Overcoming the challenges associated with CD3+T-cell redirection in cancer

The development of bispecific antibodies that redirect the cytotoxic activity of CD3+ T cells to tumours is a promising immunotherapeutic strategy for the treatment of haematological malignancies and solid cancers. Since the landmark FDA approval at the end of 2014 of the anti-CD3 x anti-CD19 bispecific antibody blinatumomab (Blincyto(R)) for the treatment of relapsed/refractory B-cell acute lymphoblastic leukaemia, similar to 100 clinical trials investigating the safety and efficacy of CD3+ bispecific T-cell redirectors for cancer have been initiated. However, despite early success, numerous challenges pertaining to CD3+ T-cell redirection in the context of cancer exist, including the recruitment of counterproductive CD3+ T-cell subsets, the release of systemic cytokines, the expansion of immune checkpoint molecules, the presence of an immunosuppressive tumour microenvironment, tumour antigen loss/escape, on-target off-tumour toxicity and suboptimal potency. The aim of the present review is to discuss novel approaches to overcome the key challenges associated with CD3+ bispecific T-cell redirection in order to achieve an optimal balance of anti-tumour activity and safety.

Automated summary

Bispecific antibodies redirecting CD3+ T cells to target tumors hold promise as an immunotherapeutic strategy. Despite early success, challenges such as recruiting counterproductive T cell subsets, systemic cytokine release, immune checkpoint molecule expansion, and an immunosuppressive tumor microenvironment need to be overcome for optimal clinical benefit.