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Table 1 Strategies to improve the efficacy and mitigate the toxicities in cellular therapies

From: Novel strategies for immuno-oncology breakthroughs with cell therapy

Area Challenges Potential solutions
Platform Failure to manufacture of engineered T cells Allogeneic or Universal CAR-T or TCR-T with gene editing [43]
Lack of efficacy of CAR-T in solid tumors TIL, TCR-T, NK CAR-T [44]
Lack of persistence of T cells Self-secretion of cytokines to maintain survival of proliferation of engineered T cell, like IL-2, IL-15 et al. [40]
Lack of efficacy Third generation with dual co-stimulatory signals [45]
PD-1 knockout, or expression of PD-1 DN [46]
Selection of specific T cell population, like γδ T cells, CD8+CD39CD69 T cells [47].
Target Lack of target Tumor neoantigens, individualized cell therapy [48]
Loss of target Dual targets CAR-T [49]
Sequential administration of CAR-T targeting different antigen [40]
Antigens shared by tumor and normal cells, like hematopoietic stem cells Low affinity CAR-T, TCR-T to avoid killing normal cells with low expression level [50]
Cellular therapy followed by stem cell transplant using gene-knockout, like CD33- hematopoietic stem cells [51]
T cell trafficking Lack of trafficking of T cells to tumor site Intra-tumor or intra tumor site (intra-pleural) administration of cellular therapy [52]
Chemotherapy (like oxaliplatin and cyclophosphamide) and/or local tumor radiation prior to infusion of T cells [53].
Expression of chemokines by the engineered T cells [40]
T cell functions T cell exhaustion at the TME PD-1 knockout or expression of PD-1 DN [46]
Re-direction of Treg by BiTEs [54]
Administration of checkpoint inhibitor after T cell infusion [55]
STING agonists [56]
Small molecules and mAbs targeting the CSF-1/CSF-1R axis to decrease suppressive macrophages [57]
Mitigation of toxicities CRS and ICANS Combinatorial antigen recognition by AND and AND-NOT logic using a synNotch receptor and iCAR [40].
Off-switch receptors or inducible suicide constructs [40]