Patients with blood cancers often respond well to existing treatments. However, those therapies do not work for everyone.
For patients whose disease resists standard treatment, options can be limited.
To address that need, the California Institute for Regenerative Medicine (CIRM) has awarded $4.1 million to support the development of a new CAR T-cell therapy for hematologic malignancies.
These cancers affect the blood, bone marrow, and lymphatic system. They include several forms of leukemia and lymphoma.
A New CAR T-Cell Therapy for Blood Cancers
The project is led by Dr. Ezra Cohen at the University of California San Diego and Oncternal Therapeutics.
The team is targeting a protein called ROR1, which appears on the surface of several blood cancers, including certain leukemias and lymphomas.
Researchers have also identified ROR1 on some solid tumors, including breast, lung, and colon cancers.
To attack these cancer cells, the team is using chimeric antigen receptor T cells, or CAR-T cells.
CAR-T therapy uses a patient’s own immune cells. Scientists collect T cells and genetically modify them to recognize specific targets on cancer cells.
The engineered cells can then seek out and destroy cancer cells throughout the body.
Targeting Cancer Cells With Precision
The new therapy builds on earlier CIRM-supported research.
Researchers previously developed an antibody therapy called cirmtuzumab, which also targets ROR1.
Now they are applying that knowledge to create a CAR-T therapy designed to recognize and eliminate cancer stem cells that express ROR1.
Cancer stem cells can drive tumor growth and contribute to disease recurrence. By targeting these cells, researchers hope to improve long-term outcomes.
The approach represents a highly focused form of immunotherapy that harnesses the body’s own defenses to fight cancer.
Advancing Toward Clinical Testing
The project has reached the late preclinical stage.
Researchers must now demonstrate that they can consistently manufacture high-quality CAR-T cells at a scale suitable for patient treatment.
The team must also complete the regulatory studies required to seek approval from the U.S. Food and Drug Administration (FDA) to begin human testing.
If the FDA authorizes a clinical trial, researchers plan to evaluate the therapy in patients with:
- Chronic lymphocytic leukemia (CLL)
- Mantle cell lymphoma (MCL)
- Acute lymphoblastic leukemia (ALL)
These patients often have limited treatment options when standard therapies fail.
Expanding Options for Patients
“CAR-T cell therapies represent a transformational advance in the treatment of hematologic malignancies,” said Dr. Maria T. Millan, CIRM’s President and CEO.
She noted that new approaches remain urgently needed for patients whose cancers resist conventional therapies.
By supporting projects at this critical stage, CIRM helps move promising discoveries closer to clinical testing and, ultimately, patients.
If successful, this therapy could provide a new treatment option for people facing some of the most difficult-to-treat blood cancers.
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.