INTEGRATING BIOREACTOR SYSTEM TO SPEED UP TUMOUR INFILTRATING LYMPHOCYTES (TILS) IMMUNOTHERAPY COMMERCIALIZATION Review Article A. D. BUDIYATI 1,2 , J. A. PAWITAN 3,4,5* 1 Doctoral Program for Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia, 2 Stem Cell and Cancer Institute, Jakarta, Indonesia, 3 Department of Histology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia, 4 Stem Cell Medical Technology Integrated Service Unit, Dr. Cipto Mangunkusumo General Hospital/Faculty of Medicine Universitas Indonesia, Indonesia, 5 Received: 23 Feb 2020, Revised and Accepted: 12 May 2020 Stem Cell and Tissue Engineering Research Center, Indonesia Medical Education and Research Institute (IMERI), Faculty of Medicine Universitas Indonesia, Indonesia Email: jeanneadiwip@gmail.com ABSTRACT One of the major breakthroughs on adoptive cell transfer (ACT) is autologous T cells transfer that either derived from tumour infiltrating lymphocytes (TILs) or genetically engineered T cells, which express tumour recognizing receptors. Between those two, when the purpose is to treat solid tumours, a more impressive clinical trial result is demonstrated by TIL therapy. The efficacy of TIL therapy is due to its highly personalized approach in generating T cells from the patient’s own tumour tissue. Regardless to its efficacy, TIL therapy in a commercial setting is limited, mainly due to the complexity and costs of cell expansion protocols. This issue has triggered the need to develop effective methods to expand TILs ex vivo, in a safe, efficient, and reproducible manner. In line with this need, there are two main types of bioreactors that have recently been used to generate T cells for ACT, which might suit the requirements for TIL manufacture. Therefore, in this review, we highlighted recent updates on TILs expansion protocol, particularly in autologous settings, as well as the aspect of each bioreactor to be considered before integrating them into TIL manufacturing process. Keywords: Adoptive cell transfer, Immunotherapy, Tumour infiltrating lymphocytes, Bioreactor, Solid tumour © 2020 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) DOI: http://dx.doi.org/10.22159/ijap.2020v12i4.37244. Journal homepage: https://innovareacademics.in/journals/index.php/ijap INTRODUCTION Adoptive cell transfer (ACT) is a treatment that uses immune system cells to eliminate cancers. In cancer therapy, an ACT-based strategy exploits the killing potency of specific T cells to generate a robust immune-mediated anti-tumor response. This anti-tumor response is achieved by manipulating T cells ex vivo, away from the patient’s immune-suppressive environment, followed by expansion and reinfusion back to the patient [1, 2]. Based on the way that T cells are manipulated, ACT-based strategy can be divided into two platforms, i.e. isolation of naturally occurring tumor-specific T cells from existing tumour masses, which is called tumour infiltrating lymphocytes (TILs) platform [1, 2], and genetic modification of blood-derived T cells to allow specific recognition of tumour cells, which is called chimeric antigen receptor (CAR) T-cell or T-cell receptor (TCR) platform [1-4]. Both platforms have demonstrated impressive, durable response in clinical settings to treat certain tumours, so that FDA approved CAR T-cell therapy for treating hematological malignancies and TIL therapy for treating melanoma and persistent cervical cancer [1, 2]. Despite various successes in treating B-cell leukaemia and lymphomas, CAR T-cell therapies have not demonstrated their efficacy in solid tumours. As hematological malignancies make up only a small fraction of all cancers, TIL platform is most likely to have broader applicability for treating solid tumours [2, 5, 6]. However, in autologous cell therapy, current TIL expansion protocols remain facing challenges that are mainly due to limited T cell number, which can be isolated from a patient tumour. Moreover, although a TIL’ rapid expansion protocol has been developed decades ago by Rosenberg in 1988 [7], the protocol still needs to be simplified to allow efficient scale-up for TIL manufacturing. For this review, we searched various databases, i.e. Pubmed, Science Direct, Springer, and Innovare Academic Sciences, using keywords: “tumour infiltrating lymphocyte” and “Bioreactor” at 30 December 2019, without time limits. Only English literatures were used. The main aim of this review is to present a brief outline of the basic concepts of TILs in treating solid tumours, as well as general protocols for ex vivo TIL expansion that are currently being used in clinical application. In addition, three bioreactors that have been used in many commercial ACT services, i.e. GE Wave, G-Rex, and Quantum are also discussed here along with general considerations of integrating them into TIL ex vivo expansion protocol. TIL basic concept in treating solid tumours TILs are a heterogeneous population of lymphocytes, which primarily consist of T and natural killer (NK) cells that naturally migrate into tumours and are potentially present in any solid tumour [1, 7, 8]. Among these two subsets, a more effective killing capability is owned by T-cells because they can recognize tumour associated antigens (TAAs) due to the presence of endogenous T cell receptors (TCRs). Therefore, exploiting TIL’ killing capacity was studied extensively to target solid tumour, which further led to FDA approval for treating cervical cancer and metastatic melanoma [2, 5]. Compared to CAR T-cell platform in terms of treating solid tumours, TILs have several advantages. Despite both CAR T-cells and TILs have the ability to recognize TAAs, TILs have a wider coverage of TAAs. TILs that are extracted from tumour resection consist of clones that are able to recognize multiple TAAs, while CAR T-cells, which require an artificial engineered antigen receptor, can only recognize a single TAA. Moreover, since TILs are naturally formed to target tumour neo- antigens, this platform offers minimum adverse effects that are caused by unpredicted off-target effects on other tissues. Table 1 describes the competitive advantages of TIL therapy on treating solid tumours in comparison with CAR T-cell platform [9]. Currently, TILs are implemented as autologous-based cell therapy, but generating highly activated T cells in sufficient numbers from tumours requires a protocol that is able to overcome the limited number of TILs, which are extracted from patient tumour tissue. Therefore, an effective and efficient expansion protocol is highly needed. General protocols for TIL ex vivo expansion Ex vivo expansion of TILs requires several steps to get a sufficient number of activated T cells. A preliminary report by Rosenberg et al. in 1988 paved the way for the development of a standard method for large-scale in vitro expansion of TILs that were isolated from a International Journal of Applied Pharmaceutics ISSN- 0975-7058 Vol 12, Issue 4, 2020