Recruiting Killer Cells for Cancer Therapy

To recruit immune killer cells for treating cancer, bispecific antibodies have been developed that bind to activating receptors on the cell surface of NK and T cells and to tumor-associated antigens (TAAs). Some are based on multivalent full-length antibodies, and others comprise only single chains of antibody variable domains. Indeed, the most successful bispecific antibody to date, a so-called BiTE for treating refractory or relapsed B-cell acute lymphoblastic leukemia (B-ALL), was constructed by linking an anti-CD3 scFv to an anti-CD19 scFv for treating B-cell malignancies. Strategies to prolong the half-life of such small constructs include fusions with albumin or with modified antibody Fc domains. In a second approach, T cells were transfected with a viral vector containing a gene cassette encoding a chimeric antigen receptor (CAR). Two such chimeric antigen receptor T cells (CAR-T cells), namely, Kymriah and Yescarta targeting CD19, achieved a high number of complete responses in the treatment of refractory or relapsed B-ALL and diffuse large B-cell lymphoma (DLBCL). An increasing number of novel strategies are being developed to optimize CAR-T cell efficacy and overcome the immunosuppressive effect of the tumor microenvironment. Progress has also been made in the development of off-the-shelf allogenic products, which would not only be much cheaper but also be more widely available. A major goal of both approaches is to develop products that reduce the risk of serious adverse events due to cytokine-related syndrome (CRS) and neurotoxicity while maintaining therapeutic efficacy.