Strategies to Circumvent the Side-Effects of Immunotherapy Using Allogeneic CAR-T Cells and Boost Its Efficacy: Results of Recent Clinical Trials

Abstract

Despite the outstanding results of treatment using autologous chimeric antigen receptor T cells (CAR-T cells) in hematological malignancies, this approach is endowed with several constraints. In particular, profound lymphopenia in some patients and the inability to manufacture products with predefined properties or set of cryopreserved batches of cells directed to different antigens in advance. Allogeneic CAR-T cells have the potential to address these issues but they can cause life-threatening graft-versus-host disease or have shorter persistence due to elimination by the host immune system. Novel strategies to create an "off the shelf" allogeneic product that would circumvent these limitations are an extensive area of research. Here we review CAR-T cell products pioneering an allogeneic approach in clinical trials.

Keywords: CAR (chimeric antigen receptor); GvHD; T cell; allogeneic; chimeric; clinical; receptor; trials.

Figure 1

Genetic modifications of allogeneic CAR-T cells. (A) Lentiviral transduction of allogeneic T cells with a CAR. Donor CAR-T cells with allogeneic TCRs administered to a patient causing GvHD. (B) After an additional gene-editing step to disrupt TCR expression, the cells do not cause GvHD but can be eliminated rapidly by the host immune system. (C) The next gene-editing step abolishes expression of MHC-I molecules, thereby ensuring the prolonged endurance and persistence of allogeneic CAR-T cells.

Figure 2

Three basic strategies to disrupt expression or signaling of TCRs. (A) Abolishing TCR expression by introduction of a double-stranded break in TRAC gene. (B) Interfering with TCR signaling using a competitive inhibitor of CD3ζ-TIM8. (C) Leveraging an RNA interference regulatory mechanism to silence mRNA coding for the CD3ζ component of the TCR. More specifically, RNase III endonuclease (Dicer) cuts the loop of the introduced shRNA homologous to the target within the CD3ζ genome. Furthermore, a guide strand (siRNA) is incorporated in the RNA-induced silencing complex (RISC), with subsequent transcriptional silencing of the target gene.

Figure 3

Choice of either autologous or allogeneic CAR-T cell therapy. *Standard lymphodepletion—conditioning regimen in which intermediate doses of chemotherapy drugs are applied. **Enhanced lymphodepletion—conditioning regimen in which high doses of chemotherapy drugs and/or additional biologic medications (monoclonal antibody, including allo-647) are applied.