Over the past decades, great advances in the knowledge of adoptive cell therapy (ACT) and in engineering of T cells with tumor antigen-targeting receptors have accelerated the clinical development of this strategy at an unparalleled pace. T cells have been engineered with either a T cell receptor (TCR) or a chimeric antigen receptor (CAR) that combines the antibody-derived part with activating and co-stimulatory signaling of T cells. The targeting of endogenous tumor antigens with T cells engineered with a TCR has shown an initial clinical success. However, clinical studies are ongoing to evaluate the efficacy of targeting neoantigens generated by tumor-specific non-synonymous mutations. Strikingly, promising results were recently described when CAR-T cells were used to target CD19 expressing refractory B-cell malignancies, with complete response rates of 50-90% and durable improvement of overall survival. These unprecedented advances in the clinical efficacy of CAR-T cells led to the approval of two products by the FDA and more recently by the EMA, tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta). In addition, promising results have been recently observed also for the treatment of other types of hematological malignancies, such as multiple myeloma.
These biological “living drugs” are produced by isolating patient’s T lymphocytes from peripheral blood mononuclear cells (PBMCs) and engineering these T cells with either gamma-retroviral (RV) or lentiviral (LV) vectors that encode for either TCRs or CARs. However, their clinical grade manufacturing is complex, requiring good manufacturing practice (GMP) facilities, a long timeline for engineering the cellular product and the availability of patient PBMCs of good quality. Serious side effects and adverse events, including cytokine release syndrome (CRS) and neurologic problems, represent additional major issues that have been documented in CAR-T cell treated patients. The experience thus far gained in this field by the principle clinical centers developing these types of clinical studies has led to strategies to control and, in most cases, even resolve these adverse events. However, further studies on the mechanisms involved in these adverse reactions and how to avoid them will grant important advances in the efficacy and safety of engineered T cells. Moreover, dose, phenotype, tumor burden, the design of receptors and their expression and the choice of target antigens are critical points that require ad hoc investigations.
In order to provide patients with immediate treatment, several groups have designed various strategies to obtain donor-derived allogeneic “off-the-shelf” CAR-T cells, with a few clinical studies already ongoing for patients with hematological malignancies. Gene editing platforms (e.g., CRISPR/CAS-9 or TALEN) to knock-out specific gene(s), such as TCR and HLA, are under development to overcome CAR-T cell-mediated graft-versus-host disease (GvHD) or host versus graft reactions, respectively. However, this approach still needs to be optimized in terms of manufacturing, reduction of the risk of toxicities and selection of the target genes.
This Research Topic will collect selected contributions in the following topics:
• The clinical evolution of CAR-T cell therapy.
• Targeting tumors with TCR engineered T lymphocytes.
• Optimizing the choice of target molecules and in vivo models for engineered T lymphocytes.
• Manufacturing implementation of engineered T cells and Pharma/Biotech perspectives.
• Allogeneic/”Off the Shelf” Therapy with CAR-T cells.
• Innovative approaches to improve the targeting of cancer cells.
• Regulatory and quality aspects of building clinical centers for advanced therapy medicinal products.
Contributors are welcome to submit Original Research, Method, Mini-review and Review articles related to the topics mentioned above.
Over the past decades, great advances in the knowledge of adoptive cell therapy (ACT) and in engineering of T cells with tumor antigen-targeting receptors have accelerated the clinical development of this strategy at an unparalleled pace. T cells have been engineered with either a T cell receptor (TCR) or a chimeric antigen receptor (CAR) that combines the antibody-derived part with activating and co-stimulatory signaling of T cells. The targeting of endogenous tumor antigens with T cells engineered with a TCR has shown an initial clinical success. However, clinical studies are ongoing to evaluate the efficacy of targeting neoantigens generated by tumor-specific non-synonymous mutations. Strikingly, promising results were recently described when CAR-T cells were used to target CD19 expressing refractory B-cell malignancies, with complete response rates of 50-90% and durable improvement of overall survival. These unprecedented advances in the clinical efficacy of CAR-T cells led to the approval of two products by the FDA and more recently by the EMA, tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta). In addition, promising results have been recently observed also for the treatment of other types of hematological malignancies, such as multiple myeloma.
These biological “living drugs” are produced by isolating patient’s T lymphocytes from peripheral blood mononuclear cells (PBMCs) and engineering these T cells with either gamma-retroviral (RV) or lentiviral (LV) vectors that encode for either TCRs or CARs. However, their clinical grade manufacturing is complex, requiring good manufacturing practice (GMP) facilities, a long timeline for engineering the cellular product and the availability of patient PBMCs of good quality. Serious side effects and adverse events, including cytokine release syndrome (CRS) and neurologic problems, represent additional major issues that have been documented in CAR-T cell treated patients. The experience thus far gained in this field by the principle clinical centers developing these types of clinical studies has led to strategies to control and, in most cases, even resolve these adverse events. However, further studies on the mechanisms involved in these adverse reactions and how to avoid them will grant important advances in the efficacy and safety of engineered T cells. Moreover, dose, phenotype, tumor burden, the design of receptors and their expression and the choice of target antigens are critical points that require ad hoc investigations.
In order to provide patients with immediate treatment, several groups have designed various strategies to obtain donor-derived allogeneic “off-the-shelf” CAR-T cells, with a few clinical studies already ongoing for patients with hematological malignancies. Gene editing platforms (e.g., CRISPR/CAS-9 or TALEN) to knock-out specific gene(s), such as TCR and HLA, are under development to overcome CAR-T cell-mediated graft-versus-host disease (GvHD) or host versus graft reactions, respectively. However, this approach still needs to be optimized in terms of manufacturing, reduction of the risk of toxicities and selection of the target genes.
This Research Topic will collect selected contributions in the following topics:
• The clinical evolution of CAR-T cell therapy.
• Targeting tumors with TCR engineered T lymphocytes.
• Optimizing the choice of target molecules and in vivo models for engineered T lymphocytes.
• Manufacturing implementation of engineered T cells and Pharma/Biotech perspectives.
• Allogeneic/”Off the Shelf” Therapy with CAR-T cells.
• Innovative approaches to improve the targeting of cancer cells.
• Regulatory and quality aspects of building clinical centers for advanced therapy medicinal products.
Contributors are welcome to submit Original Research, Method, Mini-review and Review articles related to the topics mentioned above.