About this Research Topic
Adoptive cellular therapy (ACT) includes obtaining a patient’s or donor’s cells, modifying or expanding them in ex vivo conditions, and delivering the modified or expanded cells to the patient. We could distinguish 3 mainly categories of ACT: tumor-infiltrating lymphocytes (TILs), genetically engineered Tcell receptors (TCRs), and chimeric antigen receptor T cells (CAR-Ts). TILs have proven efficacy in comparison with immune checkpoint blockade therapy, in terms of antitumor T-cell populations and specific responses mainly in advanced melanoma. Considering the durable clinical responses in the treatment of patients with the some hematological indications with CAR-Tcell, unfortunately we cant’ say the same for CAR-T therapy against solid tumors.
These unsuccessful outcomes are mainly due to the lack of suitable CAR-T target antigens in solid tumors and that the targeted antigens are usually found on healthy tissues leading to “on-target off-tumor” toxicities. Other important barriers include the poor accessibility of the target antigen by CAR-Ts that leads to inefficient CAR-T in vivo stimulation, activation, and expansion, the heterogeneous pattern of tumor antigen expression and the appliance of escape mechanisms by tumor cells to evade CAR-Ts redirected towards a single tumor antigen, the immunosuppressive nature of the TME rendering CAR-Ts non-responsive or exhausted, insufficient infiltration of CAR-Ts into the TME, and metabolic starvation.
Probably combination strategies have the potential to overcome the obstacles described above. For example the addition of checkpoint inhibitors or cytokine modulators such as CD40 can help increase T-cell infiltration, enhance proliferation, and overcome antigen escape. Targeting the tumor microenvironment and/or stroma may also improve the effectiveness of ACTs. For example, adding angiogenic therapies (eg, vascular endothelial growth factor inhibitors) to ACTs may increase tumor infiltration. The technologies of dual-specific CAR T cells, synNotch receptors, CRISPR-based modulation of the proinflammatory genes, along with inducible cytokine CAR T cells, neoantigen TCRs, and combination regimens with TILs all represent the future of enhanced ACT. As we move forward to the next paradigm shift in cancer treatment, a more informed understanding of the tumor microenvironment, target antigens, resistance mechanisms, and strategies to overcome these mechanisms is critical to improving outcomes through innovation.
This Research Topic aims to explore different types of improvement strategies for addressing translational and clinical challenges of ACT in solid tumors. Clinical and preclinical data on ACT, GMP manufacturing issues for academic products and novel immunomonitoring opportunities.
Manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this topic.
These unsuccessful outcomes are mainly due to the lack of suitable CAR-T target antigens in solid tumors and that the targeted antigens are usually found on healthy tissues leading to “on-target off-tumor” toxicities. Other important barriers include the poor accessibility of the target antigen by CAR-Ts that leads to inefficient CAR-T in vivo stimulation, activation, and expansion, the heterogeneous pattern of tumor antigen expression and the appliance of escape mechanisms by tumor cells to evade CAR-Ts redirected towards a single tumor antigen, the immunosuppressive nature of the TME rendering CAR-Ts non-responsive or exhausted, insufficient infiltration of CAR-Ts into the TME, and metabolic starvation.
Probably combination strategies have the potential to overcome the obstacles described above. For example the addition of checkpoint inhibitors or cytokine modulators such as CD40 can help increase T-cell infiltration, enhance proliferation, and overcome antigen escape. Targeting the tumor microenvironment and/or stroma may also improve the effectiveness of ACTs. For example, adding angiogenic therapies (eg, vascular endothelial growth factor inhibitors) to ACTs may increase tumor infiltration. The technologies of dual-specific CAR T cells, synNotch receptors, CRISPR-based modulation of the proinflammatory genes, along with inducible cytokine CAR T cells, neoantigen TCRs, and combination regimens with TILs all represent the future of enhanced ACT. As we move forward to the next paradigm shift in cancer treatment, a more informed understanding of the tumor microenvironment, target antigens, resistance mechanisms, and strategies to overcome these mechanisms is critical to improving outcomes through innovation.
This Research Topic aims to explore different types of improvement strategies for addressing translational and clinical challenges of ACT in solid tumors. Clinical and preclinical data on ACT, GMP manufacturing issues for academic products and novel immunomonitoring opportunities.
Manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this topic.
Keywords: Cell therapy, Cancer, Combination immunotherapy, Cell based vaccines, GMP manufacturing
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