cancers Review Adoptive Immunotherapy beyond CAR T-Cells Aleksei Titov 1,2 , Ekaterina Zmievskaya 1 , Irina Ganeeva 1 , Aygul Valiullina 1 , Alexey Petukhov 3 , Aygul Rakhmatullina 1 , Regina Miftakhova 1 , Michael Fainshtein 4 , Albert Rizvanov 1 and Emil Bulatov 1,5, *   Citation: Titov, A.; Zmievskaya, E.; Ganeeva, I.; Valiullina, A.; Petukhov, A.; Rakhmatullina, A.; Miftakhova, R.; Fainshtein, M.; Rizvanov, A.; Bulatov, E. Adoptive Immunotherapy beyond CAR T-Cells. Cancers 2021, 13, 743. https://doi.org/10.3390/ cancers13040743 Academic Editors: Seung-Hwan Lee and Scott McComb Received: 2 December 2020 Accepted: 2 February 2021 Published: 11 February 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; titov.a@blood.ru (A.T.); EAZmievskaya@kpfu.ru (E.Z.); IAGaneeva@kpfu.ru (I.G.); AjgHValiullina@kpfu.ru (A.V.); AjgulRRahmatullina@kpfu.ru (A.R.); ReRMiftahova@kpfu.ru (R.M.); Albert.Rizvanov@kpfu.ru (A.R.) 2 Laboratory of Transplantation Immunology, National Hematology Research Centre, 125167 Moscow, Russia 3 Institute of Hematology, Almazov National Medical Research Center, 197341 Saint Petersburg, Russia; petukhov_av@almazovcentre.ru 4 Mircod Biotech Inc., Boca Raton, FL 33432, USA; michael@mircod.com 5 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia * Correspondence: ERBulatov@kpfu.ru Simple Summary: The aging of the world population leads to a constant increase of cancer-related morbidity and mortality. Treatment of late-stage tumors has become a significant burden on the healthcare system globally. Adoptive cell immunotherapy is supposed to prolong life with cancer and ideally cure cancer after a single infusion of the cell product. Arguably, the most impressive clinical therapy in this field is based on chimeric antigen receptor (CAR) T-cells capable of curing up to 25–50% of previously incurable patients with B-cell malignancies. Diverse cell therapies are already efficiently used in clinics for cancer treatment (such as tumor infiltrating lymphocytes, transgenic αβ T-cells) and several novel promising cell therapies are in development (such as CAR M-cells, transgenic γδ T-cells, CAR NK-cells). Here, we summarize the recent literature data with the focus on T-cell receptor-based therapies and overview the most advanced systems for manufacturing of clinical grade cell products. Abstract: Adoptive cell immunotherapy (ACT) is a vibrant field of cancer treatment that began progressive development in the 1980s. One of the most prominent and promising examples is chimeric antigen receptor (CAR) T-cell immunotherapy for the treatment of B-cell hematologic malignancies. Despite success in the treatment of B-cell lymphomas and leukemia, CAR T-cell therapy remains mostly ineffective for solid tumors. This is due to several reasons, such as the heterogeneity of the cellular composition in solid tumors, the need for directed migration and penetration of CAR T-cells against the pressure gradient in the tumor stroma, and the immunosuppressive microenvironment. To substantially improve the clinical efficacy of ACT against solid tumors, researchers might need to look closer into recent developments in the other branches of adoptive immunotherapy, both traditional and innovative. In this review, we describe the variety of adoptive cell therapies beyond CAR T-cell technology, i.e., exploitation of alternative cell sources with a high therapeutic potential against solid tumors (e.g., CAR M-cells) or aiming to be universal allogeneic (e.g., CAR NK-cells, γδ T-cells), tumor-infiltrating lymphocytes (TILs), and transgenic T-cell receptor (TCR) T-cell immunotherapies. In addition, we discuss the strategies for selection and validation of neoantigens to achieve efficiency and safety. We provide an overview of non-conventional TCRs and CARs, and address the problem of mispairing between the cognate and transgenic TCRs. Finally, we summarize existing and emerging approaches for manufacturing of the therapeutic cell products in traditional, semi-automated and fully automated Point-of-Care (PoC) systems. Keywords: chimeric antigen receptor; CAR T-cell; CAR NK-cell; transgeneic TCR; TIL; neoantigen; neoepitope; peptide Cancers 2021, 13, 743. https://doi.org/10.3390/cancers13040743 https://www.mdpi.com/journal/cancers