stem cells. The Leukemia Team possesses stem cell expertise and has developed state of the art systems to determine whether drugs will eradicate leukemia stem cells. They have also have access to technologies that may allow them to identify patients who will respond to the treatment. The development plan established by the Leukemia Disease Team will also serve as a model for the clinical development of drugs against solid tumor stem cells, which are not as well understood. In summary, the benefits to the citizens of California from the CIRM disease specific grant in leukemia are: (1) direct benefit to the thousands of leukemia patients (2) financial savings due to definitive treatments that eliminate the need for costly maintenance therapies
Progress Report: 

Year 1

Development of Highly Active Leukemia Therapy (HALT) Leukemias are cancers of the blood forming cells that affect both children and adults. Although major advances have been made in the treatment of leukemias, many patients still succumb to the disease. In these patients, the leukemias may progress despite therapy because they harbor primitive malignant stem-like cells that are resistant to most drugs. This CIRM disease specific grant aims to develop a combination of highly active anti-leukemic therapy (HALT) that can destroy the drug-resistant cancer stem-like cells, without severely harming normal cells. During the current year of support, substantial progress has been made in achieving this goal. The CIRM investigators have shown that two different drugs that inhibit different proteins in leukemia stem cells can sensitize them to chemotherapeutic agents, and block their ability to self-renew. The CIRM investigators have also demonstrated that two different antibodies against molecules on the surface of the leukemia cells can inhibit their survival in both test tube experiments and in mouse models. Extensive experiments are underway to confirm these promising results. The results will enable the planning and implementation of potentially transforming clinical trials in leukemia patients, during the period of CIRM grant support.

Year 2

During the past 12 months, our disease team has made further progress in the development of stem cell targeted treatment for chronic lymphocytic leukemias and other leukemias. Stem cells express some molecules on the surface that are different from the corresponding molecules on adult cells. The ROR1 molecule is highly expressed by malignant cells from patients with chronic lymphocytic leukemia, as well as by progenitor cells from other forms of leukemia and lymphoma. It is not expressed by normal adult cells. With the support of the CIRM Disease Team grant, the cooperating investigators have prepared monoclonal antibodies against the ROR1 molecule, that are potent and specific. In animal models, the antibodies can retard leukemia growth and spread. Unlike other anti-cancer drugs, the new antibodies are not toxic for normal bone marrow cells. Thus, they can potentiate the action of other agents used for the treatment of leukemia. The disease team is now focused on the pre-clinical development, safety testing, and scale-up manufacturing of our new, promising agents, in preparation for their introduction into the clinic.

Year 3

During the past 12 months, our disease team has made further progress in the development of stem cell targeted treatment for chronic lymphocytic leukemias and other leukemias. Stem cells express some molecules on the surface that are different from the corresponding molecules on adult cells. The ROR1 molecule is highly expressed by malignant cells from patients with chronic lymphocytic leukemia, as well as by progenitor cells from other forms of leukemia and lymphoma. It is not expressed by normal adult cells. With the support of the CIRM Disease Team grant, the cooperating investigators have prepared a humanized monoclonal antibody against the ROR1 molecule, that is potent and specific. In animal models, the antibodies can retard leukemia growth and spread. Unlike other anti-cancer drugs, the new antibodies are not toxic for normal bone marrow cells. Thus, they can potentiate the action of other agents used for the treatment of leukemia. The disease team is now focused on the pre-clinical development, safety testing, and scale-up manufacturing of our new, promising agents, in preparation for their introduction into the clinic.

Year 4

During the past 12 months, our disease team has made further progress in the development of stem cell targeted treatment for chronic lymphocytic leukemias and other leukemias. Stem cells express some molecules on the surface that are different from the corresponding molecules on adult cells. The ROR1 molecule is highly expressed by malignant cells from patients with chronic lymphocytic leukemia, as well as by progenitor cells from other forms of leukemia and lymphoma. It is not expressed by normal adult cells. With the support of the CIRM Disease Team grant, the cooperating investigators have prepared a humanized monoclonal antibody against the ROR1 molecule, that is potent and specific. In animal models, the antibodies can retard leukemia growth and spread. The disease team has now finalized the pre-clinical development, safety testing, and scale-up manufacturing of our new, promising agent, in preparation for their introduction into the clinic.

© 2013 California Institute for Regenerative Medicine