Externally-Controlled Systems for Immunotherapy: From Bench to Bedside

Abstract

Immunotherapy is a very promising therapeutic approach against cancer that is particularly effective when combined with gene therapy. Immuno-gene therapy approaches have led to the approval of four advanced therapy medicinal products (ATMPs) for the treatment of p53-deficient tumors (Gendicine and Imlygic), refractory acute lymphoblastic leukemia (Kymriah) and large B-cell lymphomas (Yescarta). In spite of these remarkable successes, immunotherapy is still associated with severe side effects for CD19+ malignancies and is inefficient for solid tumors. Controlling transgene expression through an externally administered inductor is envisioned as a potent strategy to improve safety and efficacy of immunotherapy. The aim is to develop smart immunogene therapy-based-ATMPs, which can be controlled by the addition of innocuous drugs or agents, allowing the clinicians to manage the intensity and durability of the therapy. In the present manuscript, we will review the different inducible, versatile and externally controlled gene delivery systems that have been developed and their applications to the field of immunotherapy. We will highlight the advantages and disadvantages of each system and their potential applications in clinics.

Physiological lentiviral vectors for the generation of improved CAR-T cells

“…Latest generation LVs are very resistant to transgene silencing 6,7 and allow the control of the transgene through physiological or drug-inducible promoters. [8][9][10][11][12][13][14][15][16] We therefore searched for LVs that express transgenes on T cells following the expression kinetic of the T cell receptor (TCR) after stimulation. Since the TRAC promoter in human mature T cells is not well characterized, we focus on a well-defined promoter that controls the expression of the WAS protein (WASP), which is involved in the formation of the immunological synapse and in translating TCR signals to several T cell functions.…”

Broadly Applicable, Virus-Free Dual Reporter Assay to Identify Compounds Interfering with Membrane Fusion: Performance for HSV-1 and SARS-CoV-2

“…Since in vivo experiments revealed no immune responses after retinal application [ 42 ], adverse effects on target cells such as initiating an innate immune response using the Tet-On 3G system were expected to be negligible in the cell culture. Promising experiments using Tet-On 3G for in vivo immunotherapy have been conducted [ 43 ], providing an increase in the safety and specificity of therapies. This contrasts with other approaches used in reporter fusion assays such as T7-polymerase/T7-promoter-based reporter gene expression, which has been described to trigger unwanted innate immune responses [ 44 ].…”

Physiological (TCR-like) regulated lentiviral vectors for the generation of improved CAR-T cells

“…Improvements in CAR structure (scFV, hinge/spacer, costimulatory domains, bi-especific or multispecific CARs, etc) T cell composition or combinational therapies have already shown improved results 24 . New approaches to improve CAR-T efficacy and/or safety include the control of CAR activity and or other molecules 13 and mechanism to avoid immune-reactions against the CAR-T cells 25 .…”

“…Contrary to genome editing tools, lentiviral vectors (LVs) derived from HIV-1 have already been approved by the FDA and EMA (Kymriah, Breyanzi and Zynteglo). Latest generation LVs are very resistant to transgene silencing 6,7 , and allow the control of the transgene through physiological or drug inducible promoters 8-13 . We therefore searched for LVs that express transgenes on T cells following a TCR expression kinetic.…”