Immunology and Advanced CAR-T therapy

• Dr. Anat Globerson Levin, Lab PI, The Dotan Center for Advanced Therapies
• Dr. Galit Horn, Lab manager

Researchers

therapy for patients with multiple myeloma. This CAR T, which was developed at TASMC, is heading in the near future into a clinical trial that will performed by our new I-ACT (Ichilov-adaptive cell therapy) facility.  This project is in collaboration with the Hemato-oncology department.

for targeting ovarian tumors using CAR T cells

High-grade serous carcinoma (HGSC) is a type of epithelial ovarian cancer (EOC). EOC is the fourth most common cause of cancer-related death in women in the developed world and the leading cause of death from gynecological malignancies.  EOC is often diagnosed at advanced-stage disease with an overall 5-year survival rate of <40%. While a significant progress has been made in surgical and chemotherapeutic treatments for EOC, the survival rates for this disease have only modestly improved. We constructed a ‘dual-Chimeric Antigen Receptor’ (dCAR) for ovarian cancer. The dCAR represents a new approach that addresses the major challenge of ‘off-tumor on-target’ toxicity in CAR therapy, namely, the risk of damage to healthy tissues of the patient, which express the target antigen of the selected CAR. The underlying idea is that restricting the activity of CAR T cells against a combination of two antigens, which are co-expressed by the tumor, but not by normal tissues, can prevent off target toxicity. We analyzed the potential efficacy and safety of the dual CAR in vitro. Additionally, we compared the administration of CAR T cells locally to intravenous injection and compared it to IV injections. We show that intra- tumoral injection have a significantly superior effect in vivo.  This project is in collaboration with the Gyno-oncology department.

The challenges of CAR T cells manufacturing are that they are highly expensive and labor demanding as well as a personalized therapy treatment. We developed a lentiviral drug genetically reprogramming and redirecting endogenous T cells toward tumors.

This aims for a Universal “off-the-shelf” CAR T cell approach that can be delivered to a large population of cancer patients with minimal cost and high efficiency by in situ redirecting endogenous T cells. This project is in collaboration with the MDA, USA.

One of the main challenges of CAR T cells today, is infiltration to the solid tumor microenvironment and attacking the whole cancer tissue. EVs obtained from CAR T cells contain similar profile as their parental cells. Specifically, isolated EVs derived from T-cells expressing a chimeric antigen receptor (CAR) toward the antigen of interest, and contained cytokine and enzymes, bind to and penetrate into specific tumor cells, induce apoptosis and there by provide outstanding anti-cancer effects. As for their small size, we believe that CAR-T EVs’ may enable penetration to solid tumors and induce specific cytotoxicity against tumor cells while minimizing cytokine storm. Using CAR T EVs rather than CAR-T cells may provide an immunotherapeutic approach that may reach solid tumors, and improve therapeutic efficacy while reducing costs and risks. This project is in collaboration with the Hematology research Lab.

Hematopoietic Stem Cell Transplant in patients with malignant hematological diseases is challenging for treatment. We developed with Cell Source, in a collaboration between Prof. Yair Reisner, Prof. Zelig Eshhar & Dr. Anat Globerson Levin, a similar approach to the allogeneic “off-the shelf” transplantation, combined with CAR T cells targeting the cancer, which is currently shown to be a success in preclinical mouse models, and will be tested in the near future at MD Anderson in relapsing patients with malignant hematological diseases