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

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⁺CD39⁻CD69⁻ 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]