T- Cell Transfer as an Effective Cancer Immunotherapy: Systematic Review

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1 T- Cell Transfer as an Effective Cancer Immunotherapy: Systematic Review 1 Sami Marei Ali Alqahtani, 2 Mohammed Awn Dhafer Alqahtani, 3 Jaber Ibrahim Jaber Assiri, 4 Albara Abdullah mohammad Al mushham, 5 Saleh Saeed Ali Alqarni, 6 Hatim Abdullah Hossain Ramza, 7 Khalid Hussain Mohammed Alhassani, 8 Assaf Abdullah Assaf Alkatheri Abstract: Significant effort has been extended over the past few years to evaluate the potential for adoptive T cell transfer to treat cancer. We aimed with this Systematic review study to evaluate the effectiveness of T cell transfer for cancer immunotherapy, also aimed to discuss the different approaches using this immunomodulation of T cell, and to overview those successful trails that have performed this method of treatment. Databases, PubMed, EMBASE, were searched to identified relevant trails discussing the effectiveness of T cell transfer for cancer immunotherapy; we searched for eligible studies that were published in English languages up to December Adoptive T cell transfer for cancer and chronic infection is an emerging field that shows promise in recent trials. Artificial biology-based engineering of T lymphocytes to reveal high affinity antigen-receptors can conquer immune tolerance, which has been a major restriction of immunotherapy-based techniques. Keywords: T cell transfer, Databases, PubMed, EMBASE. 1. INTRODUCTION Cancer is a leading cause of death worldwide, and the variety of cases worldwide continues to increase (1). Inning accordance with the World Cancer Report 2014, the global burden of cancer rose to an estimated 14 million brand-new cancer cases in 2012, and this figure is anticipated to rise to 22 million every year within the next twenty years. Over the exact same period, cancer deaths are predicted to increase from an estimated 8.2 million to 13 million each year. Many cancers can be prevented or cured if identified at an early stage and treated quickly. Due to the lack of perfect cancer biomarkers for early detection and medical diagnosis (2). The field of immunotherapy has experienced remarkable advancements over the past couple of years. To this end, the FDA approval of cell T for the treatment of hormonal agent refractory prostate cancer set the stage in 2010 (3), followed by the more current approvals of the PD-1 and CTLA-4 checkpoint repressive monoclonal antibodies (mab) in cancer malignancy and non-small cell lung cancer (NSCLC) (4). Significantly, many immunoregulatory mab focused on blocking repressive or boosting stimulatory immune signaling remain in development, some of which have currently been in medical testing alone or in combination with the currently approved obstructing antibodies with promising data, e.g., CD40 agonistic antibody in melanoma (5). Likewise, the use of adoptive cell transfer (ACT) utilizing in vitro expanded tumor penetrating lymphocytes (TIL) have actually revealed very strong clinical efficacy in stage II trials (6,7), and the administration of T cells harnessed with tumor specific T-cell receptors, show excellent guarantee likewise beyond solid cancer, e.g., myeloma (8). The excellent majority up to-date targeted tumor antigens are self-antigens, typically expressed during advancement and aberrantly expressed by tumors. The striking distinction in affinity between T cell receptors specific for self-antigens expressed by tumors and T cell receptors particular for infection antigens has been summed up just recently (9). Comparative analyses have exposed that TCR from T cells that recognize self-tumor antigens have significantly lower affinities (approximately 0.5 logs) for cognate MHC: peptide complexes compared to their virusspecific equivalents (10). This observation, which shows the impact of main tolerance on the T cell collection to selfantigens, indicate the fact that T cells that get away central tolerance and have the prospective to respond to the self-target Page 699

2 antigens will manifest for the most parts suboptimal activation in regards to antitumor activity (10). The high tolerance to tumor antigens with developmental and/or regular expression combined with the potent immunosuppressive microenvironment often present at the tumor site support the premise that improving anti-tumor immunity by the adoptive transfer of "native" T cells might not be sufficient to induce tumor cell death in most patients with advanced malignancy (10).Gene-transfer based methods have been established to get rid of the consequences of immune tolerance on the tumorspecific T cell repertoire. These approaches provide the potential to reroute T cells to efficiently target tumors by the transfer of antigen-specific T cell receptor α and β chains (αβ TCR) or chimeric antigen receptors (CAR) made up of antibody binding domains fused to T cell signaling domains. In each case recipient T cells get the crafted, tumor-specific uniqueness while keeping their initial uniqueness (Figure1) (11). Figure 1: Engineered T cells that have retargeted specificity (11) We aimed with this Systematic review study to evaluate the effectiveness of T cell transfer for cancer immunotherapy, also aimed to discuss the different approaches using this immunomodulation of T cell, and to overview those successful trails that have performed this method of treatment. 2. METHODS Our study was conducted according PRISMA guideline for systematic reviews. Search methods: Databases, PubMed, EMBASE, were searched to identified relevant trails discussing the effectiveness of T cell transfer for cancer immunotherapy, we searched for eligible studies that were published in English languages up to December 2016, we did not limit our search for only human subject trails, we also included animal models and trails that were performed in vivo. in this search strategy we use couple of Mesh terms to find more appropriate articles to be included in our review and these terms were as following; T cell transfer, adaptive cell transfer AND immunotherapy, cancer, tumor, treatment. All terms were combined in several steps, we also searched references of included studies for more relevant articles to our topic. General aspects: 3. RESULTS & DISCUSSION The inherent and obtained immune systems play a vital function in immune security and immune defense (12,13). For that reason, the use of the body immune system to remove cancer is a very appealing technique for cancer treatment (14,15). Indeed, immunotherapy has actually demonstrated great prospective for cancer treatment (16,17,18,19), particularly for disease refractory to standard treatments, consisting of chemotherapy, surgery and radiotherapy. Cancer immunotherapy approaches consist of active immunization, nonspecific immune stimulation and ACT. Among these techniques, ACT has accomplished more exciting lead to cancer medical trials and therefore, holds the most promise for the treatment of malignant diseases (20,21,22,23). Cancer immunotherapy needs the activation and growth of cancer-specific T cells, which kill cancer cells by recognizing antigen targets expressed on cancer cells. Over the past 20 years, research studies have actually revealed that the generation of cancer-specific resistance needs 3 actions (Figure 2) (34). First, antigen-presenting cells (e.g., dendritic cells [ DCs] capture and procedure cancer antigens into antigenic peptides, which exist in combination with human leukocyte Page 700

3 antigen (HLA) particles for recognition by TCR of T cells (signal 1) (25). Second, T-cell activation requires the binding of the costimulatory surface molecules B7 and CD28 on antigen-presenting cells and T cells, respectively (signal 2). To accomplish ideal T-cell activation, both signals 1 and 2 are needed. On the other hand, antigenic peptide stimulation (signal 1) in the absence of costimulation (signal 2) cannot cause complete T-cell activation, therefore leading to T-cell tolerance. In addition to costimulatory particles, there are also repressive particles, such as CTLA-4 and PD-1, which induce signals to prevent T-cell activation (26). Third, activated cancer-specific T cells reach tumor sites and acknowledge tumor antigens revealed by cancer cells, therefore killing the cancer cells. Antigenic peptide stimulation initiates T-cell activation, the degree of T-cell activation is more identified by the balance between costimulation and cosuppression. Recent scientific trials have actually shown that blockade of PD-1 coinhibition with anti-pd-l1 or anti-pd-1 therapy boosts T-cell-mediated anticancer responses without severe unfavorable occasions (SAE) (27,28). Inhibition of CTLA-4 signaling has been revealed to significantly enhance the survival of patients with late-stage cancer malignancy (29,30), leading to the FDA approval of the anti-ctla-4 antibody ipilimumab (Yervoy) for metastatic melanoma in Besides T-cellintrinsic regulation, T-cell activation can likewise be controlled by external factors (extrinsic). For example, cytokines, such as IL-2, released by CD4+ assistant T cells (Th1 and Th17) can straight promote cancer-specific T cell expansion, while IL-2 might likewise moderate growth of CD4+ Treg, which antagonize function of cancer-specific T cells (31). On the other hand, myeloid-derived suppressor cells (MDSCs) and T cells, which are normally present in the tumor microenvironment, prevent cancer-specific T cell function and induce immunosuppression (32,33), causing bad immunotherapy efficacy. Figure 2: The key points in cancer immunotherapy are one activation and two inhibitions where cancer-reactive T-cell activation by cancer antigen represents the one activation and blockade of coinhibitory molecules on T cells and reversal of Treg cell-mediated immunosuppression represent the two inhibitions. DC: Dendritic cell. (34) Roles of T cell in Immunotherapy: Effective T cell-based active immunotherapy requires not only the expression of antigens by cancer cells however likewise the successful and sustained mobilization of sufficient varieties of effector T cells that recognize these antigens in order to remove the tumour. T cell activation is started by stimulation of the antigen receptor (T cell receptor (TCR)) with significant histocompatibility complex (MHC) particles, which present peptides that are derived from tumour antigens. For efficient activation, this must be accompanied by co-stimulatory signals mediated by the binding of CD28 on the T cell surface to B7 proteins (such as CD80 or CD86) on the antigen-presenting cell (APC). This is mediated by the administration of the T-cell development factor interleukin 2 (IL2) and can activate endogenous tumour-reactive cells in vivo and reproducibly trigger the regression of some human strong cancers (35,36,37) The resilience of the cancer regressions induced by IL2 resulted in its approval by the US Food and Drug Administration for the treatment of patients with metastatic kidney cancer in 1992 and metastatic cancer malignancy in IL2 administration leads to toxicity owing to a capillary leakage syndrome, experience with the administration of this cytokine has resulted in treatmentrelated mortalities of <1% (38). More just recently, antibody-mediated blockade of a cell surface area repressive molecule, cytotoxic T-lymphocyte-associated 4 (CTLA4), has resulted in objective clinical reactions in % of patients, but once again just consistently in those with metastatic melanoma or renal cancer, recommending that these 2 tumour types are remarkable in their ability to naturally create endogenous anti-tumour cells of adequate avidity and in sufficient numbers to moderate cancer regression when properly promoted in vivo (39,40). Page 701

4 Sipuleucel-T (Provenge) and ipilimumab (Yervoy) have actually been authorized by the FDA for treatment of prostate cancer and metastatic melanoma, respectively (7,8), and a Phase III scientific trial of the gp100 peptide-based vaccine in patients with cancer malignancy likewise produced encouraging results (11). Nevertheless, the medical advantages reported for these representatives have actually fallen far except complete reactions and long-term treatments, although the scientific data for ipilimumab are still emerging. On the other hand, ACT therapy using cancer antigen-specific T cells including TILs, peptide-induced T cells and engineered T cells (TCR and CAR) has actually shown significant strength in cancer treatment (20,21), leading to complete and long lasting actions in some patients with late-stage and refractory disease. Here, we will present a summary of the most amazing clinical outcomes gotten with ACT summarized in (Table 1) and also discuss future instructions of ACT-based cancer immunotherapy. Table 1: Identified clinical trials using T-cell-based immunotherapy. Malignancy Patient number Type of T cells infused Target antigen Clinical outcomes Metastatic melanoma 20 TIL Unknown 1 CR, 10 PR, 1 MR Metastatic melanoma 13 TIL Unknown 6 PR, 4 MR Metastatic melanoma 93 TIL Unknown 22 CR, 34 PR Metastatic melanoma 10 CD8 + T cells MART1/MelanA or gp SD, 1 MR, 2 minor response Metastatic melanoma 11 CD8 + T cells MelanA 1 CR, 1 PR, 1 MR, 1 SD Metastatic melanoma 1 CD4 + T cells NY-ESO-1 1 CR Metastatic melanoma 14 CD8 + T cells MelanA 2 CR, 4 PR, 1 SD Metastatic melanoma 11 CD8 + T cells MART1/Tyr/gp CR, 5 SD Metastatic melanoma 17 TCR T cells MART1 2 PR, 1 MR Metastatic melanoma 36 High affinity TCR T cells MART1 or gp CR, 8 PR Metastatic melanoma 3 TCR T cells CEA 1 PR Metastatic melanoma/ synovial sarcoma 17 TCR T cells NY-ESO-1 2 CR, 7 PR Metastatic melanoma 9 High affinity TCR T cells MAGEA3/MAGEA12 1 CR, 4 PR Metastatic melanoma/ myeloma 2 High affinity TCR T cells MAGEA3/Titin Not evaluable Neuroblastoma 19 CAR T cells GD2 3 CR Renal carcinoma 12 CAR T cells CAIX Not evaluable Colon cancer 1 CAR T cells (CD28-4-1BB- CD3ζ) ERBB2 Lymphoma 1 CAR T cells (CD28-CD3ζ) CD19 1 PR Not evaluable Lymphoma and CLL 8 CAR T cells (CD28-CD3ζ) CD19 1 CR, 5 PR, 1 SD CLL 3 CAR T cells (4-1BB-CD3ζ) CD19 2 CR, 1 PR ALL 2 CAR T cells (4-1BB-CD3ζ) CD19 2 CR ALL 5 CAR T cells (CD28-CD3ζ) CD19 5 CR ALL 16 CAR T cells (CD28-CD3ζ) CD19 14 CR Ref. (41) (42) (7) (43) (44) (45) (46) (47) (48) (49) (50) (51) (52) (53,54) (55) (56) (57) (58) (59) (60,61) (62) (63) (64) ALL: Acute lymphoblastic leukemia; CAR: Chimeric antigen receptor; CEA: Carcinoembryonic antigen; CLL: Chronic lymphocytic leukemia; CR: Complete response; MR: Mixed response; PR: Partial response; SD: Stable disease; TCR: T- cell receptor; TIL: Tumor-infiltrating lymphocyte. Page 702

5 4. CONCLUSION Adoptive T cell transfer for cancer and chronic infection is an emerging field that shows promise in recent trials. Artificial biology-based engineering of T lymphocytes to reveal high affinity antigen-receptors can conquer immune tolerance, which has been a major restriction of immunotherapy-based techniques. Advances in cell engineering and culture techniques to make it possible for efficient gene transfer and ex vivo cell growth have actually helped with broader examination of this technology, moving adoptive transfer from a "shop" application to the cusp of a mainstream technology. The major obstacle currently facing the field is to increase the uniqueness of engineered T cells for tumors, since targeting shared antigens has the potential to cause on-target off-tumor toxicities, as observed in current trials. Recently deficiency of T reg cells has actually been revealed to enhance reactivity to tumor/self-antigens in tumor avoidance models, but we reveal for the very first time that T reg cells can hinder aid of self-reactive CD4+ T cells and avoid effector CD8+ T cells from initiating autoimmunity. T reg cells control peripheral self-tolerance through yet unknown systems, but our company believe that gradually growing tumors shed or secrete self-antigens that consequently trigger naturally taking place T reg cells. REFERENCES [1] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2): [2] Wagner PD, Srivastava S. New paradigms in translational science research in cancer biomarkers. Transl Res. 2012;159(4): [3] nyder A, Tepper JE, Slovin SF. Perspectives on immunotherapy in prostate cancer and solid tumors: where is the future? Semin Oncol. 2013;40: [4] First Immunotherapy Combo Approved for Cancer: Cancer Discov 2015;5: [5] Honeychurch J, Cheadle EJ, Dovedi SJ, Illidge TM. Immuno-regulatory antibodies for the treatment of cancer. Expert Opin Biol Ther. 2015;15: [6] Andersen R, Donia M, Ellebaek E, Holz Borch T, Kongsted P, Iversen TZ, Rosenkrantz Hölmich L, Westergren Hendel H, Met O, Hald AM, thor Straten P, Svane IM. Long-lasting complete responses in patients with metastatic melanoma after adoptive cell therapy with tumor-infiltrating lymphocytes and an attenuated IL-2 regimen. Clin Cancer Res Epub ahead of print. [7] Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, Citrin DE, Restifo NP, Robbins PF, Wunderlich JR, Morton KE, Laurencot CM, Steinberg SM, White DE, Dudley ME. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17: [8] Rapoport AP, Stadtmauer EA, Binder-Scholl GK, Goloubeva O, Vogl DT, Lacey SF, Badros AZ, Garfall A, Weiss B, Finklestein J, Kulikovskaya I, Sinha SK, Kronsberg S, Gupta M, Bond S, Melchiori L, Brewer JE, Bennett AD, Gerry AB, Pumphrey NJ, Williams D, Tayton-Martin HK, Ribeiro L, Holdich T, Yanovich S, Hardy N, Yared J, Kerr N, Philip S, Westphal S, Siegel DL, Levine BL, Jakobsen BK, Kalos M, June CH. NY-ESO-1-specific TCRengineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med. 2015;21: [9] Aleksic M, Liddy N, Molloy PE, Pumphrey N, Vuidepot A, Chang KM, Jakobsen BK. Different affinity windows for virus and cancer-specific T-cell receptors: implications for therapeutic strategies. Eur J Immunol. 2012;42: [10] Cole DK, Pumphrey NJ, Boulter JM, Sami M, Bell JI, Gostick E, Price DA, Gao GF, Sewell AK, Jakobsen BK. Human TCR-binding affinity is governed by MHC class restriction. Journal of immunology. 2007;178: [11] Kalos M, June CH. Adoptive T cell Transfer for Cancer Immunotherapy in the Era of Synthetic Biology. Immunity. 2013;39(1): /j.immuni doi: /j.immuni [12] Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 2011;29: Page 703

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