Engineering Induced Pluripotent Stem Cells for Cancer Immunotherapy

Abstract

Cell-based immunotherapy, such as chimeric antigen receptor (CAR) T cell therapy, has revolutionized the treatment of hematological malignancies, especially in patients who are refractory to other therapies. However, there are critical obstacles that hinder the widespread clinical applications of current autologous therapies, such as high cost, challenging large-scale manufacturing, and inaccessibility to the therapy for lymphopenia patients. Therefore, it is in great demand to generate the universal off-the-shelf cell products with significant scalability. Human induced pluripotent stem cells (iPSCs) provide an “unlimited supply” for cell therapy because of their unique self-renewal properties and the capacity to be genetically engineered. iPSCs can be differentiated into different immune cells, such as T cells, natural killer (NK) cells, invariant natural killer T (iNKT) cells, gamma delta T (γδ T), mucosal-associated invariant T (MAIT) cells, and macrophages (Mφs). In this review, we describe iPSC-based allogeneic cell therapy, the different culture methods of generating iPSC-derived immune cells (e.g., iPSC-T, iPSC-NK, iPSC-iNKT, iPSC-γδT, iPSC-MAIT and iPSC-Mφ), as well as the recent advances in iPSC-T and iPSC-NK cell therapies, particularly in combinations with CAR-engineering. We also discuss the current challenges and the future perspectives in this field towards the foreseeable applications of iPSC-based immune therapy.

Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

“…Safeguard systems which could mitigate such risks are the use of non-integrating engineering methods and the introduction of inducible suicide genes [270]. Clone selection and undifferentiated cell removal are also necessary [271]. Nevertheless, questions on the best iPSC starting material, on robustness of differentiation approaches and on optimal management of off-target risk of gene modifications, remain to be better clarified [271].…”

“…Clone selection and undifferentiated cell removal are also necessary [ 271 ]. Nevertheless, questions on the best iPSC starting material, on robustness of differentiation approaches and on optimal management of off-target risk of gene modifications, remain to be better clarified [ 271 ]. Given the risks, genomic/epigenomic abnormalities should be analyzed in both pluripotent and differentiated states, to distinguish and track iPSCs (and derived NK cells) best suited for therapeutic applications [ 272 ].…”

Enhancing CAR T-cell therapies against solid tumors: Mechanisms and reversion of resistance

“…However, the process of iPSCs to T-cells are relative time consuming (about 40 days). The αβT-iPSCs have more possibility to differentiated to CD8 + T-cells rather than CD4 + T-cells ( 131 , 132 ). Highly potential proliferate T-iPSCs could cause spontaneous cancer which makes the balance between safety and efficiency a dilemma.…”

“…In hepatocellular carcinoma, Glypican-3-specific CAR-NK T-cells also mediated potent antitumor activity while the chondroitin sulfate proteoglycan 4 (CSPG4) CAR-NK T-cells demonstrated the efficacy against melanoma ( 141 , 142 ). In addition to the CAR-NK T-cells, MAIT is another rise star for CAR T-cells, which expresses the Vα7.2–Jα33 invariant TCR α-chain in humans and can penetrate into solid tumors ( 132 ). Mikail Dogan et al.…”

Harnessing the Power of Mucosal-Associated Invariant T (MAIT) Cells in Cancer Cell Therapy

“…As is the case for other innate-like T cells, MAIT cells have been proposed as good candidates for implementing ‘off-the-shelf’ immune therapy for cancer ( Figure 3 ) [ 44 ]. The rationale is based on the following:…”