From Adoptive Immunity to CAR Therapy: An Evolutionary Perspective

From Adoptive Immunity to CAR Therapy: An Evolutionary Perspective Michel Sadelain, Memorial Sloan Kettering Cancer Center, New York, NY, USA Ó 2016 Elsevier Ltd. All rights reserved.

Abstract Adoptive cell transfers have been used in basic immunology for over half a century, enabling detailed functional characterization of immune cells including T lymphocytes. This experimental approach inspired multiple human cell therapies, spanning both allogeneic and autologous T cell transfers. The use of lymphokine-activated killer cells, tumor-infiltrating lymphocytes, donor leukocyte infusions, and virus-specific lines or clones has taught us a great deal about the biological and clinical challenges of developing safe and effective T cell–based therapies to treat cancer. The advent of T cell engineering in the 1990s changed the adoptive cell therapy paradigm from one based on the isolation and expansion of available donor or patient T cells to the design and genetic recomposition of T cells with optimal antitumor properties. The rise of second generation chimeric antigen receptors, in particular those targeting CD19, epitomizes this paradigm shift from classic cellular immunology to synthetic biology.

Introduction T lymphocytes are essential effectors of immune responses, involved in microbial defense and tumor immunity. Together with B lymphocytes, they mediate the cognate antigen–specific responses that are the hallmark of our adaptive immune system. T cells are essential for the maintenance of organismal integrity, immune regulation, and immunological memory. Their absence, whether hereditary or acquired, exposes to potentially deadly infectious and neoplastic pathologies. A large fraction of all immunotherapies thus seek to recruit T cells to recognize and destroy undesirable intruders such as virus-infected cells and cancer cells. The ontogeny of T cells was revealed in studies of virus-induced leukemia, which led Jacques Miller to uncover the origin and critical role of thymus-derived cells in viral clearance and tumor susceptibility (Miller, 1961, 1962). Until then, the thymus was a mysterious organ, filled with lymphocytes but devoid of antibodies and apparently dispensable when removed from adult animals. Neonatal thymectomies revealed the immune devastation that occurs in the absence of postnatal thymopoiesis (Miller, 1962). The technique of cell transfer, already established by the 1950s, had revealed that cellular components of the immune system were implicated in the rejection of tumors (Mitchison, 1955; Winn, 1959; Klein et al., 1960). The identification of T cells, combined with a better understanding of immunogenetics and histocompatibility, would now enable to more precisely study T cell function. Using the adoptive transfer technique, Henry Claman thus uncovered that adult thymic cells cotransferred with bone marrow or adult spleen cells, could enable the latter to produce hemolytic antibodies (Claman et al., 1966), which was later defined as T cell help (Mitchison, 1971). It should not come as a surprise that the broad use and demonstrated efficacy of T cell transfers would eventually inspire the use of T cell transfer for therapeutic purposes (Miller and Sadelain, 2015). A significant body of work would soon demonstrate that immune lymphocytes administered to animals, prior to challenge

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with tumor cells, could prevent subsequent tumor engraftment, and later that adoptively transferred immune cells could sometimes mediate rejection of established tumors, reviewed in Rosenberg and Terry (1977). These results would inspire some of the first attempts of adoptive T cell therapy for STs (solid tumors). On a separate track, bone marrow transplantation ushered the use of allogeneic T cells to recognize and destroy hematological malignancies, exploiting what was eventually defined as the graft-versus-leukemia (GVL) effect (Butturini et al., 1987; Champlin, 1991). These early cell transfer approaches gave way to subsequent cell therapies aiming to increase efficacy and reduce toxicity, which included acute graft-versus-host disease (GVHD). Lymphokine-activated killer (LAK) cell therapy and donor leukocyte infusion (DLI) showed improved safety profiles but limited efficacy. The ability to isolate and expand tumor-infiltrating lymphocytes (TILs) and virus-specific T cells (VSTs) enabled the clinical use of antigen-specific T cells, albeit still showing significant limitations in the setting of antitumor therapy. The advent of T cell engineering singularly altered these original concepts. Armed with genetic technologies, it would no longer be a cell harvested from the patient or a donor that would be adoptively transferred, but a cell product that was designed and repurposed through ex vivo genetic engineering. The prime example for this concept is chimeric antigen receptor (CAR) therapy.

The First Adoptive T Cell Therapies Targeting Cancer Following in the foot steps of murine studies that demonstrated antitumor activity of cells harvested from immune tumorbearing animals (Delorme and Alexander, 1964; Fefer, 1969; Mihich, 1969; Borberg et al., 1972), some of the first T cell therapies attempting to treat STs utilized allogeneic cells harvested from tumor-immunized donors. The infusion of donor white blood cells harvested from donors subcutaneously immunized with recipient tumors showed rare responses in patients with advanced melanoma (Nadler and Moore, 1969). This approach

Encyclopedia of Immunobiology, Volume 4

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Tumor Immunology j From Adoptive Immunity to CAR Therapy: An Evolutionary Perspective was soon abandoned, but pointed to the need to develop the means to culture and expand ‘sensitized’ lymphocytes. At about the same time, bone marrow transplanters had begun infusing T cell–replete marrow grafts in allogeneic recipients to rescue their failing hematopoiesis from chemotherapy-induced myelosuppression (Santos, 1979). It eventually became clear that the T cells present in the graft played a key role in the success of bone marrow transplantation, extending the benefits attributed to chemotherapy (Martin et al., 1988; Kernan et al., 1989). The GVL effect did not require tumor priming and appeared to be a subsidiary of the natural alloreactivity of donor T cells, which also accounted for the morbidity and mortality linked to GVHD (Martin and Kernan, 1990). The dilemma of allogeneic T cell transfer was thus clearly delineated well over two decades ago: donor T cells may be beneficial in mediating the GVL effect, enhancing hematopoietic engraftment and accelerating immune recovery, but posed a potentially lethal threat in the form of acute GVHD. These early experiences with allogeneic adoptive cell transfers made it clear that T cell therapies would have to be cautiously developed to achieve efficacy with tolerable toxicity. The transfer of autologous T cells enriched in antitumor tumor reactivity or of donor T cells lacking GVHD-inducing potential would have to be developed.

Lymphokine-Activated Killer Cells In the early 1980s, Steve Rosenberg and colleagues reported that incubating mouse splenocytes or human lymphocytes with interleukin (IL)-2, a newly found T cell growth factor, could expand lymphoid cells capable of lysing fresh tumor cells in vitro (Grimm et al., 1982, 1983). These LAK cells were cytolytic against a broad range of human and murine tumors, spared normal cells, and were not HLA-restricted (Rosenberg and Lotze, 1986). LAK cells were eventually determined to mostly consist of activated NK cells (Kiessling, 1976), admixed with some nonspecifically activated T cells (Phillips and Lanier, 1986; Melief, 1992). High-dose IL-2 therapy, with or without LAK cells, induced partial tumor regressions in 10–20% of patients with renal cell carcinoma or metastatic melanoma (Borden and Sondel, 1990; Lotze, 1990; Melief and Kast, 1990). However, the toxicity associated with LAK cell/IL-2 therapy was substantial, due in large part to increased capillary vascular permeability. LAK cells thus displayed limited therapeutic efficacy and unacceptable toxicity. Their use has been discontinued. It became clear that greater specificity, best mediated by antigen-specific T cells, would be needed to increase the efficacy and decrease the toxicity of the LAK/IL-2 regimen (Old, 1992; Greenberg, 1991).

Tumor-Infiltrating Lymphocytes The realization that adoptive cell therapy should utilize specific T cells led to focus on TILs in immunogenic cancers, based on the notion that the tumor would be enriched in tumor-specific T cells relative to circulating T cells from blood, as previously seen with thoracic duct or lymph node cells (Delorme and Alexander, 1964; Old and Boyse, 1964). In the setting of

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immunogenic carcinogen–induced murine tumors, TILs were found to be enriched for therapeutically active cells (Rosenberg et al., 1986) and to recognize unique tumor-associated antigens (Barth et al., 1990). TILs administered in combination with IL-2 and cyclophosphamide were found to be highly active against metastatic tumors in mouse models, significantly outperforming LAK/IL-2 therapy (Rosenberg et al., 1986). The activity of TILs is markedly enhanced in conjunction with IL-2 administration and host conditioning with cyclophosphamide or total body irradiation (Rosenberg and Lotze, 1986). The depletion of suppressor cells was shown to enhance the activity of adoptively transferred T cells (North, 1982). Host conditioning has since been revealed to act on multiple levels, including regulatory T cell depletion, elimination of cytokine sinks, and activation of antigen-presenting cells (APCs) (Muranski et al., 2006). The presence of tumor-specific T cells among TILs explained their superiority over LAK cells generated from peripheral blood cells (Melief, 1992). The moderate activity of LAK cells was attributed to their activity against target cells expressing low levels of HLA class I target cells (Ljunggren and Karre, 1990). Thus, while antigen-specific T cells require more time and effort for their production, they appeared to have greater therapeutic potential. TILs remain in use today. They can be isolated from at least 60% of melanoma patients, but less frequently for most other cancers (Wu et al., 2012). Their limited availability commanded that other means to isolate and/or generate tumor-specific T cells be discovered.

From Donor Leukocyte Infusion to VSTs The first deliberate T cell infusions performed in conjunction with allogeneic hematopoietic stem cell transplantation (HSCT) were based on the premise that donor peripheral blood T cells could provide antitumor and antiviral protection to the HSCT recipient (Hromas et al., 1994; Porter et al., 1994; Kolb et al., 1995). In terms of antiviral activity, peripheral blood T cells from donors exposed to virus could indeed contain memory T cells specific for viruses threatening bone marrow transplant recipients, such as adenovirus, cytomegalovirus (CMV) and Epstein–Barr virus (EBV). Unfortunately, broad application of DLI is limited by the low frequency of VSTs compared with the much higher frequency of alloreactive T cells, which may cause GVHD (Leen et al., 2014). This evidence called for the need to isolate and expand VSTs from donor peripheral blood in order to increase their therapeutic efficacy and remove the risk of GVHD. Several groups developed over the past two decades a range of techniques aiming to enable the adoptive transfer of pathogen-specific T cells as a therapeutic and prophylactic approach for control of viral infections in the posttransplant period. This approach requires the identification of relevant viral antigens and means to expand VSTs. Over the years, epitopes derived from adenovirus, CMV, and EBV have been well characterized (Saglio et al., 2014). A more thorny issue has been to easily access effective APCs to expand VSTs. The APCs required for antigenspecific expansion need to present the viral epitopes on matched HLA molecules.

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The B cell–immortalizing properties of EBV proved to be a gift to transplant immunologists, as EBV-mediated B cell transformation provided a means to at once establish APC lines and present several EBV epitopes. Donor T cells could thus be expanded on donor-derived EBV-transformed B cells, which provided a replenishable source of isogenic, high-quality APCs. T cells expanded in this manner induced durable remissions of EBV lymphoproliferative disease without the risk of GVHD (Papadopoulos et al., 1994; Heslop et al., 1994; Melenhorst et al., 2015). T cell–depleted HSCT provides a favorable platform for such therapies because these grafts do not require posttransplant prophylaxis with immunosuppressive drugs, which would compromise the activity of adoptively transferred T cells (O’Reilly et al., 2011). Other techniques were developed over time to more expeditiously isolate or expand VSTs. Some make use of artificial APCs (Latouche and Sadelain, 2000; Papanicolaou et al., 2003; Kim et al., 2004) and others of various tetramer or cytokine-based T cell capture systems designed to rapidly isolate antigen-specific T cells (Knabel et al., 2002; Feuchtinger et al., 2010; Peggs et al., 2011; Odendahl et al., 2014; Bucholz et al., 2015). These approaches have made considerable progress, but it should be well understood that they are made possible by the high antigenicity of viral antigens and the relatively high frequencies of VSTs in immune donors. These essential features do not extend to most tumor antigens. The isolation and expansion of tumor antigen–specific T cells from healthy donors has indeed proven to be challenging and labor intensive, whether using artificial APCs (Dupont et al., 2005; Butler and Hirano, 2014) or other strategies (Yee, 2014). Something else would be needed to enable the rapid generation of tumor-targeted T cells.

The Advent of T Cell Engineering The rationale for attempting to engineer T cells in the late 1980s was the perspective of creating T cells of any desired specificity and furthermore, in our vision, to enhance the therapeutic potency of antitumor T cells. In principle, genetic engineering could provide a means to rapidly generate antitumor T cells for any cancer patient, starting from easily accessible T cells – the patient’s own peripheral blood mononuclear cells. Thus, if natural TILs were not available or were impaired or were vulnerable to systemic or local tumor suppression, one could perhaps create cells capable of overcoming these deficiencies. This first required to devise means to genetically modify primary T cells. Up to the 1990s, the only available approaches to genetically modify T cells were to generate transgenic mice or to transfect surrogate leukemia cell lines or immortalized T cell hybridomas. The emergence of replication-defective viral vectors had however created new opportunities for the study of primary cells (Mann et al., 1983). Recombinant retroviruses were first used to genetically mark hematopoietic cells and track their fate after transplantation (Williams et al., 1984; Keller et al., 1985). The genetic modification of murine primary T lymphocytes became possible after we understood that high-titer ecotropic vectors, and precisely timed activation were required to enable stable gene transfer (Sadelain and Mulligan, 1992). This method was subsequently

adapted for the transduction of human T lymphocytes, using the gibbon ape leukemia virus (GALV) envelope to mediate retroviral vector entry (Mavilio et al., 1994; Bunnell et al., 1995; Gallardo et al., 1997). This advance was pivotal for developing T cell engineering. A variety of receptors and signaling molecules could now be studied in primary T cells (Sadelain and Mulligan, 1992). This methodology remains the foundation for many of today’s clinical trials based on T cell engineering, which frequently make use of GALV envelope–pseudotyped packaging cell lines (Miller et al., 1991) and the SFG vector or variant g-retroviral vectors (Riviere et al., 1995; Morgan et al., 2006; Hollyman et al., 2009; Savoldo et al., 2011). Improved packaging cell lines (Ghani et al., 2009) and enhanced vector production processes (Wang et al., 2015) are available today, as are an array of T cell transduction methods, utilizing either g-retroviral, lentiviral, and nonviral DNA or RNA-based vectors (reviewed in Wang and Rivière, 2015).

Single-Chain TCR Mimetics, Now Known as First Generation CARs To reset the specificity of a T cell requires the introduction of a receptor for antigen capable of activating the T cell. Such a receptor may consist of a physiological ab or gd TCR (T cell receptor) (Ho et al., 2003; Stone and Krantz, 2013; Stromnes et al., 2014; Blankenstein et al., 2015) or one of a variety of synthetic receptors (Sadelain et al., 2003), which we eventually regrouped under the term of CARs (Sadelain et al., 2009). The first embodiments within the latter category consisted of fusion receptors intended to mimic the TCR/CD3 complex. zchain fusion receptors had been previously shown by the Weiss, Seed, and Klausner groups to be sufficient to initiate T cell activation in a T cell leukemia cell line (Irving and Weiss, 1991; Romeo and Seed, 1991; Letourneur and Klausner, 1991). T bodies, as they were named by Zelig Eshhar, comprised an scFv to directly bind to antigen – in lieu of the TCR heterodimer – and the z-chain of the CD3 complex (or the related FcRg cytoplasmic domain), covalently linked to the antigen-binding domain, rather than noncovalently associated as in the natural TCR/CD3 complex, so as to recapitulate antigen-specific T cell activation (Eshhar et al., 1993; Brocker et al., 1993). Unlike the TCR, these receptors mediate antigen recognition independent of HLA and can target proteins as well as carbohydrates or glycolipids (Eshhar et al., 1996; Sadelain et al., 2003). In lieu of an scFv, some CARs utilize receptors or ligand domains as their targeting moiety, derived, for example, from heregulin (Altenschmidt et al., 1996), IL-13 (Kahlon et al., 2004), or the NK cell lectin-like receptor NKG2D (Barber et al., 2009), which bind to their cognate ligands or receptor counterparts. CARs can also be designed to target HLA–peptide complexes, allowing for recognition of intracellular target proteins (Willemsen et al., 2000; Stewart-Jones et al., 2009). Functionally, however, z chain–based receptors for antigen effectively redirect cytotoxicity, but do not afford T cell expansion upon repeated exposure to antigen (Gong et al., 1999) and induce T cell anergy in transgenic mice (Brocker, 2000). When they were first evaluated in cancer patients, these first generation CARs indeed failed to induce significant clinical responses

Tumor Immunology j From Adoptive Immunity to CAR Therapy: An Evolutionary Perspective (Kershaw et al., 2006; Lamers et al., 2006; Till et al., 2008; Pule et al., 2008). A different kind of receptor would have to be invented to effectively retarget and repurpose human T cells.

Dual-Signaling Receptors, Now Known as Second Generation CARs The inability of CD3z-chain-based CARs to support T cell expansion and function upon repeated exposure to antigen undermined their clinical potential. Devising an unnatural receptor design in which multiple signaling domains were combined, Maher et al. (2002) showed that interposing a costimulatory signaling domain between the transmembrane and T cell–activating domains of a z-chain fusion could enable the CAR to direct human primary T cells to proliferate and increase in numbers upon serial exposure to antigen (Maher et al., 2002). Some configurations of the dual-signaling units did not function properly, indicating that structural constraints restrict combinatorial possibilities, but some dual-signaling designs did provide both activating and costimulatory functions (Maher et al., 2002). These and other contemporary studies (Finney et al., 1998; Hombach et al., 2001; Imai et al., 2004) paved the way for engineering multifunctional receptors. These dual-signaling receptors are now known as second generation CARs (Sadelain et al., 2009) and may comprise any of a number of different costimulatory domains (Sadelain et al., 2013). Those comprising the cytoplasmic domains of CD28 (Maher et al., 2002; Finney et al., 1998) or 4-1BB (Imai et al., 2004) are the best known to date (Van Der Stegen et al., 2015). These second generation CARs entered the clinic in 2009, based on the CD19 paradigm. Compared to first generation CARs, CD28/z CARs induce more IL-2 secretion, increase T cell proliferation and persistence, and mediate greater tumor rejection (Brentjens et al., 2007; Kowolik et al., 2006; Milone et al., 2009; Zhong et al., 2010). These results were corroborated in a clinical study where both z- and CD28/z-based CAR T cell populations were coinfused and tracked over time, which confirmed the greater persistence of T cells expressing the second generation CAR (Savoldo et al., 2011). 4-1BB costimulatory domains also extend T cell survival compared to first generation CARs, albeit with different pharmacokinetics (Van Der Stegen et al., 2015). 4-1BB/z CARs impart greater longevity to T cells than do CD28/ z CARs, resulting in higher CAR T cell accumulation over time (Milone et al., 2009; Carpenito et al., 2009; Zhao et al., 2015). Additional research is needed to better delineate the respective properties of these and other second generation CARs that incorporate OX40, ICOS, DAP-10, NKG2D, and other costimulatory domains (Jensen and Riddell, 2015; Van Der Stegen et al., 2015).

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possibly extending to a role in tumor biology. CD19 was also chosen for its highly restricted expression in normal tissues, where it is confined to the B cell lineage. Thus, a successful CD19 CAR therapy would be expected to induce B cell aplasia, as was indeed observed in murine models (Pegram et al., 2012; Davila et al., 2013) and later in patients given CD19 CAR therapy. It has been almost 15 years since we reported that CD19 CAR therapy utilizing human peripheral blood T lymphocytes eradicated lymphoma and leukemia in immune-deficient mice, also providing the first demonstration that human CAR T cells of any specificity could eradicate systemic tumors established in mice (Brentjens et al., 2003). In these models, a single intravenous infusion of CD19 CAR T cells resulted in complete eradication of established, diffused B cell malignancies (Brentjens et al., 2003). We later showed that the 19-28z CAR vastly outperformed a first generation CD19 CAR in an aggressive acute lymphoblastic leukemia (ALL) model (Brentjens et al., 2007). Successful B cell tumor eradication was eventually obtained with different CD19 CARs (Cooper et al., 2003; Brentjens et al., 2003, 2007; Kowolik et al., 2006; Milone et al., 2009; Pegram et al., 2012; Davila et al., 2013), paving the way for multiple, ongoing CD19 CAR clinical trials. The attractiveness of CD19 as a CAR target was confirmed by its subsequent selection by the groups at the National Cancer Institute (NCI), the University of Pennsylvania, City of Hope National Medical Center, Fred Hutchinson Cancer Research Center, MD Anderson Cancer Center, and Baylor College of Medicine when they launched their clinical CAR programs. CD19 is by far the most investigated CAR target today. The most dramatic and consistent outcomes obtained with CD19 CAR therapy have occurred in ALL (Brentjens et al., 2013; Grupp et al., 2013; Davila et al., 2014; Maude et al., 2014; Lee et al., 2015). The first published results were obtained in adult patients with relapsed, chemo-refractory disease who were infused with autologous peripheral blood T cells collected by apheresis and transduced with the second generation 19-28z CAR (Hollyman et al., 2009). Four of four patients with measurable disease went into complete, molecular remission within 4 weeks of the T cell infusion (Brentjens et al., 2013). MSKCC, the Children’s Hospital of Philadelphia, and the NCI subsequently published follow-up studies in adult and pediatric ALL patients (Grupp et al., 2013; Davila et al., 2014; Maude et al., 2014; Lee et al., 2015), all showing comparable outcomes, reviewed in Sadelain et al. (2015). Collectively, the preclinical and clinical studies on CD19 CARs have validated the invention of second generation CARs, established the feasibility of implementing T cell engineering in the clinic, and demonstrated the effective potency of CAR therapy in at least one cancer, ALL (Sadelain, 2015).

CARs, CCRs, and iCARs The CD19 Paradigm CD19 is a cell surface antigen found on most B lineage lymphomas and leukemias (Lebien and Tedder, 2008). We selected it as a CAR target based on its cell surface expression and involvement in B cell development and function (Carter and Fearon, 1992; Engel et al., 1995; Rickert et al., 1995),

An expanding range of synthetic receptors is now being designed to further enhance cancer immunotherapy. The best known and most studied to date are CARs, including the early TCR mimetics and dual-signaling receptors (Figure 1(a) and 1(b)). Chimeric costimulatory receptors (CCRs) and inhibitory receptors (iCARs) are other members of this new class of

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Figure 1 CARs, CCRs, and iCARs. The top panels show examples of first and second generation chimerc antigen receptors (CARs), which respectively mimic TCR-mediated activation (a) or provide synthetic activation and (costimulation) (b). The lower left panel depicts chimeric costimulatory receptors (CCRs), which do not initiate T cell activation but provide antigen-dependent costimulation (c), eventually enabling combinatorial antigen recognition to enhance the tumor selectivity of TCR or CAR-targeted T cells (Kloss et al., 2013). Inhibitory chimeric receptors for antigen (iCARs) are neither CARs nor CCRs, as they achieve the opposite goal of dampening immune activation in response to antigen (d).

molecules used to enhance tumor specificity and avert T cell– mediated toxicity. Unlike CARs, CCRs do not trigger T cell activation, nor do they retarget tumor rejection. CCRs provide costimulatory support in the absence of the physiological costimulatory ligands (Figure 1(c)). CCRs may be antigen-specific, such as a GD2 ganglioside–dependent CD28-like receptor (Krause et al., 1998), or serve as a signal converter as in PD-1/CD28 fusion receptors, which transduce an activating costimulatory signal upon binding to the inhibitory PD-1 ligand (Prosser et al., 2012). CCRs are thus valuable T cell–engineering devices that provide context-dependent costimulatory support. CCRs can be coexpressed with CARs to achieve ‘combinatorial antigen recognition’ to increase the tumor selectivity of CAR T cells (Kloss et al., 2013). iCARs are not CARs – as they do not trigger T cell activation – nor CCRs – as they do not enhance T cell function or persistence. iCARs inhibit T cell function in an antigen-specific fashion. Such recombinant receptors (Figure 1(d)) can mimic checkpoint blockade receptors such as PD-1 and CTLA-4 to restrain T cell cytotoxicity and cytokine secretion but in antigen-specific fashion (Fedorov et al., 2013). The main reason for utilizing iCARs is to reduce collateral damage to normal tissues without resorting to lymphotoxic interventions such as high-dose corticosteroid therapy or the activation of a suicide gene. The latter approaches indeed enforce effective safety by deleting the infused T cells, thus terminating the therapeutic process. In contrast, iCARs act reversibly (Fedorov et al., 2013), similar

to checkpoint blockade receptors and killer inhibitory receptors in T cells and NK cells. iCARs are still little known but offer in principle a means to design T cells capable of discriminating between tumor and normal cells expressing a target antigen.

Conclusions and Perspectives CAR therapy is the most advanced T cell therapy, building on a rich and varied legacy of earlier adoptive cell therapies, but augmented through the incorporation of T cell engineering (Figure 2). It intersects cell therapy, gene therapy, and immunotherapy. The CD19 paradigm, which is the culmination of 25 years of research on T cell engineering, is rooted in the principles of T cell biology, gene transfer biology, and tumor immunology. CD19 CARs have revealed the enormous potential of CAR technology. Adoptive cell therapies, including CAR therapy, are now poised to tackle STs. To this end, CAR targets will have to be chosen thoughtfully to limit damage to normal tissue, which will not always be as tolerable as B cell aplasia. T cells will also have to be selected and engineered to overcome inhospitable tumor microenvironments and persist long enough to induce deep remissions without causing unacceptable toxicity including severe cytokine release syndrome or GVHD-like reactions. These goals are attainable, in principle. Much progress in T cell engineering, which is now facilitated by the

Tumor Immunology j From Adoptive Immunity to CAR Therapy: An Evolutionary Perspective

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availability of gene-editing technologies (Corrigan-Curay et al., 2015; Spence et al., 2015), is still needed. What T cell subset is the best substrate for CAR therapy remains to be elucidated. While the favorable clinical outcomes of CD19 CAR therapy in ALL patients have been obtained with bulk peripheral blood T cells comprising variable CD4þ/CD8þ T cell ratios and naïve/memory/effector T cell subsets, preclinical studies suggest that some T cell compositions may be superior to others (Gattinoni et al., 2011; Klebanoff et al., 2012; Riddell et al., 2014). Finally, T cell engineering may enable the use of T cells from alternative sources, such as VSTs (Cruz et al., 2013) and pluripotent stem cell–derived T cells (Themeli et al., 2013, 2015).

See also: MHC Structure and Function: Ligand Selection and Trafficking for MHC I; Origin and Processing of MHC-I Ligands. Signal Transduction: Kinase and Phosphatase Effector Pathways in T Cells; Signal Transduction by the B Cell Antigen Receptor; TCR Signaling: Proximal Signaling. Structure and Function of Diversifying Receptors: Structure and Function of TCRab Receptors; Structure and Function of TCRgd Receptors. Tumor Immunology: CD4 T Cells in Antitumor Immunity; CD8 T Lymphocytes in Antitumor Immunity.

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