Cancer is a tenacious and unpredictable disease. Instead of designing external treatments that follow cancer’s lead, Prof. Cyrille Cohen and his research team are focused on calibrating the human body’s immune response using white blood cells engineered to maximize their disease-fighting potential. Prof. Cohen is a Senior Lecturer at the Mina and Everard Faculty of Life Sciences at Bar-Ilan University, and one of Bar-Ilan’s 2011 Outstanding Lecturers.
Cytotoxic T-lymphocytes are cells responsible for the targeting of viral-infected and transformed cells. Interestingly, these cells are able to infiltrate malignant tissues and can therefore serve as potent anti-cancer agents. Although these tumor specific lymphocytes are difficult to isolate, Cohen and his research team devised a way, by modifying the genes of unspecified, or “naïve,” white blood cells, to transform these white blood cells into tumor-killing agents.
Using these non-specific T-lymphocytes as a blank canvas, Cohen’s team is currently working on improving gene-manipulating techniques by generating immune cells that are able to sustain themselves over a long period of time in the body and have the ability to target specific malignancies such as lung, liver or breast cancer.
T-lymphocytes are the immune system’s basic response to any invader, and how efficiently the immune system fights that invader is critical. Cohen’s laboratory team’s engineering of the T-lymphocytes begins with the T-cell receptors (TCRs), which varies in each kind of T-lymphocyte. While several factors, such as the tumor micro-environment or tumor-escape mechanisms, are of importance, cytotoxic CD8+ T-lymphocytes are a key player in the anti-tumor response.
The TCR recognizes antigens as short peptides bound to Major Histo-Compatibility (MHC) class I molecules. These peptides, or epitopes, derived from TAA (tumor-associated antigens) have been identified in the past few years and the presence of tumor-specific MHC-peptide complexes on the surface of tumor cells may represent a unique and specific target for the immune system.
Although adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TIL) is an effective approach for the immunotherapy of patients, it is not always possible to isolate or expand TIL that pre-exist in the patient. Therefore, TCR-gene transfer procedures to human lymphocytes have been developed as a therapeutic alternative. (The procedures have yielded encouraging results in clinical trials conducted at the National Institutes of Health by the laboratory whereProf. Cohen trained during his post-doctoral fellowship.)
Cohen’s laboratory team investigates the dynamics of TCR-gene transfer in human cells and works to improve this process by combining molecular and structural biology as well as gene therapy approaches. They are also exploring new ways to improve the anti-tumor response of the T-lymphocytes by endowing them with other immune molecules that would enhance their biological activity and expansion.
In the laboratory Cohen and his team are able to reprogram T-lymphocytes with an anti-tumor TCR to generate cancer-specific targeting. Through genetic engineering they can then program the cell to combat one—or several—specific invaders to the body. Cells can be isolated from tumors and their metastases; Cohen’s team can then use the TCR recognition to modify a T-lymphocyte into a way to infiltrate the cancer successfully. A danger lies in the tumor counterattacking and inhibiting the T-lymphocytes that recognize them.
The goal is to generate long-lasting, highly functional T-cells that improve the lifetime “immune memory” of the patient. Cohen and his team are working with actual tumors—most frequently malignant melanomas—but he cautions this process as a targeted cancer therapy is not yet available to cancer patients.
The current goals of the team include better understanding the nature of the immune response against cancer, targeting other types of cancer (such as lung, colon, breast, liver, ovarian cancers and leukemia) using new classes of immune receptors, optimizing and enhancing the quality of the engineered lymphocytes by modifying co-stimulation and activation pathways, and making them resistant to tumor-induced inhibitory influences.
They are exploring new ways to create and improve the anti-cancer response by patients’ immune cells, which could have important implications for the clinical treatment of cancer using immunotherapy approaches.