The Modern-Day Magic Missile: Arming the T-Cells with Cancer-Targeting Antibody

When Kohler and Milstein developed hybridoma technology in 1975, a monoclonal antibody was thought to be the “Magic Bullet” to treat cancer since it can go directly to the targeted cancer cells. Therapeutic monoclonal antibodies have come to fruition such as rituximab for lymphoma and herceptin for breast cancer. However, monoclonal antibody therapy alone did not fulfill its original promise. On the other hand, the cellular arm of the immune system has shown to be even more effective against cancer cells. One such example is allogeneic transplant where donor T-cells eliminate residual cancer cells, resulting in a cure in many different kinds of hematologic malignancies. However, this process is not precise and off-target killing occurs in the form of graft-versus-host disease (GVHD). One way to bring these two potentially powerful anti-cancer therapeutics together is by arming the T-cells with a monoclonal antibody that recognizes molecule(s) on the cancer cells. Thus far, the most successful approach is the chimeric antigen receptor (CAR) T-cells. In this strategy, the patient’s own T-cells are genetically engineered to produce a hybrid molecule (the CAR) on these tumor-killing cells. The extracellular portion of the CAR molecule is composed of the antigen-recognizing part of a monoclonal antibody, while the intracellular portion contains the activating motifs of the T-cell receptor. When CAR T-cells are infused into the body, the antigen-recognizing part brings these cells to the targeted cancer cells and drives CAR-T cell proliferation. Upon contact with cancer cells, CAR T-cells will be activated to kill the targeted cancer cells. Since February 2016, 7 patients with refractory diffuse large B-cell have received CD19-CAR T-cells targeting the CD19 molecule on the lymphoma cells. While some experienced significant therapy-related side effects, all recovered fully with several patients achieving tremendous tumor shrinkage as demonstrated in one such example shown below. To facilitate clinical trials employing cellular immunotherapies such as CAR T-cells, Dr. Crystal Mackall, director of the Stanford Cancer Immunotherapy Program, will work closely with faculty members in BMT to develop novel cancer cellular immunotherapies. 

Dr. David Miklos leads the way introducing the clinical trials with CAR T-cell therapeutics at Stanford. While the initial study was for patients with lymphoma, this new technology can potentially benefit patients with a variety of hematologic malignancies and even solid tumors. Dr. Miklos will continue to work with Dr. Mackall to develop a robust clinical program.