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Review
. 2022 Jun 1;30(6):2130-2152.
doi: 10.1016/j.ymthe.2022.02.002. Epub 2022 Feb 9.

The generation and application of antigen-specific T cell therapies for cancer and viral-associated disease

Amy B Hont  1 , Allison B Powell  1 , Danielle K Sohai  1 , Izabella K Valdez  2 , Maja Stanojevic  3 , Ashley E Geiger  1 , Kajal Chaudhary  1 , Ehsan Dowlati  3 , Catherine M Bollard  1 , Conrad Russell Y Cruz  4
Affiliations
Review

The generation and application of antigen-specific T cell therapies for cancer and viral-associated disease

Amy B Hont et al. Mol Ther. .

Abstract

Immunotherapy with antigen-specific T cells is a promising, targeted therapeutic option for patients with cancer as well as for immunocompromised patients with virus infections. In this review, we characterize and compare current manufacturing protocols for the generation of T cells specific to viral and non-viral tumor-associated antigens. Specifically, we discuss: (1) the different methodologies to expand virus-specific T cell and non-viral tumor-associated antigen-specific T cell products, (2) an overview of the immunological principles involved when developing such manufacturing protocols, and (3) proposed standardized methodologies for the generation of polyclonal, polyfunctional antigen-specific T cells irrespective of donor source. Ex vivo expanded cells have been safely administered to treat numerous patients with virus-associated malignancies, hematologic malignancies, and solid tumors. Hence, we have performed a comprehensive review of the clinical trial results evaluating the safety, feasibility, and efficacy of these products in the clinic. In summary, this review seeks to provide new insights regarding antigen-specific T cell technology to benefit a rapidly expanding T cell therapy field.

Keywords: adoptive immunotherapy; antigen-specific T cells; cancer; manufacturing protocols; virus infection.

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Conflict of interest statement

Declaration of interests C.M.B. has stock or ownership in Cabaletta Bio, Catamaran Bio, Neximmune, and Repertoire Immune Medicines. C.M.B. also has equity interest in Mana Therapeutics, which subsequently licensed some of the T cell manufacturing technology described in this review. C.R.Y.C. is a cofounder of Mana Therapeutics, where he also has equity interest and serves on the scientific advisory board. He is also a consultant for Catamaran Bio. The other authors declare no competing interests.

Figures

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Graphical abstract
Figure 1
Figure 1
Schematic of the antigen-specific T cell ex vivo expansion process T cell expansion from cell harvest to QC release is depicted. Broadly, cells are harvested from various sources in order to generate the cells that will present antigens in different forms. T cells are then selected and expanded, and subsequently released for infusion. At each major stage (teardrop-shaped circles in gradients of red; labeled in blue rectangles), the examples of several alternatives involved in replicating the in vivo stimulation of T cells are shown. (A) Cell sources differ, from patient-derived (auto/autologous), donor-derived/third party-derived (allo/allogeneic), to umbilical cord blood-derived (umbilical cord). Depending on the cell source, different protocols to expand the specific population of antigen-specific T cells are used. (B) Antigens can be delivered in many forms, one of the most common being overlapping peptide libraries that span a single protein. Other forms include whole tumor lysate, antigens expressed in the form of DNA or RNA, and antigens encoded by a virus, such as adenovirus. (C) APCs also take different forms: more potent APCs such as dendritic cells are limited by numbers, while less potent APCs such as PBMCs do not express all the costimulatory molecules or secrete the necessary cytokines for optimal engagement. Other APCs in between these two extremes include cells performing antigen-presenting functions in vivo (including monocytes and B cells), and transformed cells (LCL, lymphoblastoid cell lines that are generated by EBV infection). (D) T cells that will be stimulated by the APCs are either selected or unselected. Selected T cells can be derived by gamma capture, selection of naive populations, or expression of receptors indicating antigen engagement (such as CD154). (E) T cell expansion often uses a variety of different cytokines and subsequent stimulations (see text and Table S1). Finally, after multiple rounds that can last for as few as 10 days to as much as 2 months, cells are then ready for release testing. Times shown are estimated ranges. Created with BioRender.com.
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References

    1. Topalian S.L., Muul L.M., Solomon D., Rosenberg S.A. Expansion of human tumor infiltrating lymphocytes for use in immunotherapy trials. J. Immunol. Methods. 1987;102:127–141. doi: 10.1016/s0022-1759(87)80018-2. - DOI - PubMed
    1. Rosenberg S.A., Spiess P., Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science. 1986;233:1318–1321. doi: 10.1126/science.3489291. - DOI - PubMed
    1. Heslop H.E., Brenner M.K., Rooney C.M. Donor T cells to treat EBV-associated lymphoma. N. Engl. J. Med. 1994;331:679–680. doi: 10.1056/NEJM199409083311017. - DOI - PubMed
    1. Riddell S.R., Watanabe K.S., Goodrich J.M., Li C.R., Agha M.E., Greenberg P.D. Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science. 1992;257:238–241. doi: 10.1126/science.1352912. - DOI - PubMed
    1. Leen A.M., Myers G.D., Sili U., Huls M.H., Weiss H., Leung K.S., Carrum G., Krance R.A., Chang C.C., Molldrem J.J., et al. Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinically relevant effects in immunocompromised individuals. Nat. Med. 2006;12:1160–1166. doi: 10.1038/nm1475. - DOI - PubMed

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