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Hematologic malignancies are cancers that affect the blood, bone marrow and lymph nodes and include different forms of leukemia and lymphoma. Current treatments can be effective, but in those patients that do not respond, there are few treatment options. Today, the governing Board of the California Institute for Regenerative Medicine (CIRM) approved investing $4.1 million in a therapy aimed at helping patients who have failed standard therapy.
Dr. Ezra Cohen, at the University of California San Diego, and Oncternal Therapeutics are targeting a protein called ROR1 that is found in B cell malignancies, such as leukemias and lymphomas, and solid tumors such as breast, lung and colon. They are using a molecule called a chimeric antigen receptor (CAR) that can enable a patient’s own T cells, an important part of the immune system, to target and kill their cancer cells. These cells are derived from a related approach with an antibody therapy that targets ROR1-binding medication called Cirmtuzumab, also created with CIRM support. This CAR-T product is designed to recognize and kill cancer stem cells that express ROR1.
This is a late-stage preclinical project so the goal is to show they can produce enough high-quality cells to treat patients, as well as complete other regulatory measures needed for them to apply to the US Food and Drug Administration (FDA) for permission to test the therapy in a clinical trial in people.
If given the go-ahead by the FDA the therapy will target patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and acute lymphoblastic leukemia (ALL).
“CAR-T cell therapies represent a transformational advance in the treatment of hematologic malignancies,” says Dr. Maria T. Millan, CIRM’s President and CEO. “This approach addresses the need to develop new therapies for patients whose cancers are resistant to standard chemotherapies, who have few therapeutic options and a very poor chance or recovery.”
The Stem Cellar 
Clinical investigation showed that tumors of patients from the same origin of tissues and organs showed distinct phenotype. The heterogeneity of antigenic phenotype in tumors had been studied by individuals monoclonal reagents. Intense staining of some cells was observed, whereas little, if any, binding could be detected to other cells within the same tumor nodule. This observation supported the evidence that tumors are heterogeneous in genotype and phenotype. They have no stability of genetic and potential of each individual of tumor cells to mutate is varying from one to another. Using a combination of five murine monoclonal antibodies, however more than 95% of tumor cells could be stained intensely in more than 90% of tumors. Hence, concluded that it is possibly more than one murine monoclonal antibody need to be utilized if serotherapy is to be effective. Another study by exploring the binding of multiple monoclonal antibodies to the extracellular domain of HER-2/neu. Epitopes have been shown to be functionally distinct. In assays of anchorage independent growth performed in sort agar, seven of eleven antibodies inhibited SKBr3 growth from 40-80% and the other four antibodies were inactive when used individually. When used in combination, each of these antibodies proved active for inhibiting clonogenic tumor growth.
Current clinical study to investigate the efficiency of CAR-T cells to target protein ROR1 on tumor cells and kill many types of tumors. Most tumor cells are heterogeneous in genotype and phenotype. Serology studies proved that some tumor cells expressed high levels of certain antigenic phenotype wheras others expressed distinct antigenic phenotype. If the CAR-T cells are designed specifically to only one antigenic protein ROR1 on cancers may result small proportion of tumor cells being killed. The low efficacy of therapy may not beneficial to cancer patients in the long run. Therefore, designing of CAR-T cells with multiple targets to tumor antigens may potential the efficiency of CAR-T cells to eradicate majority of cancer cells in patients. This approach may provide additional advantage to improve the safety and efficacy of therapy with CAR-T cells.