Genetic engineering strategies to enhance antitumor reactivity and reduce alloreactivity for allogeneic cell-based cancer therapy

Abstract

The realm of cell-based immunotherapy holds untapped potential for the development of next-generation cancer treatment through genetic engineering of chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapies for targeted eradication of cancerous malignancies. Such allogeneic “off-the-shelf” cell products can be advantageously manufactured in large quantities, stored for extended periods, and easily distributed to treat an exponential number of cancer patients. At current, patient risk of graft-versus-host disease (GvHD) and host-versus-graft (HvG) allorejection severely restrict the development of allogeneic CAR-T cell products. To address these limitations, a variety of genetic engineering strategies have been implemented to enhance antitumor efficacy, reduce GvHD and HvG onset, and improve the overall safety profile of T-cell based immunotherapies. In this review, we summarize these genetic engineering strategies and discuss the challenges and prospects these approaches provide to expedite progression of translational and clinical studies for adoption of a universal cell-based cancer immunotherapy.

Advancements in CRISPR screens for the development of cancer immunotherapy strategies

“… 177 , 178 , 179 , 180 Precise CRISPR-mediated modifications in allogeneic cells allow for the disruption of immune checkpoints, manipulation of chemokine pathways, enhancement of T cell signaling, recruitment of anti-tumor immune cells, and modulation of the immunosuppressive TME. 73 , 181 , 182 , 183 Additionally, CRISPR techniques hold great potential for manipulating and reprogramming cell fate, including hematopoietic stem cells (HSCs) and induced pluripotent stem cells (iPSCs), with the aim of developing stem-cell-derived therapeutic cell products for cancer immunotherapy. 184 , 185 , 186 , 187 , 188 , 189 , 190 …”

Efficient shRNA-based knockdown of multiple target genes for cell therapy using a chimeric miRNA cluster platform

“… 12 In addition, the successful generation of allogeneic therapies relies on the tight control of the expression of surface molecules involved in alloreactivity and allorejection (TCR, major histocompatibility complex class I [MHC class I], MHC class II) or of their regulators (e.g., CIITA). 13 The ability to modulate the levels of multiple target genes at once is therefore crucial to develop the next generation of adoptive cell therapies.…”