Potential advantages of CD1-restricted T cell immunotherapy in cancer

Molecular Immunology 103 (2018) 200–208

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Molecular Immunology journal homepage: www.elsevier.com/locate/molimm

Potential advantages of CD1-restricted T cell immunotherapy in cancer Michela Consonni , Paolo Dellabona, Giulia Casorati ⁎

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Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy

ARTICLE INFO

ABSTRACT

Keywords: Adoptive cell therapy CD1 molecules NKT cells Lipid antigen Engineered T cells Acute leukemia

Adoptive cell therapy (ACT) using tumor-specific “conventional” MHC-restricted T cells obtained from tumorinfiltrating lymphocytes, or derived ex vivo by either antigen-specific expansion or genetic engineering of polyclonal T cell populations, shows great promise for cancer treatment. However, the wide applicability of this therapy finds limits in the high polymorphism of MHC molecules that restricts the use in the autologous context. CD1 antigen presenting molecules are nonpolymorphic and specialized for lipid antigen presentation to T cells. They are often expressed on malignant cells and, therefore, may represent an attractive target for ACT. We provide a brief overview of the CD1-resticted T cell response in tumor immunity and we discuss the pros and cons of ACT approaches based on unconventional CD1-restricted T cells.

1. Introduction Adoptive Cell Therapy (ACT) is an immunotherapy approach for cancer treatment that consists of the infusion into cancer patients of tumor-specific T cells that have been previously expanded in vitro. It is successfully applied to both solid and hematological malignancies, the latter one often in the context of allogeneic Hematopoietic Stem Cell Transplantation (HSCT). “Conventional” MHC-restricted adaptive T cell immunity has attractive properties for cancer treatment: (I) selective T Cell Receptor (TCR)-mediated specificity, (II) robustness and (III) memory. These T cells can specifically recognize, via their TCR, MHCrestricted peptides derived from proteins expressed by malignant cells but, in most cases, not by healthy tissues. Upon activation in vitro, tumorspecific T cells can undergo substantial clonal expansion, giving rise to large effector T cell populations with anti-tumor activity that can traffic to cancer sites, resulting in tumor cell killing and substantial clinical effects (June and Sadelain, 2018; Klebanoff et al., 2016). In several therapeutic applications, the transferred T lymphocytes can persist long-term in vivo, preventing tumor recurrence (June and Sadelain, 2018; Klebanoff et al., 2016; Louis et al., 2011; Xu et al., 2014; Zacharakis et al., 2018). ACT approaches differ in the source of tumor-specific T cells that can be obtained, which can be originated either from tumor-infiltrating lymphocytes (TILs) that are enriched for tumor-antigen specificities

compared to circulation, or can be derived ex vivo by tumor antigenspecific expansion or genetic engineering of polyclonal T cell populations. To date, all these strategies have been applied mainly to conventional T cells. However, the immune system contains a substantial fraction of “unconventional” T lymphocytes that are not restricted for MHC molecules, such as T cells specific for lipid antigens presented by CD1 molecules. In this review, we will discuss which are the possible advantages and drawbacks to exploit unconventional CD1-restricted T cells in ACT. 2. Adoptive T cell therapy strategies 2.1. Tumor infiltrating lymphocytes (TILs) therapy From the first trials of ACT using autologous TILs conduced in patients with metastatic melanoma (Rosenberg et al., 1988), TIL therapy proved effective to induce stable tumor regression in metastatic melanoma patients (Rosenberg and Restifo, 2015). To exploit naturally occurring autologous TILs in ACT, different sublines of TILs from each patient were generated from multiple tumor fragments independently cultured with IL-2 for 2–3 weeks. TIL sublines were tested for their ability to specifically recognize the tumor and those with higher activity were selected and expanded in the presence of irradiated feeder lymphocytes, OKT3 and IL-2 to obtain > 1011 cells to transfer into patients.

Abbreviations: ACT, adoptive cell therapy; MHC, major histocompatibility complex; TCR, T cell receptor; TIL, tumor-infiltrating lymphocyte; TAA, tumor-associated antigen; APC, antigen-presenting cell; DC, dendritic cell; HSCT, hematopoietic stem cell transplantation; GvHD, graft versus host disease; GvL, graft versus leukemia; CAR, chimeric antigen receptor; PBMC, peripheral blood mononuclear cell; iNKT, invariant natural killer T; α-GalCer, α –GalactosylCeramide; AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; mLPA, methyl-LysoPhosphtidic acid; MoDC, monocyte-derived DC ⁎ Corresponding author at: Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milano, Italy. E-mail address: [email protected] (M. Consonni). https://doi.org/10.1016/j.molimm.2018.09.025 Received 14 June 2018; Received in revised form 1 September 2018; Accepted 29 September 2018 0161-5890/ © 2018 Elsevier Ltd. All rights reserved.

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To increase the clinical response and persistence of TILs, patients received a lymphodepleting treatment before infusion (Besser et al., 2010; Itzhaki et al., 2011; Rosenberg and Restifo, 2015). In addition to be labor intensive, this expansion protocol to generate TILs required that tumor specimens were readily available and enriched for TILs with anti-tumor reactivity. In addition to melanoma, natural occurring TILs have been characterized in other solid tumors, such as cervical carcinoma (Stevanović et al., 2015), head and neck squamous carcinoma (Balermpas et al., 2014), ovarian cancer (Sato et al., 2005), renal cell carcinoma (Q. J. Wang et al., 2012) gastrointestinal cancers (Turcotte et al., 2013) and breast cancer (Zacharakis et al., 2018). However, one of the main challenges in developing TIL therapy remains the inability to consistently expand in vitro T cells with a relevant anti-tumor reactivity in most cancer type besides melanoma (Baldan et al., 2015; Turcotte et al., 2013; Q. J. Wang et al., 2012).

In TCR gene therapy, the tumor-specific TCRs have been isolated from circulating or TIL-derived T cells of patients, and also through the immunization with tumor antigens of human HLA transgenic mice. The murine TCRs usually display higher affinity for the human TAA-derived peptide epitopes, compared to those cloned from patients PBMCs or TILs, because they do not undergo central and/or peripheral tolerance caused by the expression of the corresponding human proteins (M. Wang et al., 2014). Retroviral or lentiviral vectors are usually utilized to transfer cDNAs encoding the desired tumor-specific TCRs into T cells isolated from peripheral blood of patients. TCR-transduced T cells are then expanded in vitro prior to infusion into pre-conditioned patients. TCR gene therapy is complicated by the possible mispairing between transduced and endogenous TCR α/β chains, which may result in the formation of new heterodimers with unknown specificity (possibly tissue self-reactivity) that may also compete with the transduced TCR chains for CD3 association and membrane transport (Maus et al., 2014). To overcome this obstacle, different methods that favor the preferential pairing of transduced TCR chains over the endogenous ones have been described: (I) murinization of the constant regions (Cohen, 2006); (II) addition of disulfide bonds to the human constant regions (Cohen et al., 2007); (III) alteration of the knob-into-hole directional interaction of endogenous TCR constant regions (Voss et al., 2007); (IV) addition of signaling domains to the intracellular portions of the transduced TCR (Sebestyen et al., 2008); (V) transduction of TCR α/β chains into recipient TCR γ/δ T cells (Hiasa et al., 2009); and (VI) knockdown of the endogenous TCR by shRNA (Ochi et al., 2011; Okamoto et al., 2009), or targeted gene editing of C regions (Provasi et al., 2012). Moreover, following a recent example with CAR-T cell engineering (Eyquem et al., 2017), the CRISPR/Cas9 system may be exploited to target the integration of the transduced TCR chains into the T-cell receptor α constant (TRAC) locus, resulting in both the knock out of the endogenous TCR α chain expression and in the targeted integration of the transduced TCR. Indeed, T cells in which a CAR construct was targeted to their TRAC locus, placing it under the control of endogenous regulatory elements, not only had a more constant CAR expression, but were also more potent effectors thanks to reduced tonic signaling and delayed T-cell exhaustion (Eyquem et al., 2017). TCR gene therapy using TCRs specific for various shared non-mutated TAAs (including MART-1, gp100, p53, NY-ESO-1, MAGE-A3, MAGE-A4 and CEA) has been used to treat melanoma, breast cancer, colon cancer and multiple myeloma with remarkable clinical responses. However, adverse events have occurred with a high frequency in many of these clinical trials, highlighting the need to develop preclinical strategies and to identify new targets to minimize the off-tumor toxicities for an effective immunotherapy (Ikeda, 2016). Moreover, TCR gene therapy targeting peptide TAAs is limited by the necessity to identify a different TCR for any given HLA allele in the population (Humphries, 2013), considering that the most frequent MHC class I allele in the Caucasian population (HLA-A*0201) is expressed in 30% of individuals (Cao et al., 2001). CAR T-cell therapy does not have the HLA restriction limitation, because CARs directly recognize native cell surface structures (Eshhar et al., 1993). In analogy with TCR gene therapy, patient’s T cells are transduced ex vivo with a construct encoding the CAR, expanded and infused back into preconditioned patient (Maus and June, 2016). To date there are several clinical trials with CAR-T cells, but the most promising results have been achieved with CD19-specific CAR-T cells targeting B cell malignancies (follicular lymphoma, large B cell lymphoma, chronic lymphocytic leukemia and acute lymphocytic leukemia) (Biondi et al., 2017; Salter et al., 2018). However, the infusion of CD19-specific CAR-T cells causes not only B cell aplasia, which is overcome by the periodic administration of immunoglobulin to reduce the risk of infection, but also the cytokine release syndrome (Davila et al., 2013; Kalos et al., 2011; Kochenderfer et al., 2012) and neurotoxicity (Davila et al., 2013; Maude et al., 2014). The transfer of CAR-T cell therapy to solid tumors has been delayed so far mainly by the reduced number of target antigens homogeneously

2.2. Tumor antigen-specific ACT To increase the generation of tumor-specific T cells for ACT, the stimulation of patient’s T cells in vitro with tumor-associated antigen (TAA)derived peptide epitopes has been pursued. MHC class I-restricted epitopes are preferred because they stimulate cytotoxic CD8+ T cells, recognized as the most efficient effectors for eliminating cancer cells. Indeed, tumor-specific CD8+ T cell clones can be generated in vitro from repeated antigen-specific stimulation of patient-derived T cells or HLAmatched donor-derived T cells, using autologous Antigen Presenting Cells (APCs), typically DCs, or artificial APCs (magnetic beads, HLA-engineered K562 or insect cells) modified to present peptides derived from TAA (Ho et al., 2006; Turtle and Riddell, 2010). Autologous TAA-induced specific T cells have been used for the treatment of metastatic melanoma, resulting in tumor regression with no serious toxicity (Chapuis et al., 2012; Dudley et al., 2002; Hunder et al., 2008; Khammari et al., 2009; Mackensen et al., 2006; Yee et al., 2002), whereas allogeneic tumor antigen-induced CD8+ T cells specific for the Wilms’ tumor antigen 1 (WT1) could be infused into leukemia patients who relapsed after HSCT, with a transient anti-leukemic effect and no Graft-versus-Host Disease (GvHD) (Chapuis et al., 2013). More accurate DNA sequencing and gene expression analysis techniques are simplifying the identification of increasing numbers of TAAs useful to expand and/or select tumor-specific T cells in vitro for ACT, which prove efficacious in epithelial cancers (Stevanović et al., 2017; Tran et al., 2015, 2016; Zacharakis et al., 2018). However, the use for ACT with conventional peptide-specific T cells is limited by their presentation by MHC molecules, which are extremely polymorphic in the population, and enforce the therapeutic application essentially to the autologous setting (M. Wang et al., 2014). 2.3. Genetic engineered lymphocytes for ACT T cells can be genetically modified to redirect their specificity against tumor cells. In order to do this, two main approaches have been pursued. The first one consists of the transfer of tumor-specific TCR gene therapy, while the second one involves the transfer of artificial proteins called Chimeric Antigen Receptors (CAR)s, which bind to native membrane tumor antigens via their extracellular domain, constituted by a single-chain variable fragment derived from a monoclonal antibody, fused to the intracellular signaling domains of CD3ζ and other T-cell costimulatory molecules (Eshhar et al., 1993; Humphries, 2013; Maus and June, 2016). T cells expanded and engineered in vitro with tumor-specific TCRs or, particularly, CARs often display the fundamental ability to persist long term (≥2 years) in the recipient patients (Louis et al., 2011; Xu et al., 2014). The persistence in vivo of the transferred engineered T cells correlates with the depth and duration of the clinical response (Louis et al., 2011; Xu et al., 2014), possibly due to the emergence in vivo of long-lived memory cells endowed with stem cell capacity that maintain effective anti-tumor immunesurveillance over time (Gattinoni et al., 2017; Oliveira et al., 2015). 201

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expressed on tumor cells and not on normal cells (Yong et al., 2017). To mitigate toxicity of genetic engineered T lymphocytes, and enhance the specificity, safety, and programmability of CARs, different mechanisms have been exploited, such as: (I) transient expression of the transduced CAR by RNA electroporation (Ruella and Kalos, 2014); (II) addition of a suicide or antibody targeting gene in the CAR coding vector, to delete the transduced T cells if necessary (Bonini et al., 2007; Griffioen et al., 2009; Straathof et al., 2005; X. Wang et al., 2011); (III) Generation of split, inducible and tunable CARs which are composed by a universal receptor expressed on T cells, which is specific for a “tag” appended to scFv adaptor molecules specific for different tumor antigens (Cho et al., 2018; Rodgers et al., 2016).

lipid antigens derived from infectious pathogens (Barral and Brenner, 2007; De Libero and Mori, 2005; Porcelli and Modlin, 1999; Tupin et al., 2018), but are also overtly self-reactive and can directly recognize CD1expressing APCs without exogenous lipid addition. Because of this dual antigen specificity, CD1-restricted T and iNKT cells are implicated in antimicrobial immunity, as well as autoimmunity and cancer immunosurveillance, in which self-antigens play a key role for the immune response (Bagchi et al., 2017, 2016; Beckman et al., 1994; Consonni et al., 2017; de Jong et al., 2013; Dellabona et al., 1993, 2015; Lepore et al., 2014; Porcelli et al., 1989; Shamshiev et al., 1999).

3. Harnessing the CD1-restricted T cells for cancer immunotherapy

CD1 isoforms are essentially non-polymorphic (Brigl and Brenner, 2004) therefore, targeting T cells against a lipid antigen presented on tumor cells by one CD1 isoform has the potential to overcome the HLA barrier restriction and allow the generation of universal donor-unrestricted effector T cells, widening the application of ACT to larger numbers of patients. Furthermore, in an allogeneic setting, targeting lipid antigens that are presented by group 1 CD1, which are not expressed on parenchymatous tissues, would minimize the risk of GvHD upon ACT. Hematological malignancies are the appropriate therapeutic context that can be envisaged for this approach, because they represent the tumor counterpart of the hematopoietic cells that normally express group 1 CD1. We have indeed recently shown that group 1 CD1 molecules are expressed on acute leukemia blasts from either pediatric and adult patients with characteristic expression patterns (Lepore et al., 2014). CD1c is frequently expressed on Acute Myeloid Leukemia (AML) blasts (51% of patients) and B-Acute Lymphoblastic Leukemia (B-ALL) blasts (71% of patients), whereas CD1a and CD1b are most frequent on T-ALL (75% of patients). These data support that group 1 CD1 molecules are potential targets for the immunotherapy of these diseases. CD1d is also expressed at different extent on hematological malignancies (AML, B-ALL, chronic lymphocytic leukemia, lymphomas and multiple myeloma), but also on some solid tumors (glioma, medulloblastoma, renal cell carcinoma, breast and prostate cancers) (Chong et al., 2015; Hix et al., 2011; Liu et al., 2013; Metelitsa, 2011; Nair and Dhodapkar, 2017; Nowak et al., 2010).

3.1. CD1 molecules expression pattern on normal and malignant cells

Although current TCR gene therapy proved effective for the generation of clinically efficacious T cells for adoptive immunotherapy, the use of TCR that recognize peptide antigens presented by MHC molecules poses two main problems that limit the approach outside the autologous setting, namely: (I) the extreme polymorphism of MHC molecules which restricts the number of patients that can benefit from the transfer of T cells engineered with any given tumor-specific TCR; and (II) the impossibility of using allogeneic donor T cells for TCR gene therapy because of the danger of inducing GvHD upon transfer into patients. CD1-restricted T cells have several characteristics that can overcome these problems and make them attractive effectors for ACT. CD1-restricted T cells recognize lipid antigens presented by CD1 molecules, a group of MHC class I-related that in humans contains five members: CD1a, CD1b, CD1c, collectively classified into group 1, CD1d (group 2), the only one also expressed in mice, and CD1e (group 3) that is not expressed on the cell surface (Godfrey et al., 2015). Group 1 and 2 CD1 molecules differ for their expression pattern (Dougan et al., 2007). CD1a, CD1b and CD1c are only found on cells of hematopoietic origins, mainly professional APCs (DCs monocytes, macrophages, Langerhans cells for CD1a and CD1c, and B cells for CD1c) and on developing thymocytes (Allan et al., 2011; Brigl and Brenner, 2004; Delia et al., 1988; Dougan et al., 2007; Elder et al., 1993; Exley et al., 2000; Kasinrerk et al., 1993; Sallusto and Lanzavecchia, 1994). CD1d has wider expression pattern, which includes thymocytes, monocytes, macrophages, B cells and at low level on DCs, some epithelia, keratinocytes, vascular smooth cells and Schwann cells (Allan et al., 2011; Brigl and Brenner, 2004; Exley et al., 2000; Im et al., 2006; Kasinrerk et al., 1993). Most group 1 CD1-restricted T cells have a polyclonal TCR usage, include CD4+, CD8+ or CD4CD8 double negative cells (de Lalla et al., 2011a), and appear to undergo clonal expansion in the periphery after antigen encounter resulting in a delayed effector response, consistent with an adaptive-like behavior similar to what is observed for conventional T cells (de Lalla et al., 2011a). Upon activation, group 1 CD1-restricted T cells produce a wide range of type 1, 2, and 17 cytokines (de Jong et al., 2010; de Lalla et al., 2011a). CD1d is recognized mainly by a group of innate-like cells called Natural Killer T (NKT), of which invariant (i)NKT cells are the best characterized ones owing to their highly conserved semi-invariant TCR made of the invariant TRAV10-2-TRAJ18 chain paired to diverse TRBV25-1 in humans, and homologous invariant TRAV11-TRAJ18 paired to diverse TRBV13-2/TRBV1/TRBV29 chains in mice. These semi-invariant TCRs recognize the strong lipid agonist αGalactosylceramide (α-GalCer) presented by CD1d. It is possible to unequivocally detect iNKT cells by reagents that selectively stain their semiinvariant TCR, such TCR-specific monoclonal antibodies and α-GalCerloaded CD1d tetramers (Benlagha et al., 2000; Dellabona et al., 1994; Exley et al., 2008; Matsuda et al., 2000). Upon cognate TCR engagement, iNKT cells release copious amount of diverse cytokines, such as IFN-γ, TNF-α, IL-4, IL-13, IL-21 and IL-22 (Coquet et al., 2008; Gumperz et al., 2002), and they can also respond to innate signals, such as IL-12 and IL18, independently of TCR triggering (Brigl et al., 2011; Leite-De-Moraes et al., 1999). Collectively, CD1-restricted T and iNKT cells recognize both

3.2. Recognition of self-lipid antigens on tumor cells At steady state, normal CD1-expressing cells are poorly recognized by self-reactive CD1-restricted T lymphocytes. Stress conditions (inflammation, infection and oncogenesis), upregulate lipid species with modified structures compared to resting conditions, due to modifications of cellular lipid metabolism (Hakomori, 1981). This generates selflipid antigens that are presented by CD1 molecules and become visible to the immune system by activating the cognate T cells (Kain et al., 2014). Recently, we identified the novel tumor-associated self-lipid antigen, mLPA (methyl-lysophosphatidic acid) that accumulate in leukemia blasts and is presented by CD1c to a group of self-reactive T cell clones (Lepore et al., 2014), which specifically recognize and kill CD1cexpressing leukemia blasts in vitro and upon ACT in vivo in a xenogeneic mouse model (Lepore et al., 2014). mLPA is characterized by the presence of an ether bond that links the alkyl-chain to glycerol, Indeed, ether lipids are involved in oncogenic signaling and their level is higher in cancer cells compared to normal cells (Benjamin et al., 2013). Furthermore, exploiting a humanized transgenic mouse model expressing group 1 CD1 molecules, Bagchi et al. showed that CD1b-restricted selfreactive T cells recognized tumor-derived phospholipids more than lipids isolated from normal cells. The adoptive transfer of CD1b-restricted T cells in mice bearing CD1b-tranfected mouse T cell lymphoma resulted in tumor control, demonstrating the antitumor potential of CD1b-autoreactive T cells (Bagchi et al., 2016). Lipid antigens, unlike peptide antigens, do not undergo structural changes when subjected to the strong selective pressure of specific 202

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immune responses. Alterations of entire lipid biosynthetic pathways are often incompatible with cell survival, thus making loss of lipid antigens in tumor cells an unlikely mechanism of cancer immune evasion (Matsushita et al., 2012). Therefore, the selection of antigen-loss tumor variants is minimal and this represents an additional advantage for the immunotherapy. Collectively, these findings support group 1 CD1 and self-lipids as new attractive targets for leukemia immunotherapy and the potential of CD1-restricted self-reactive T cells for ACT.

assessment of safety and efficacy of ACT with group-1 CD1 restricted T cells would greatly benefit from a transgenic mouse model expressing group 1 CD1 molecules (Felio et al., 2009). Differently from group 1 CD1 restricted T cells, the large amount of data available on iNKT cells and tumor immunosurveillance from preclinical mouse models has granted their exploitation in clinical trials. Most studies have focused on the use of α-GalCer-pulsed APCs to improve iNKT-mediated tumor response. These clinical trials conducted in patients with solid tumors demonstrated that the therapeutic regimen was well-tolerated, and it induced systemic iNKT cell expansion, augmented IFN-γ production and NK and T cells activation, leading mainly to disease stabilization in the 29–78% of patients depending on each study, but also to a partial tumor regression in a subset of patients (Chang et al., 2005; Ishikawa et al., 2005; Motohashi et al., 2009; Nagato et al., 2012; Nicol et al., 2011; Nieda et al., 2004; Uchida et al., 2008). Similarly, ex vivo expansion and adoptive transfer of autologous iNKT cells into non-small lung cancer and advanced melanoma patients resulted in increased iNKT cell counts and IFN-γ serum level, although the treatments were not effective on tumor progression (Exley et al., 2017; Motohashi et al., 2006). In head and neck squamous cell cancer patients, the combination of the two therapies (α-GalCer-pulsed APCs submucosal injection followed by the adoptive transfer of ex vivo expanded autologous iNKT cells into tumor feeding artery) increased the antitumor response compared to the monotherapies, causing the tumor regression (in the a 38–50% of patients) or stabilizing cancer growth (in the 50% of patients) (Kunii et al., 2009; Yamasaki et al., 2011). Protocols to generate in vitro large numbers of functional iNKT cells have been developed starting from as little as 0.1% of peripheral blood and bone marrow T cells (Godfrey et al., 2000). Interestingly, even though the number of functional iNKT cells decreases in almost every tumor examined, it is possible to restore their function upon activation with strong agonist and cytokines in vitro, and also in vivo (Dhodapkar et al., 2003; Exley et al., 2017; Nowak et al., 2010; Richter et al., 2013). To try to overcome this problem, functional iNKT cells have also been generated from human adult hematopoietic stem-progenitor cells (Sun et al., 2015) and from induced pluripotent stem cells (iPSCs) (Kitayama et al., 2016; Yamada et al., 2016), offering a promising strategy for effective anticancer immunotherapy. More recently Heczey et al. engineered human iNKT cells with a CAR specific for GD2, a ganglioside expressed by neuroblastoma. CARNKT cells were strongly cytotoxic against tumor cells in vitro and exerted a potent anti-tumor activity in vivo, regardless CD1d expression and without inducing GvHD, unlike CAR-T cells (Heczey et al., 2014). iNKT cells were also successfully redirected against a B cell malignancies using a CAR specific for CD19 and achieved a sustained tumor regression (Tian et al., 2016). These results suggest that iNKT cells can be exploited as recipient of tumor specific receptors, including TCR. The advantage of engineering iNKT cells with mLPA-specific TCR would be the generation of universal effector T cells for adoptive immunotherapy of patients bearing a CD1c+ leukemia, endowed with potential dual targeting of tumor cells and microenvironment.

3.3. iNKT cells in tumor immunity There are several evidences on the protective role of iNKT cells in cancer immunity. In different solid or hematological tumors, iNKT cell infiltration or functional impairment and loss correlate with a positive and negative prognosis, respectively (Cortesi et al., 2018; de Lalla et al., 2011b; Dhodapkar et al., 2003; Gorini et al., 2017; Hishiki et al., 2018; Metelitsa et al., 2004; Najera Chuc et al., 2012; Schneiders et al., 2012; Tachibana et al., 2005; Tahir et al., 2001). iNKT cells are able to directly lyse CD1d-expressing tumor cells in a CD1d-dependent manner (Nair and Dhodapkar, 2017). However, they can also indirectly control tumor progression by both promoting innate and adaptive anti-tumor responses (Crowe et al., 2002; Nair and Dhodapkar, 2017; Nakagawa et al., 2001), and modulating immunosuppressive cells in the tumor microenvironment, such Tumor-Associated Macrophages (TAMs) (Cortesi et al., 2018; Metelitsa, 2011; Song et al., 2008) or myeloidderived suppressor cells (MDSC) (De Santo et al., 2010, 2008; Ko et al., 2009). Moreover, in the context of leukemia immunotherapy, iNKT cells can promote Graft versus Leukemia (GvL), while preventing GvHD (Chaidos et al., 2012; de Lalla et al., 2011b; Pillai et al., 2007). 3.4. CD1-restricted T cells and ACT Since group 1 CD1 genes are absent in mice (Porcelli and Modlin, 1999) and group 1 CD1 tetramers have been developed over the last few years mainly with lipid antigens from bacteria (Kasmar et al., 2011, 2013; Ly et al., 2013), the role of group 1 CD1-restricted T cells in tumor immunosurveillance need to be defined. Nonetheless, in our study we showed that polyclonal T cells from healthy donors can be engineered with a high affinity mLPA-specific TCR using lentiviral vectors (Lepore et al., 2014), generating large numbers of CD4+ and CD8+ T cells specific for CD1c-expressing leukemia. Considering acute leukemia the appropriate pathology for this strategy, the transfer of donor-derived mLPA-retargeted T cells into acute leukemia patients can occur at the same time of allogeneic HSCT, the current treatment for acute leukemia together with chemotherapy) as prophylaxis for leukemia recurrence, or upon post-transplant disease relapse as therapeutic intervention. In this particular setting, however, the expression of the endogenous TCRs on the transduced allogeneic T lymphocytes may cause GvHD upon transfer into unrelated patients, therefore molecular strategies to edit the endogenous TCR genes are necessary (Provasi et al., 2012). Moreover, it is important to rule out the possible side effects resulting from on-target off-tumor recognition by mLPAretargeted T cells. Indeed, we know that healthy circulating B cells, monocytes and DCs have low contents of mLPA and are poorly recognized and killed by mLPA-specific T cell clones (Lepore et al., 2014). However under particular stress condition they might over-express the antigen or up-regulate the CD1c molecules and become visible to mLPA-TCR transduced T cells. Only monocytes-derived DCs (MoDCs) differentiated in vitro from circulating CD14+ monocytes precursors with GM-CSF and IL-4 contain mLPA at concentration comparable to leukemia cells and express high level of group 1 CD1 molecules (Lepore et al., 2014), becoming strong stimulators of mLPA-specific T cells in vitro. However, it must be taken in consideration that ex vivo generated MoDCs represent a different populations from blood monocytes or blood and tissue DCs (Alcántara-Hernández et al., 2017), which may not have a comparable counterpart in vivo. Hence, a thorough

4. Conclusions Currently, there are different approaches employing conventional T cells as source for ACT that have shown therapeutic efficacy (summarized in Fig. 1); yet they all still show limitations that preclude widespread applications. CD1-restricted T and iNKT cells offer several advantages that may be exploited to overcome those limitations for ACT, both by exploiting their tumor-restricted antigen-specificity, the lack of histocompatibility barriers due to the reduced CD1 polymorphism and the possibility to be utilized as donor unrestricted effector cells with no tissue toxicity in allogeneic settings. Further investigation in newly developed CD1 humanized mouse models (Bagchi et al., 2017, 2016; Felio et al., 2009; Kim et al., 2016) will increase our knowledge on fundamental aspects of the CD1-restricted self-reactive T cell responses and help assessing their potential for cancer immunotherapy. 203

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Fig. 1. Different approaches of adoptive cell therapy with conventional or unconventional CD1-restricted T cells. TILs from each patient are generated and expanded from multiple tumor fragments after surgical resection of the tumor. Tumor antigen specific T cells are produced by in vitro repeated antigen-specific stimulation of patient-derived T cells using autologous APCs or artificial APCs. T or iNKT cells can be engineered with MHCrestricted TCRs-, CARs- or lipid specific CD1-restricted TCRs. Engineered T cells are produced from peripheral blood T lymphocytes usually transduced with viral vectors to express the desired receptor. Before the infusion, patients receive a lymphodepleting treatment to increase the clinical response and persistence of adoptive transferred T cells.

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