Two is Better Than One: Arming the T-Cells with Dual Cancer-Targeting Antibodies

One way to bring the powerful cellular immunity and antibody directed targeting together is to construct 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 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 cancer cells.

Thus far, the most experience was with CAR T-cells targeting CD19 in patients with either acute lymphoblastic leukemia (ALL) or B-cell lymphoma. In fact, the first-inclass CAR T-cells targeting CD19 was approved by FDA to treat patients with B-cell ALL. While the CD19-targeting CAR T-cells can be very effective, not all patients responded to this strategy and the ability of maintaining long term disease control is still to be determined due to concern of emerging resistant cancer cells after CAR T-cell therapy. Recent study has shown that more than half of the disease relapse after CD19-targeting CAR T-cells involved cancer cells lacking the target, CD19 (i.e., the CD19 immune escape). One strategy to overcome this immune escape is to direct the CAR T-cells to additional target(s) on the cancer cells besides CD19. The Stanford team lead by Dr. Crystal Mackall, Director of the Stanford Cancer Immunotherapy Program has designed a novel loop CAR molecule that contains two targeting motifs against both CD19 and CD22 (another highly expressed protein on cancer B-cells). The idea is that the additional targeting to CD22 can significantly decrease the chance for immune escape. This novel Stanford manufactured dual CD19/CD22 CAR T-cells are being tested in an ongoing clinical trial. Another strategy is to apply other immunomodulating agent(s) such as checkpoint blockade along with CAR T-cells. In this case, the addition of immunomodulating agent can enhance the cytotoxic effect of the CAR T-cells. It is the vision of Stanford team that these novel cellular immunotherapies can be applied to a variety of cancer type, and become standard of care.

The design of the novel dual targeting CD19/CD22 loop CAR molecule

Dr. David Miklos leads the way introducing the clinical use of CAR T-cell therapeutics at Stanford. While the most of initial study was for patients with hematologic malignancies, this new technology can potentially benefit patients with solid tumor. Dr. Miklos will continue to work with Dr. Mackall to develop a robust clinical program, including Stanford-manufactured novel agents.