Overcoming tumor resistance mechanisms in CAR-NK cell therapy

Abstract

Despite the impressive results of autologous CAR-T cell therapy in refractory B lymphoproliferative diseases, CAR-NK immunotherapy emerges as a safer, faster, and cost-effective approach with no signs of severe toxicities as described for CAR-T cells. Permanently scrutinized for its efficacy, recent promising data in CAR-NK clinical trials point out the achievement of deep, high-quality responses, thus confirming its potential clinical use. Although CAR-NK cell therapy is not significantly affected by the loss or downregulation of its CAR tumor target, as in the case of CAR-T cell, a plethora of common additional tumor intrinsic or extrinsic mechanisms that could also disable NK cell function have been described. Therefore, considering lessons learned from CAR-T cell therapy, the emergence of CAR-NK cell therapy resistance can also be envisioned. In this review we highlight the processes that could be involved in its development, focusing on cytokine addiction and potential fratricide during manufacturing, poor tumor trafficking, exhaustion within the tumor microenvironment (TME), and NK cell short in vivo persistence on account of the limited expansion, replicative senescence, and rejection by patient’s immune system after lymphodepletion recovery. Finally, we outline new actively explored alternatives to overcome these resistance mechanisms, with a special emphasis on CRISPR/Cas9 mediated genetic engineering approaches, a promising platform to optimize CAR-NK cell function to eradicate refractory cancers.

Polymer Micropatches as Natural Killer Cell Engagers for Tumor Therapy

“…NK cells have also recently demonstrated superior safety compared to their T-cell counterparts in several clinical trials . Efforts to engineer NK cells have led to CAR-NK cells ,− and NK engagers. − These approaches rely on NK cells reaching the tumor and interacting with the cancer cells for their antitumor activity. An inherent limitation of this approach is patient-to-patient tumor heterogeneity, which makes it difficult to identify target markers for all tumors. ,,− These approaches also do not address the issue of maintaining the activation state of NK cells within the immunosuppressive tumor microenvironment (TME), which can cause the cells to rapidly exhaust before encountering the tumor cell. ,− Cytokine pretreatment is widely used to expand and activate NK cells prior to infusion; however, its effect is transient and quickly diminishes after withdrawal of activating stimuli in vivo .…”

High-efficiency editing in hematopoietic stem cells and the HUDEP-2 cell line based on in vitro mRNA synthesis

“…Genome editing of hematopoietic cells has already reached significant milestones. For inherited disorders this includes early achievement of treatment end points by CTX001 treatment of β-hemoglobinopathies in clinical trials ( Frangoul et al, 2020 ) and many other preclinical and clinical evaluations ( Koniali et al, 2021 ; Cleared et al, 2022 ), and for cancer treatment this includes clinical application of autologous CAR-T cells and allogeneic CAR-NK and CAR-T cells ( Ottaviano et al, 2022 ; Valeri et al, 2022 ; Zhang et al, 2022 ). Much of this progress is based on ex vivo delivery by electroporation, which when suitably optimized achieves great efficiencies even in HSPCs as cells recalcitrant to transfection ( Hoban et al, 2015 ; Frangoul et al, 2021 ; Chu et al, 2021 ).…”

Chasing Uterine Cancer with NK Cell-Based Immunotherapies

“…Another study has also supported that CXCR4 overexpression increases NK cell migration to the target site [148]. Hence, TRACKs and other CAR-NK cell-based immunotherapies have great potential for different tumors, including overcoming the tumor resistance mechanisms [149][150][151][152]. Early clinical trials have proven that NK-targeted therapy is safe for humans, but more research is needed to understand its effectiveness.…”

“…Furthermore, memory-like NK cells armed with a neoepitopespecific chimeric antigen receptor (CAR) are potent antitumor immune cells [164]. CAR-NK cell-based therapies can overcome resistant tumors, including glioblastoma [149,165,166]. The details of CIML NK cells are discussed elsewhere [163,[167][168][169].…”