"Community Series in Engineered Immune Cells in Cancer Immunotherapy (EICCI), volume III".

Please see volume I here..

Please see volume II here.

Over the past decades, great advances in the knowledge of adoptive cell therapy (ACT) and in the 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 chimeric antigen receptors (CARs) that combines an antigen-binding part (often derived from an antibody) with an activating domain that triggers the T cell response.

TCR-transgenic T cells have a strong potential due to their ability to recognize cytoplasmic and nuclear antigens presented by HLA. Also, they can be multiplexed to specifically target tumor cells, leaving intact healthy tissues. In fact, several clinical studies are ongoing to evaluate the efficacy and safety of TCR-T cells that target multiple neoantigens generated by tumor-specific non-synonymous mutations.

It is now well established the therapeutic potential and limitations of CAR-T cells targeting CD19 and BCMA for refractory B-cell malignancies. The complete response rates go up to 50-90% and the improvement of overall survival is unquestionable for the six CAR-T cells products approved. However, there is still much room for improvement in the treatment of several leukemias and lymphomas. Also, the therapeutic efficacy of CAR-T cells for solid tumors is really low due in part to the immunosuppressive TME and the absence of specific tumor antigens. Several strategies are been implemented to improve CAR-T cells efficacy without increasing safety. Different logic gates (AND, OR, IF, etc) could potentially solve the problems of tumor specificity but will still need to work on efficiency. In this sense, the new genome editing tools could play an important role to increase CAR-T cell potency by eliminating receptors involved in controlling T cells activity (PD1, LAG3, etc)

Another important point to address is related to the manufacturing of the CAR-T cells or the transgenic TCR-T cells. 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 principal 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.

Notably, recently the first Tumor Infiltrating Lymphocyte (TIL) therapy for solid tumors has been approved by the FDA, opening promising advances for additional cell therapy strategies.

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.
• New CARs designs.
• Strategies to overcome barriers encountered in solid tumors for an efficient immunotherapy
• Advances in Tumor Infiltrating Lymphocyte (TIL) therapy.
• Optimizing the choice of target molecules and in vivo models for engineered T lymphocytes.
• Allogeneic/”Off the Shelf” Therapies.
• Gene editing strategies to improve the efficacy and the safety of cell therapies.
• Manufacturing implementation of engineered T cells and Pharma/Biotech perspectives.
• 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.

Topic Editor Dr. Francisco Martin is the founder of LentiStem Biotech and owns Patents PCTEP2019081346, WO2018083274A1and EP23382393_9. The other Topic Editors declare no competing interests with regard to the Research Topic subject.

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