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Cellular Therapy for Melanoma

  • Udai S. KammulaEmail author
  • Michael T. Lotze
Living reference work entry

Abstract

Melanoma was one of the first tumor types that responded to modern immunotherapy with the cytokines interferon alpha and interleukin 2. Indeed, since T cells can be identified before an invasive melanoma arises, the disease could be considered one of both melanocytes and T cells. We now know that the high mutational frequency, potential neoepitope abundance, remarkable 85% surgical cure rate for primary lesions, and predominant T-cell infiltrate found in cutaneous melanomas drove early immunotherapy (and likely surgical) successes. Demonstrating that the T cells were important for resistance to the tumor is most facilely demonstrated with adoptive transfer of tumor-specific T cells. Adoptive transfer of tumor infiltrating lymphocytes (TIL) is unusually successful in patients with melanoma. Prior to the development of checkpoint inhibitors, TIL transfer could generate objective responses in a majority of patients. The complete responses in TIL-treated patients are remarkably durable with most patients never recurring even when followed out for several years. The current era has allowed another important observation that uveal melanoma, a low mutational load tumor with few neoepitope targets, can respond to adoptive transfer of TIL. Future approaches will enable the use of T cells with new properties that can overcome the highly evolved, immunosuppressive environment of the melanoma. These include the abrogation and manipulation of nominal checkpoints, expression of common T-cell receptors in transfected autologous T cells, the development of allogeneic off-the-shelf reagents, and delivery of immunologic cytokines and signaling molecules that can sustain a durable long-term response.

Hence, it would seem fair to conclude that the lymphocyte is a necessary factor in cancer immunity – James B. Murphy and John J. Morton (January 1915) (Murphy and Morton 1915)

T Cells Mediate Recognition of Melanoma

Basic immunology. In the four billion years or so of life on the planet earth, organisms evolved sophisticated means to respond to damage or injury by identifying and responding to so-called damage-associated molecular pattern molecules (DAMPs). In particular ultraviolet radiation, associated not only with mutation in genes but also altering proteins, required both the evolution of DNA damage and repair processes (Rothschild 1999) as well as development of means for proteostasis (Quan et al. 2010). DAMPs are manifested primarily by unscheduled release of intracellular molecules (Hou et al. 2013; Huang et al. 2015). These molecules include the highly conserved high mobility group box 1 (HMGB1) protein, heat shock proteins, ATP, crystals of uric acid or Galectin 10, and DNA itself (Hou et al. 2013; Huang et al. 2015). Similarly, as life evolved, means to protect cells from pathogens allowed identification of cytosolic nucleotides or other pathogen-specific signals including those derived from bacteria and viruses, the so-called pathogen-associated molecular pattern molecules (PAMPs) (Janeway et al. 1996; Medzhitov 2009). Rather promiscuous pattern recognition receptors (PRRs) expressed on the cell surface and in the cytosol including the Toll-like receptors (TLRs) (Kaczanowska et al. 2013; Patidar et al. 2018), AIM2-like receptors (ALRs) (Harada et al. 2001; Liu et al. 2004), RIG-I-like receptors (RLRs) (Goubau et al. 2014; Malathi et al. 2007; Yoneyama et al. 2005), and NOD-1-like receptors (NLRs) (Lu et al. 2012; Bruchard et al. 2015; Janowski et al. 2016; Yoshihama et al. 2016) could respond to both PAMPs and DAMPs. More recently, cytosolic sensing through the cGAS/STING pathway of nuclear or mitochondrial DNA has been found central to many of the innate and subsequent adaptive immune responses to cancer (Bronte 2014; Woo et al. 2014; Demaria et al. 2015; Gajewski et al. 2017; Wang et al. 2017). Although many cells, both immune and nonimmune, express some or all of these receptors, they have primarily been studied in inflammatory cells and are the major mechanism for triggering so-called innate immunity. Much of the response to the genomic damage associated with UV-induced carcinogenesis in melanocytes triggers this initial response (Bald et al. 2014). The inflammatory cells involved in these responses are largely myeloid cells including neutrophils and monocytes. Innate responses are typically “hardwired,” rapid, and, when excessive, associated with profound inflammation and on occasion cellular and/or organismal death.

Adaptive immunity emerged in jawed fishes approximately 500 million years ago (Flajnik 2018) and is largely dependent on antecedent innate responses to PAMPs or DAMPs, the so-called Signal 0’s, postulated by the late Charles Janeway (1989). In actual fact, the jawless fishes had an alternative means for generating diversity using remarkably parallel classes of adaptive immune cells homologous to our T cells and B cells (Flajnik 2018). The adaptive immune response allows a more protracted response to microbes and damaged cells based on generation of novel receptors responding to linear encoded peptides varying in length from 8 to 20 amino acids; “shape” changes in either novel molecules or self-molecules modified by glycosylation, oxidation, or other changes; and more recently defined metabolites derived from stressed pathogens or host cells (see also chapter “Immunology of Melanoma”).

How does cellular therapy differ from other immunotherapies? Immunotherapies can be divided in three primary ways:
  1. (i)

    Innate versus adaptive. Innate immune responses are defined by hardwired receptors that are encoded in the somatic genome and provide a rapid and evolutionarily (at the species level) means to respond to pathogens and injury. Typically, they include Toll-like receptors (TLRs), Nod1-like receptors (NLRs), AIM2-like receptors (ALRs), RIG-I-like receptors (RLRs), and the more recently acquired (only in mammals) receptor for advanced glycation end products (RAGE) (Liu et al. 2014) encoded within the MHC class III region, important for scavenging extracellular DNA and cellular debris. Adaptive immune responses emerged with the jawless fishes 500 million years ago and have continuously included at least three elements – an alpha beta T cell (Jorritsma et al. 2007; Parkhurst et al. 2017; Zhang et al. 2012) responding to major histocompatibility presented linear peptide or lipid fragments; a gamma delta T cell responding to stress signals, phosphoantigens, and metabolites derived from pathogens or damaged/stressed tissues (Harrer et al. 2017; Nieda et al. 2015); and antibodies, typically consisting of a heavy and light (kappa and lambda) chain which recognize three-dimensional structures (Chen et al. 1998; Gnjatic et al. 2003; Houghton et al. 1985). Most effective cellular therapies employ T cells as effective agents although interest in modifying myeloid cells (especially dendritic cells) and NK cells persists in the field.

     
  2. (ii)

    Active versus passive. Classically any agent which elicits an immune response in the host is considered active, whereas those therapies employing immunologically effective therapeutic agents themselves (such as antibodies or T cells) are considered passive (Rosenberg and Terry 1977). Vaccination strategies including the use of dendritic cells (Celluzzi et al. 1996; Mayordomo et al. 1997) to elicit a host response or the employment of nonspecific immunostimulants would largely be considered active immunotherapies. Thus, the adoptive T-cell therapies described below would be considered adaptive AND passive immunotherapies.

     
  3. (iii)

    Afferent versus efferent. One other means to consider emergent immunity to cancer is with a nosology where all of those elements necessary to deploy immune effectors arising in the bone marrow and thymus that are proximal to the secondary (or tertiary in tumor) lymphoid sites in lymph nodes and the spleen are considered afferent. Those antibodies produced by plasma cells and/or emigrant T cells that mediate effector function within tissues would be considered efferent. As such, particularly for extant T-cell therapy, all successful strategies have employed efferent limb expansion of T cells of defined or presumed antitumor specificity.

     

Efforts have been made to deploy active, afferent, innate immune stimulation to elicit an effective immune response. The reality is that cancer in adults (but not in children) largely arises in the setting of chronic inflammation, primarily within epithelial tissues such as the lung, gut, and skin (Vakkila et al. 2006). As such, adaptive immune responses mediated by T and B cells have been under coevolutionary development within an individual with the emergence of cancers for as long as 7–10 years before a tumor is recognized as such. Now widely recognized is the fact that the effective immunotherapies mediating important objective antitumor responses stimulate existing effector cells or disable already extant suppressors. This would include the application of T-cell growth factors such as IL-2 (Kaufman et al. 2013), the use of checkpoint inhibiting antibodies such as those targeting CTLA4 (Maker et al. 2005; Shin et al. 2012), PD-1/PD-L1 (Hui et al. 2017), LAG3 (Andrews et al. 2017; Zhang et al. 2017), or TIM3 (Tang and Lotze 2012) and the adoptive transfer of expanded tumor infiltrating lymphocytes (TIL). An exception to this general rule would be the ability to confer novel properties on T cells by inserting either a chimeric antigen receptor with primarily an antibody moiety linked to T-cell signaling molecules or T-cell receptors themselves recognizing MHC-restricted peptides (Eshhar et al. 1982, 1993; Gorochov et al. 1992; Gross and Eshhar 1992; Hwu et al. 1993). Interestingly, all of these effective immunotherapies employ heightened numbers of immune effectors that are capable of mediating an effective immune response based on overwhelming force.

Immunosurveillance provides a backdrop to the complex network of the progressive coordinate Darwinian interactions of the immune system and cancer. Redefining the concept of immunosurveillance, now commonly referred to as immunoediting (Dunn et al. 2002, 2006), focuses on individual components of tumor interaction with the immune system. Cancer immunoediting is a dynamic process occurring over time that is comprised of three phases – elimination, equilibrium, and escape. The three self-explanatory “E” suggest: (a) elimination is the classic immunosurveillance phase referred to above wherein the immune system constantly surveys the host tissues for nascent transformed and genomically unstable cells, (b) equilibrium represents the period when a balanced immune response keeps the tumor in a state of functional dormancy (Schreiber 2005; Schreiber et al. 2011) resulting in incomplete destruction of tumor cells arising within the elimination phase, and (c) escape occurs when the immune system fails to fully control the tumor resulting in tumor outgrowth and tumor cells emerge as clinical disease. The process of immunoediting has been developed and reviewed in the recent literature (Mittal et al. 2014; Teng et al. 2015; Fridman 2018). The use of cellular therapies is mitigated by each of these processes, and there have been numerous examples suggesting that initial responses to either checkpoint therapies or adoptive transfer of cells are lost when tumors escape by loss of antigens, MHC-presenting molecules, interferon gamma signaling pathways, or upregulation of immune exclusion pathways (Spranger and Gajewski 2015; Passarelli et al. 2017) (see also chapter “Immunology of Melanoma”).

Historical perspective of cell therapy. The circulation of blood and its subsequent successful transfusion in dogs occurred in the seventeenth century. In 1818, the British obstetrician James Blundell performed a successful transfusion of human blood to a woman for hemorrhage following delivery (Walton 1974). Subsequent rapid development of modern blood typing ensued at the beginning of the twentieth century. Although first reported in 1910 by W.W. Duke (1983), it wasn’t until the 1970s that routine platelet infusions could be performed with successful warm storage. White cell infusions for infection and cancer were initiated in the early 1970s as well (Raubitschek et al. 1973; Higby et al. 1974). Bone marrow transplantation, first in beagle dogs in the late 1950s and subsequently in man, was performed at the Mary Imogene Bassett Hospital in Cooperstown, NY, a Columbia affiliate, by E. Donnall Thomas who subsequently received the Nobel Prize for his work (Thomas and Ferrebee 1960; Thomas et al. 1959). Much of the pioneering work in bone marrow transplantation moved to the Fred Hutchinson Cancer Research Center in Seattle with his departure from Cooperstown to there.

The earliest studies of immunity are commonly ascribed to vaccination to smallpox, the subsequent assessment of serologic responses to various vaccines, and the rather limited understanding of the critical role of lymphocytes and cellular responses until the 1950s. Cancers in adults (and not children) arise in the setting of chronic inflammation (Vakkila et al. 2006). Indeed, cancer in adults, with rare exception (glioma, sarcoma), is associated with secondary genomic instability that is associated with an emergent macrophage infiltration and variable T-cell response. Metastatic cancer still is for the most part incurable, even though the tumor cells are surrounded by immune cells, a situation known as the Hellstrom Paradox (Lukashev et al. 2007). The Hellstroms developed the microcytotoxicity assay and were among the first to identify cytolytic immune cells, now recognized as NK and T cells, infiltrating tumors that were growing in the mid-1960s (Hellstrom 1967; Hellstrom and Hellstrom 1966, 1967, 1969; Hellstrom et al. 1968a, b). The concept of cancer immunosurveillance dates back to the 1970s, when several scientists (Doll and Kinlen 1970; Keast 1970; Papatestas and Kark 1970; Prehn 1971; Klein 1973a, b; MacGregor 1973) hypothesized that this occurred based on observations of patients who underwent solid organ transplantation. Immunosuppression to avoid organ rejection was associated with an increased likelihood of cancer with no demonstrable viral etiology. This was actually suggested as early as 1957 in a series of prescient thought pieces by Sir Macfarlane Burnet, who later went on to win the Nobel Prize, along with Peter Medawar (Burnet 1957a, b).

Cellular therapies for cancer emerged initially with the pioneering studies of Alex Fefer and his colleagues (Cheever et al. 1977; Fefer 1969; Fefer et al. 1967) based on the ability to treat the FBL3 lymphoma, a virally induced tumor with adoptively transferred T cells. Robert North, (North 1982; North and Bursuker 1984; North and Kirstein 1977; North et al. 1976; Berendt and North 1980; Berendt et al. 1978) at the Trudeau Institute, demonstrated many of the principles of adoptive cell therapy in murine models including the critical role of macrophages, the presence of so-called suppressor cells, the need for cyclophosphamide depletion of these cells, and the critical need for “helper” CD4+ T cells as well as “cytotoxic,” CD8+ cells. Within the Surgery Branch of the NCI, pioneering studies (Rosenberg et al. 1978a, b, 1980a, b) that were conducted demonstrated the ability to grow and clone murine T cells as well as to expand lymphoid cells infiltrating syngeneic solid tumors (Yron et al. 1980), subsequently termed TIL. These cells, particularly when coupled with administration of IL-2, mediated important antitumor effects of progressively growing, immunogenic methylcholanthrene-induced tumors (Rosenberg et al. 1983, 1985, 1986). In parallel, adoptively transferred lymphokine-activated splenocytes could also mediate important antitumor effects in these murine models (Mule et al. 1986).

The initial human clinical trials of the adoptive transfer of pig lymphocytes specifically sensitized to human tumors were carried out by Norman Wolmark in the Surgery Branch, but these studies were never published (referenced in A Commotion in the Blood by Stephen Hall). These studies utilized human IL-2-activated lymphokine-activated killer cells (Lotze et al. 1980, 1981; Lotze and Rosenberg 1981). Subsequent clinical trials of IL-2 alone, first with the Jurkat cell line-derived IL-2 (Lotze et al. 1984, 1985a) and subsequently with recombinant IL-2 (Lotze et al. 1985b, 1986a, b, c, 1987a, b; Lotze and Rosenberg 1986), paved the way for subsequent evaluation of other T-cell growth factors and cytokines including IL-4 (Kawakami et al. 1988; Custer and Lotze 1990; Stotter and Lotze 1991; Lotze 1992; Lotze et al. 1992), IL-7 (Stotter and Lotze 1991; Lotze 1992; Lotze et al. 1992; Conlon et al. 2019), IL-10 (Naing et al. 2016), IL-12 (Zitvogel et al. 1994; Tahara and Lotze 1995; Elder et al. 1996; Del Vecchio et al. 2007; Atkins et al. 1997; Robertson et al. 1999), IL-18 (Jonak et al. 2002), and IL-24 (Fisher et al. 2003; Inoue et al. 2006). The only approved agent for treating patients with melanoma of these remains IL-2.

Identifying Tumor-Associated Antigens and Stress Ligands Recognized by T Cells

Overview. That tumors could be rejected by cellular immune reagents was abundantly clear for many years, but the molecular identification of the targets for T cells required the development of molecular cloning strategies and subtraction strategies. The earliest identified targets were the melanosomal antigens, found in both melanocytes and melanomas; the subsequent identification of so-called cancer-germline antigens, since they are found in both settings represented most notably by the MAGE family and NY-ESO-1; and more recently clear identification of neoepitopes generated by mutations, frameshifts, and indels. Indeed, early on it was clear that the majority of antigens recognized by T cells in melanoma were private specificities unique to that individual and an individual tumor (Anichini et al. 1996). A rather unexplored area is the role of stress ligands and metabolites recognized by non-MHC-restricted NK and gamma delta T cells (Argentati et al. 2003; Laggner et al. 2009; Toia et al. 2016; Wistuba-Hamprecht et al. 2016) (see also chapter “Immunology of Melanoma”).

Melanosomal antigens: MART1/Melan A, tyrosinase, gp100, TRP-1, and TRP-2. Autoimmune vitiligo has been recognized for many years and emerged as an important indicator of a T-cell-mediated response to melanoma in patients and murine models. The first identification and characterization of these molecules were carried out in the Thierry Boon and Steven Rosenberg laboratories (Knuth et al. 1989; van der Bruggen et al. 1991; Boon 1992; Kawakami et al. 1998a, b; Wang et al. 1999; Yee et al. 2000; Steitz et al. 2006) with confirmation using mass spectrometric identification of eluted peptides in Pittsburgh (Storkus et al. 1993; Itoh et al. 1994; Castelli et al. 1995; Celluzzi et al. 1996). Vaccination strategies were based on the use of adjuvants or dendritic cells (Celluzzi et al. 1996). Melanosomal glycoproteins are transported and excreted from melanosomes after delivery by a melanosomal transport protein (Wang et al. 1999). Many of the self-determinants display a rather low major histocompatibility complex affinity, suggesting escape from self-tolerance. Direct evidence of T cells recognizing MART1 that were transferred with subsequent confirmation of these cells based on CDR3 region identification could be identified in a patient’s T cell harvested from sites of vitiligo (Yee et al. 2000). Why melanosomes should harbor substantially immunogenic proteins may be related to their active excretion from melanocytes and uptake by both keratinocytes and dermal macrophages as well as other antigen presenting cells in the skin.

Cancer-germline antigens (CGA) including MAGE family of antigens and NY-ESO-1. The identification of novel tumor antigens also expressed in the testis and occasionally in the ovary and placenta was made possible by the development of serological analysis of recombinant cDNA expression libraries (SEREX) using tumor mRNA expression and autologous patient serum (Chen et al. 1997, 1998; Jager et al. 2000; Gnjatic et al. 2003; Derre et al. 2008). In a patient with esophageal carcinoma, an antigen, NY-ESO-1, had restricted mRNA expression in normal tissues and high-level expression only in the testis and ovary. It is found in many human cancers, including melanoma, bladder cancer, breast cancer, hepatocellular carcinoma, prostate cancer, and synovial sarcoma. NY-ESO-1 encodes a protein of approximately 18 kD with no homology with other known proteins. NY-ESO-1 belongs to a family of antigens that are detected by either cytotoxic T cells (MAGE, BAGE, GAGE-1) or antibodies – HOM-MEL-40(SSX2) and NY-ESO-1. As such they represent potential targets for cancer vaccination. For NY-ESO-1, clinical trials using dendritic cell targeting have been tested (Dhodapkar et al. 2014; Pollack et al. 2017). It has been widely applied as a means to assess immunity and the role of checkpoint inhibitors in melanoma patients (Fourcade et al. 2014).

The MAGE family of antigens were discovered early and found to be recognized by cytolytic T cells from patients with melanoma (Traversari et al. 1992; Zakut et al. 1993; Mukherji et al. 1995; Anichini et al. 1996). Over 40 human MAGE family proteins have been identified in many tumor types and are generally associated with more aggressive tumors with enrichment in stem cell-like properties. This family has expanded in number among eukaryotes, particularly in mammals. The MAGE-A, MAGE-B, and MAGE-C subfamily are located on the X chromosome, and type II MAGES (MAGE-D, MAGE-E, MAGE-F, MAGE-G, MAGE-H, MAGE-L) are not restricted to the X chromosome (Weon and Potts 2015). Although initially thought to be reexpressed as a consequence of demethylation (De Smet et al. 1996), they may have a more nefarious role and may be selected for their ability to provide stimulation for their E3 ubiquitin ligase activity (Kozakova et al. 2015; Lee and Potts 2017; Weon et al. 2018). CTLA-4 checkpoint blockade in patients with metastatic melanoma is futile when a subcluster of MAGE-A cancer-germline antigens, located on chromosome Xq28, is expressed (Shukla et al. 2018). This is not true for targeting PD-1. Autophagy is apparently suppressed by the MAGE-TRIM28 ubiquitin ligase, and ATG8 (LC3B) is negatively associated with MAGE-A protein levels in human melanomas. This suggests that enhancing autophagy could synergize with CTLA-4 inhibitors. Aggressive vaccination strategies have sadly largely failed (Dreno et al. 2018; Daud 2018) in patients with melanoma.

Neoantigens and neoepitopes. It is now abundantly clear that unique mutations in melanoma drive many of the peptides recognized in the context of T-cell therapies (Duan et al. 2014; Bassani-Sternberg et al. 2016; Spranger et al. 2016; Wood et al. 2018) (see also chapter “Molecular Pathology and Genomics of Melanoma”). Neoepitope immunogenicity is associated with peptide novelty assessed by tumor/normal peptide binding affinity differences, sequence similarity, other human peptide sequence similarity, and closest microbial peptide sequence similarity (Wood et al. 2018). In The Cancer Genome Atlas (TCGA) low repetition among individual HLA alleles and in neoepitopes is more similar to other human peptides, bacterial or viral peptides, than their paired normal counterparts. Using these personal targets for selecting TIL for therapy (see below) or for vaccine strategies (Hu et al. 2018) has captured substantial interest although only modest evidence of vaccine efficacy has been demonstrated (Ott et al. 2017).

Stress ligands and metabolites. One of the major means for T-cell or NK-cell recognition of tumor is through expression of stress ligands on the cell, arising from metabolic stress, ER stress, genomic stress, hypoxia, or nutrient depletion (Maccalli et al. 2009; Paschen et al. 2009, 2014). The NKG2D molecule is expressed by T and NK cells. Melanoma may express NKG2D ligands (NKG2DLs: MICA/B, ULBPs). Release of soluble form of NKG2DLs can impair immunity. NKG2D+ T cells can be found at the tumor site in melanoma, and new immunotherapeutic interventions could target these molecules. Alternatively other metabolites (Cascone et al. 2018; Fischer et al. 2018; McQuade et al. 2018) including changes in fatty acid metabolites, lactate production, pH changes, and other cytokines such as IL-9 (Forget et al. 2018) could represent novel means by which immune mechanisms are activated or suppressed. Given that phosphoantigens generated from mevalonate synthesis pathways are a target for a subset of gamma delta T cells in non-MHC-restricted activation, their appearance in skin and role in tumor immunity to melanoma (Argentati et al. 2003; Gao et al. 2003) are of great interest. Recent information suggests that in CTLA4 antibody-treated patients, those with Vδ1 cells predominant in the blood, did worse than those harboring the more common Vδ2 cells (Wistuba-Hamprecht et al. 2016). To our knowledge, no patients have been treated with γδ T cells or TIL with melanoma.

Adoptive Cell Therapy Using Tumor Infiltrating Lymphocytes

Overview. Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes (TIL) represents a personalized cancer immunotherapy strategy, targeting shared and unique tumor antigens expressed by a patient’s tumor. The basis for this treatment stems from the fundamental observation that tumor reactive lymphocytes are often found infiltrating the tumor microenvironment (TME) (Rosenberg et al. 1986). Further, numerous reports have correlated higher levels of these TIL with improved outcome in a variety of solid tumors including melanoma (Erdag et al. 2012), colorectal cancer (Galon et al. 2014), lung cancer (Horne et al. 2011), ovarian cancer (Webb et al. 2014; Zhang et al. 2003), breast cancer (Ali et al. 2014; Ibrahim et al. 2014), and squamous cell carcinomas (Wang et al. 2014; Balermpas et al. 2014) but not in pediatric tumors (Vakkila et al. 2006). Adoptive transfer of TIL aims to exploit these naturally occurring immune responses by liberating these TILs from the suppressive TME, expanding and activating the cells to large numbers ex vivo, and finally re-infusing the product back into the host (Fig. 1). This therapy has several scientific and practical advantages over active immunization and nonspecific immune stimulation. First, isolation can be performed of antigen experienced T cells with specificity against a broad array of patient-specific tumor antigens, including tumor differentiation antigens, mutated tumor neoantigens, and cancer-germline antigens (Kawakami et al. 1994, 1995, 1998a; Robbins et al. 2013; Tran et al. 2015, 2017). Second, ex vivo expansion of these tumor antigen-reactive T cells can be accomplished in the absence of host suppressive factors, such as the presence of CD4+CD25+ regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and inhibitory macrophages that are often present in the TME. Finally, the host can be conditioned immediately prior to adoptive transfer with lymphodepleting regimens that can eliminate endogenous suppressive influences and enhance the availability of homeostatic cytokines (i.e., IL-7, IL-15, and IL-21) to provide an optimal milieu for the transferred TILs (Gattinoni et al. 2005; Klebanoff et al. 2005) and to enhance engraftment and expansion.
Fig. 1

Schema for adoptive cell therapy using TIL

Initial ACT trials using TIL for metastatic cutaneous melanoma. Initial human studies of adoptive transfer using TIL were conducted in patients with metastatic cutaneous melanoma in the Surgery Branch, NCI. These early efforts were largely driven by the observation that melanoma metastases were frequently enriched with T cells having autologous antitumor reactivity and that these cells could be expanded in vitro to large numbers (Rosenberg et al. 1988, 1994). These pilot trials also explored the concept of host preparation with the administration of a single intravenous dose of cyclophosphamide (at 25 mg/kg) prior to TIL administration. In total, 86 patients with metastatic melanoma were treated with autologous TIL plus high-dose intravenous bolus IL-2 (720,000 IU/kg every 8 h). Fifty-seven of the 86 patients received cyclophosphamide conditioning. The overall objective response rate was 34% and was similar in patients receiving TIL and IL-2 alone (31%) or with cyclophosphamide (35%). Further, there was no significant difference in response between IL-2 refractory patients (32%) and with patients not previously treated with IL-2 (34%). Although these pioneering studies provided a framework for future efforts, the clinical responses observed in these patients were often of short duration. A compelling explanation for these transient clinical responses were the low levels of TIL engraftment and persistence based upon the tracking of gene-marked TIL in the peripheral blood by RT-PCR 1 month following infusion (Rosenberg et al. 1990).

An improved approach to TIL ACT for metastatic cutaneous melanoma. A revamped approach to TIL therapy for melanoma patients was introduced by the NCI almost a decade later with several modifications based upon improvements in cell manufacturing and a better appreciation of host lymphodepletion prior to cell transfer from murine models. In contrast to earlier studies in which TIL were grown without stringent selection from pools of enzymatically digested tumor tissue, the new approach accounted for intra-tumoral heterogeneity by identifying and selecting TIL with superior antitumor reactivity from different regions of the tumor (Dudley et al. 2003). Briefly, after surgical procurement, the fresh tumors underwent sterile dissection to generate geographically discrete 1–3 mm3 tumor fragments (typically 24 fragments) which were placed individually in wells of a 24-well culture plate containing complete media with human AB serum and recombinant IL-2 (6000 IU/ml). Remaining autologous fresh tumor was processed by enzymatic digestion to provide single-cell tumor suspension for reactivity testing. After approximately 2 weeks of growth, the individual fragment T-cell cultures were selected for further expansion based upon proliferative capacity and evidence of autologous antitumor reactivity using a standardized IFN-γ release assay. Final large-scale expansion of selected TIL cultures utilized a potent rapid expansion protocol (REP) utilizing anti-CD3 antibody and IL-2 (3000 IU/ml) in the presence of irradiated peripheral blood mononuclear cells (PBMC) as feeder cells (Riddell and Greenberg 1990) working in Seattle at the Fred Hutchinson Cancer Research Center. In addition to these improvements in cell manufacturing were modifications to the host preparative chemotherapy administered prior to TIL infusion. In contrast to the earlier studies using a single dose of cyclophosphamide (25 mg/kg), the new regimen consisted of a significantly higher dose of cyclophosphamide (60 mg/kg) for 2 days followed by fludarabine (25 mg/m2) for an additional 5 days [Cy/Flu regimen]. Enhanced lymphodepletion efforts were prompted by growing evidence from murine models that negative immune regulatory cells in the host tumor microenvironment could be hindering the activity of adoptively transferred T cells. Elimination of CD4+CD25+ Tregs in these animal studies prior to adoptive cell transfer dramatically improved antitumor efficacy (Antony et al. 2005). Additional delineated benefits of lymphodepletion included the induction of homeostatic cytokines, such as IL-7 and IL-15, and the elimination of endogenous cellular elements that may act as a sink for these cytokines (Gattinoni et al. 2005). Ultimately, the translation of these key elements to human adoptive cell therapy was reported in a seminal study in 2002, marking a new era in TIL therapy for metastatic melanoma (Dudley et al. 2002). Subsequently, a series of clinical trials evaluating the efficacy of lymphodepletion combined with TIL transfer in patients with metastatic cutaneous melanoma were reported by the Surgery Branch of the NCI (Dudley et al. 2005, 2008, 2010, 2013; Goff et al. 2016). Objective response rates (ORR) ranged from 49% to 72%, with long-term durable and potentially curative complete response (CR) rates of up to 20% (Rosenberg et al. 2011). Factors associated with objective response included longer telomeres of the infused cells, the number of CD8+CD27+ cells infused, and the persistence of the infused cells in the circulation at 1 month. Similar efficacy in patients with metastatic melanoma was reproduced outside of the NCI in TIL therapy trials conducted at MD Anderson Cancer Center (Radvanyi et al. 2012), Moffitt Cancer Center (Pilon-Thomas et al. 2012), Herlev Hospital in Copenhagen (Junker et al. 2011; Andersen et al. 2012; Donia et al. 2012, 2013, 2015, 2017; Svane and Verdegaal 2014; Andersen et al. 2016), Fred Hutchinson Cancer Research Center (Lee and Margolin 2012; Veatch et al. 2018) in Toronto (Nguyen et al. 2010; Crome et al. 2017), and Sheba Medical Center in Israel (Besser et al. 2013).

The main toxicities of adoptive TIL transfer with the Cy/Flu preparative regimen are predominantly derived from chemotherapy-induced bone marrow suppression. In the NCI studies, the nonmyeloablative Cy/Flu preparative regimen was associated with expected hematologic toxicities including neutropenia, lymphopenia, and thrombocytopenia in all patients. Typically, these toxicities were transient and resolved with supportive care after approximately 1 week. Clinically significant infectious sequelae were rare; however, the NCI did report 1 treatment-related death in a series of 93 metastatic cutaneous melanoma patients which occurred in a patient who had an undetected diverticular abscess prior to beginning therapy, emphasizing the need for proper patient selection (Dudley et al. 2008). Interestingly, in contrast to the significant autoimmune adverse events observed with immune checkpoint inhibitors, clinically significant autoimmune toxicities were rarely observed after TIL therapy, suggesting an important benefit of repopulating the host immune system with a skewed repertoire of tumor-derived lymphocytes.

Evaluation of intensive myeloablative conditioning. In an attempt to improve the efficacy of ACT, more intensive lymphodepletion prior to cell transfer was evaluated in the pmel-1 murine model (Wrzesinski et al. 2010). These studies suggested that more profound myeloablation with total body irradiation (TBI) given together with hematopoietic stem cell (HSC) transplantation significantly enhanced ACT by augmenting innate immunity, by increasing T-cell access to homeostatic cytokines, and by depressing the numbers of regulatory T cells and myeloid-derived suppressor cells. However, with increasing ablation, there was also greater host toxicity thought to derive from elevated lipopolysaccharide levels in the sera and heightened levels of systemic inflammatory cytokines. To determine if increased-intensity myeloablative regimens could translate to improved clinical responses in patients with metastatic melanoma, ACT with TBI conditioning was evaluated at the NCI in two sequential pilot clinical trials. Either 2 or 12 Gy of TBI was added to cyclophosphamide and fludarabine prior to cell transfer, and the results were compared to a prior group of patients who received the nonmyeloablative chemotherapy alone (Dudley et al. 2008). Patients receiving Cy/Flu conditioning had previously demonstrated an objective response rate of 49%. When 2 or 12 Gy of TBI was added, the response rates were 52% and 72%, respectively. Although these overall response rates were not significantly different, there was a suggestion that the TBI conditioning was associated with greater complete responses. This prompted the NCI to formally evaluate the importance of adding TBI to the adoptive transfer of TIL (Goff et al. 2016). A total of 101 patients with metastatic melanoma, including 76 patients with M1c disease, were randomly assigned to receive nonmyeloablative chemotherapy with or without 12 Gy TBI before transfer of TIL. At the time of reporting, there was no difference in CR rates (24% in both groups), nor was there a difference in OS (median OS, 38.2 vs. 36.6 months). The cohort receiving TBI did experience greater weight loss, more prolonged neutropenia, and the unique development of thrombotic microangiopathy in 13 patients (27%). Although these findings did not support that more intensive lymphodepletion with TBI could augment TIL therapy, efforts to identify safer and more effective preconditioning regimens for cell transfer remain an important pursuit.

ACT using TIL for metastatic uveal melanoma patients. Uveal melanoma (UM) is the most common primary malignancy arising within the adult eye. Overall, however, this is a rare cancer with an annual incidence of ~6 per million in the USA, accounting for 3.7% of all melanomas (McLaughlin et al. 2005). These tumors originate from transformed melanocytes within the pigmented uveal tract (which include the choroid, ciliary body, and iris) and are notable for characteristic cytogenetic changes (Harbour 2012), oncogenic mutations in GNAQ or GNA11 (Van Raamsdonk et al. 2009, 2010), and an unusual predilection to aggressively metastasize to the liver resulting in a dismal prognosis. Although significant and potentially curative metastatic cancer regression can be achieved in patients with metastatic cutaneous melanoma (CM) by augmenting preexisting antitumor T-cell responses with either systemic cytokines (Atkins et al. 1999), antibodies blocking checkpoint molecules (Hodi et al. 2010; Hamid et al. 2013; Larkin et al. 2015), or adoptive transfer of autologous TIL (Rosenberg et al. 2011), the use of immune-based therapies in uveal melanoma has been disappointing, thus far. In recent published reports of immune checkpoint inhibitors targeting either CTLA-4, PD-1, or PD-L1, objective regression of metastatic UM by standardized oncologic criteria has been rare (Zimmer et al. 2015; Kottschade et al. 2016) (see also chapter “Systemic Therapy for Mucosal, Acral and Uveal Melanoma”).

These findings have led to hypotheses that UM may represent a tumor variant that is poorly recognized by the host immune system and consequently resistant to immunotherapeutic strategies. It has been speculated that since the primary tumor arises in the eye, an immune privileged site, the primary tumor and its metastases harbor local immunosuppressive or cellular immuno-evasive factors that render immunotherapies unsuccessful (Niederkorn 2012). Another theory proposes that since sun-shielded ocular melanomas have far fewer somatic mutations compared to sun-exposed cutaneous melanomas, there are consequentially fewer potential mutated neoepitope targets for effective antitumor immunity. However, a recent discovery has challenged the dogma that UM are non-immunogenic tumors. Through screening of TIL cultures derived from freshly resected CM and UM liver metastases, the frequent presence of highly reactive T cells with specificity for autologous tumor were identified in both melanoma variants (Rothermel et al. 2015) (Fig. 2). The existence of these naturally primed tumor-specific TILs from the metastases of several UM patients suggested that immunotherapies that augment their in vivo activity might play an important role in treating this rare form of melanoma. To provide insight into the clinical antitumor capability of these TILs, a pilot ACT clinical trial in metastatic uveal melanoma patients was conducted at the NCI (Chandran et al. 2017). This study demonstrated that a single infusion of TIL after a nonmyeloablative lymphodepleting conditioning regimen could induce objective tumor regression in 7 of 20 (35%) metastatic uveal melanoma patients, including individuals whose disease had shown prior progression after both anti-CTLA-4 and anti-PD-1 checkpoint blockade. These encouraging findings might be explained by several potential advantages of adoptive T-cell therapy when compared to other immune-based therapies. First, T-cell populations having optimal recognition of autologous UM tumor antigens can be preferentially isolated ex vivo for therapy. Next, these selected T cells can be expanded to large numbers utilizing in vitro conditions that overcome tolerizing factors that might exist within the tumor microenvironment. Importantly, the host can be conditioned prior to cell transfer to eliminate regulatory and immunosuppressive factors. The combinations of these actions may explain how the transfer of TIL in this study could induce regression of metastatic UM when previous immunotherapies were ineffective.
Fig. 2

IL cultures derived from cutaneous melanoma (CM) and uveal melanoma (UM) liver metastases have autologous tumor reactivity. Autologous tumor reactivity of individual TIL cultures derived from cutaneous melanoma and uveal melanoma liver metastases. Each dot represents the IFN-g production of a single TIL culture in response to overnight coculture with autologous tumor digest minus the background cytokine levels of unstimulated TIL and tumor digest alone. Bar represents the mean of approximately 24 TIL cultures. Dashed line marks 100 pg/mL of IFN-γ on the y-axis, above which is considered significant reactivity. (Adapted from Rothermel et al. 2015)

Patient selection and operative considerations for TIL ACT. A multidisciplinary team including surgeons, oncologists, specialized nursing, and pharmacy support are critical to select appropriate patients, procure tumor tissue, and administer TIL therapy with optimal outcomes. Patients being considered for TIL ACT often have progressed through several conventional therapies and present with advanced-stage disease and limited life expectancy. Eligible candidates for ACT should demonstrate adequate performance status (ECOG 0 or 1). The commonly used lymphodepleting regimen of cyclophosphamide (60 mg/kg) and fludarabine (25 mg/m2) can result in transient neutropenia for approximately 6–10 days, during which patients are vulnerable to septic complications. Thus, it is relatively contraindicated to treat patients at high risk of bacterial infections, such as those with biliary obstruction, chronic cholangitis, or indwelling biliary or ureteral stents. Lymphodepletion may further exacerbate chronic viral infections such as hepatitis C, hepatitis B, and human immunodeficiency virus; however there are minimal data on the outcomes of such patients after this type of preparative regimen. Transient thrombocytopenia is also common and, thus, bleeding risk, for example from gastrointestinal or brain metastases, should be assessed prior to therapy. Many ACT protocols administer high-dose bolus intravenous IL-2 with cell transfer because it is thought to promote in vivo persistence and effector function of TIL. The administration of IL-2 can induce progressive capillary leak syndrome which may cause respiratory compromise (Lotze et al. 1985b, 1986a; Atkins et al. 1999; Kammula et al. 1998). Thus, eligible patients should have sufficient cardiopulmonary and renal reserve to tolerate the treatment. Pregnancy is an absolute contraindication to ACT given the inherent risks to both the mother and fetus. Small, asymptomatic brain metastases are not a contraindication to ACT as durable regression of such lesions has been observed (Hong et al. 2010). However, symptomatic brain metastases, lesions larger than 1 cm or those with edema or active bleeding should be managed before cell therapy to minimize neurologic complications. ACT is contraindicated in the setting of primary autoimmune disorders requiring pharmacologic immunosuppression, because of the suppressive effects on the transferred T cells. Although checkpoint inhibitors (including anti-CTLA-4 and anti-PD-1 antibodies) have been associated with severe autoimmune side effects (including colitis, pneumonitis, and irreversible hypophysitis), these types of adverse events are rarely seen with TIL therapy (see also chapter “Checkpoint Inhibitors in the Treatment of Metastatic Melanoma: Mechanisms of Resistance to Checkpoint Immunotherapy”). There is no evidence that extensive tumor bulk directly impedes the efficacy of ACT, but patients with extensive and rapidly progressive tumor burden often have limited time to wait for the manufacturing of a TIL product. Nonetheless, when appropriately timed, ACT can have a therapeutic impact in the most highly advanced patients.

After patient selection, the next major decision is identification of metastatic tumors for resection. Surgical approaches should consider metastases that will provide sufficient tumor tissue to generate TIL, yet cause minimal morbidity, thereby ensuring that patients can undergo rapid recovery and undergo ACT in a timely manner. Although tumor size does not correlate with efficacy of TIL therapy, tumors should be at least 2 cm in largest diameter to ensure an adequate quantity of tissue for successful processing. Larger tumors may have hypoxic and necrotic centers and do not necessarily yield higher quantities of TIL. There is no known correlation between site of metastasectomy and the capacity to generate TIL. TIL cultures have been successfully initiated and expanded from diverse sites including the liver, lymph node, lung, and gastrointestinal tract (Goff et al. 2010). Lymph nodes remain ideal sources of TIL because they can often be recovered with minimal postoperative morbidity. It should be cautioned that tumors procured from the lumen of the GI tract, or have occult colonization with bacteria or yeast, often develop prohibitory contamination during ex vivo culture. An additional theoretical concern arises when isolating TIL from lymphoid-rich tissues including the spleen or bowel. Bystander T cells may expand ex vivo, but will lack antitumor immune specificity. Thus, it is essential to confirm the presence and extent of tumor involvement when procuring lymphoid tissues. Resection of visceral tumors can often be performed with a minimally invasive approach, as described in a series of 22 patients with stage M1c melanoma who underwent laparoscopic liver resection to procure tumor tissue for TIL generation (Alvarez-Downing et al. 2012). For many patients with widely metastatic disease, resection of metastases for TIL therapy does not demand wide surgical margins or major organ resection that is typically employed for curative procedures. Once excised, tumors should be kept on ice and immediately transferred to a laboratory with personnel trained to dissect the tumor and initiate cultures. After isolation and expansion from fresh tumors, TIL in single-cell suspension can be cryopreserved for delayed treatment. Patients on clinical trials often require at least one evaluable target lesion be present so that the response to therapy can be measured by standard oncologic criteria, such as RECIST.

Despite attempts to optimize patient selection, some patients may experience a decline in functional status after tumor procurement due to cancer progression or surgical complications to the point that they are no longer candidates for ACT. Furthermore, although experienced laboratories can routinely generate TIL cultures from metastatic tumors, there are circumstances when the harvested tumor fail to yield sufficient numbers of T cells for a treatment due to exhaustion of the T cells, lack of tumor reactivity, or culture contamination. Accumulation of these risks implies a proportion of patients will undergo TIL harvest but will ultimately not be eligible for ACT. Patients should be counseled regarding this possibility.

ACT Using T Cells Transduced to Express Antitumor Receptors

Overview. An alternative approach to ACT utilizes T cells genetically modified to express receptors targeting cancer antigens. This strategy obviates the need to isolate and expand autologous tumor-reactive T cells from the host, such as TIL. Instead, the antigen reactivity of open repertoire peripheral blood lymphocytes can be redirected using gamma retroviruses or lentiviruses to stably introduce genes encoding antigen-specific T-cell receptors (TCR) or chimeric antigen receptors (CAR). CARs represent synthetic hybrid molecules composed of immunoglobulin variable regions recognizing tumor antigens fused to signaling domains of the TCR ζ chain (Eshhar et al. 1993) and costimulatory molecules, such as CD28 and 4-1BB to enhance activation and cell survival (Brentjens et al. 2007; Long et al. 2015). T cells transduced with CARs (CAR-T) are capable of MHC independent recognition of molecules expressed on the surface of target cells. Although CAR-T cells have shown remarkable efficacy in the treatment of some hematologic cancers (Brentjens et al. 2011, 2013; Lee et al. 2015; Kochenderfer et al. 2012, 2014), their ability to cause solid tumor regression has been limited thus far (Tanyi et al. 2017; Beatty et al. 2018). Murine models suggest that further modification of the vectors used to include cytokines such as TNF and IL-2 may be of value (Watanabe et al. 2018). In contrast, the clinical experience using TCR-transduced T cells has been more extensive, especially for the treatment of metastatic cutaneous melanoma. These studies have elucidated the therapeutic capabilities for TCR gene therapy technology but have also demonstrated the potential risks associated with this approach, as outlined below.

TCRs targeting melanocyte differentiation antigens. MART-1/Melan A and gp100 are melanocyte differentiation antigens (MDA) that are expressed in both normal melanocytes and melanoma tumors. Since the original identification, over 20 years ago, of HLA-A2-restricted MART-1/Melan A and gp100 epitopes recognized by naturally occurring TIL (Kawakami et al. 1993, 1994, 1995), there has been great hope that the immunotherapeutic targeting of these MDAs would result in the successful treatment of patients with metastatic melanoma. Enthusiasm stemmed from a number of observations that suggested that MDAs represented an ideal therapeutic target for melanoma. First, these proteins were reported to be commonly and highly expressed in the metastases of most melanoma patients (de Vries et al. 2001). Second, the MDAs were found to be highly immunogenic. A number of unique MHC I- and II-restricted epitopes have been described over the years for this class of antigens with high frequencies of primed CD8+ and CD4+ T cells found in peripheral blood or tumor-derived lymphocyte populations (Kawakami et al. 2000; Benlalam et al. 2001; Dudley et al. 2001).

There has been a long observed and intriguing association between the development of autoimmunity against normal melanocytes (e.g., uveitis and vitiligo) and melanoma tumor regression in patients treated with immune therapies (Rosenberg and White 1996; Palermo et al. 2001; Yee et al. 2000). Not surprisingly, one of the earliest clinical trials administering TCR-engineered cells targeted an immunodominant HLA-A0201-restricted epitope from MART-1 (MART-127–35). This MART-1-reactive TCR had been isolated from the TIL of a melanoma patient who had previously demonstrated a clinical response to TIL ACT. The delivery of these genetically engineered T cells followed the administration of the Cy/Flu conditioning regimen that had been successfully used in prior ACT trials. This pilot trial reported only 2 of 15 melanoma patients (13%) achieving an objective tumor regression with both patients displaying high levels of engraftment of the MART-1 TCR-engineered T cells (Morgan et al. 2006). Despite targeting a tumor antigen with shared expression on normal melanocytes, none of these patients developed autoimmune toxicities. In retrospective, in vitro functional analysis of the TCR used in this trial revealed that this receptor possessed intermediate affinity for its target epitope compared with a panel of other TCRs against the same peptide. It was postulated that a higher affinity receptor might result in greater therapeutic efficacy. Thus, a second-generation TCR with greater affinity for MART-127–35 was tested in a subsequent clinical trial (Johnson et al. 2009). Although ACT using this high-affinity TCR resulted in modestly improved clinical results with 6 of 20 melanoma patients (30%) experiencing partial tumor responses, this treatment induced profound autoimmune destruction of normal melanocytes residing in the skin, eyes, and ears. Sixteen of 20 patients (80%) manifested a skin rash, uveitis, hearing loss, or a combination of these adverse events. Efforts to target another MDA, gp100, with TCR- transduced T cells resulted in strikingly similar results (Johnson et al. 2009). A murine TCR specific for the human gp100154–162 epitope was generated from an HLA-A2 transgenic mouse. The human epitope (KTWGQYWQVL) differs from the mouse epitope (KTWGKYWQVL) by a single amino acid thus allowing the isolation of high-affinity T cells that have not undergone thymic selection. Administration of the Cy/Flu regimen with T cells transduced with this high-affinity gp100-specific TCR resulted in clinical responses in only 3 of 16 melanoma patients (19%), but autoimmune skin, eye, or ear toxicity was observed in 15 of the patients (94%).

In sum, the experience using MDA-specific TCRs provided clear proof of concept that PBL could be genetically engineered, adoptively transferred, and demonstrate in vivo persistence in patients with metastatic cutaneous melanoma. Problematically, the autoimmune toxicity resulting from the targeting of normal melanocytes in the skin, eye, and ear was far greater than the antitumor efficacy in metastatic melanoma patients. These studies suggested that identifying alternative antigenic targets with expression restricted to tumors or tumors and nonessential normal tissues might result in a greater therapeutic window.

TCRs targeting cancer-germline antigens. Cancer-germline (CG) antigens represent a unique and attractive target for TCR-engineered T cells. Unlike the MDAs, this family of antigens is expressed in a wide array of histologic tumor types and are often not expressed in any adult tissues with the exception of germline cells that are protected from immunologic recognition by T cells due to their lack of HLA class I and class II expression (Caballero and Chen 2009). NY-ESO represents a prototypic CG antigen that has garnered particular interest for immunologic targeting. Originally discovered in an esophageal cancer patient by screening sera for antitumor IgG responses using the SEREX technique (Chen et al. 1997), the NY-ESO protein was subsequently found to be expressed in a variety of tumors including melanoma, synovial sarcoma, non-small cell lung cancer, cholangiocarcinoma, and breast cancer (Hofmann et al. 2008). An affinity-enhanced TCR specific for the HLA-A2-restricted NY-ESO-1157–165 epitope was generated by amino acid substitutions in the CDR3α chain (Robbins et al. 2008). In a pilot clinical trial, HLA-A2 patients with metastatic melanoma and synovial sarcoma, whose tumors expressed high levels of NY-ESO, received lymphodepleting preparative chemotherapy followed by adoptive transfer of autologous PBL that were retrovirally transduced with this high-affinity NY-ESO-reactive TCR (Robbins et al. 2011, 2015). Eleven of 20 patients (55%) with melanomas and 11 of 18 patients (61%) with synovial cell sarcomas demonstrated objective clinical responses including some complete and durable tumor regression. Of note, no treatment-related autoimmunity was evident in these treated patients, consistent with the tumor-restricted expression of this CG antigen.

Based upon the encouraging results targeting NY-ESO, other CG antigens have been investigated as targets for TCR gene-modified T cells. The MAGE-A gene family has been shown to be one of the most widely expressed of the CG genes with greater than 30% expression in common epithelial malignancies including esophageal cancer, melanoma, head and neck cancer, breast, and lung cancer (Hofmann et al. 2008). A high-avidity TCR against MAGE-A3112–120 was generated by peptide vaccination of HLA-A2 transgenic mice (Chinnasamy et al. 2011). This TCR was also capable of recognizing MAGE-A9 (which expresses the same epitope) and epitope variants expressed in MAGE-A12, MAGE-A2, and MAGE-A6. Genetic modification of the TCR was performed by site-directed mutagenesis in the CDR3 region to further increase its avidity while maintaining MAGE-A gene specificity. Adoptive transfer of autologous MAGE-A3 TCR-engineered T cells was conducted in nine patients, seven with metastatic melanoma, one with synovial sarcoma, and one with esophageal cancer (Morgan et al. 2013). Five patients experienced objective clinical regression including a melanoma patient with a complete response ongoing more than 15 months. However, in dramatic contrast to the lack of autoimmune toxicity seen after targeting NY-ESO, the administration of the MAGE-A3 TCR-engineered T cells resulted in severe neurological toxicities in four patients. These cases initially manifested as profound mental status changes, progressing to coma and subsequently death in two patients. Post-mortem examination of brain tissue at autopsy demonstrated necrotizing leukoencephalopathy with extensive white matter defects associated with infiltration of CD3+CD8+ T cells. Investigative studies into the mechanism of this toxicity included molecular assays of human brain samples using real-time quantitative-polymerase chain reaction, Nanostring quantitation, and deep sequencing which revealed that MAGE-A12 (and possibly MAGE-A1, MAGE-A8, and MAGE-A9) was expressed in human brain. It was postulated that MAGE-A3 TCR cross-reactivity against a nonidentical HLA-A2-restricted epitope present in MAGEA12 was the initiating event of a TCR-mediated inflammatory response that resulted in neuronal cell destruction.

Additional cross-reactivity concerns associated with MAGE-A3-specific TCRs were subsequently reported by independent investigators evaluating an affinity-enhanced human TCR targeting an HLA-A1-restricted epitope of MAGE-A3 (Cameron et al. 2013; Linette et al. 2013). The genetic sequence of this TCR had four amino acid substitutions in CDR2α to enhance its avidity for MAGE-A3 recognition. Despite extensive preclinical investigations revealing no off-target antigen recognition concerns, the first two patients, one with melanoma and the other with multiple myeloma, developed cardiogenic shock and died within a few days of receiving autologous T cells transduced to express the affinity-enhanced MAGE-A3 TCR. Gross findings at autopsy revealed severe myocardial damage, and histopathological analysis revealed myocardial T-cell infiltration. Although no MAGE-A3 expression was detected in heart autopsy tissues, there were elevated levels of genetically engineered cells in the myocardial tissue. Exploratory studies revealed that the affinity-enhanced anti-MAGEA3 TCR, but not by the parental TCR, were capable of recognizing beating cardiac myocytes. Interestingly, normal resting cardiac myocytes were not recognized by the affinity-enhanced TCR suggesting conditional expression of the putative target protein. Using an amino acid scanning approach, a peptide from the striated muscle protein, titin, was identified as a cross-reactive alternative target for the MAGE-A3 TCR and the most likely cause of the observed in vivo toxicity.

The initial clinical experience with TCR-engineered T cells in melanoma patients highlights both the therapeutic potential and the critical safety concerns that should be considered in future gene therapy development. First, although the targeting of self-antigens (such as the MDAs) have been associated with significant and predictable toxicity, the targeting of tumor antigens with restricted expression can also be perilous. Epigenetically regulated human gene products, (such as the CG antigens) may have negligible expression on normal tissues in preclinical screening studies but may have unrecognized induced expression in vivo. Second, cross-reactivity of TCRs against nonidentical epitopes from apparently unrelated proteins can be difficult to predict and associated with significant clinical morbidity. Efforts to synthetically generate high-affinity TCRs may result in considerable augmentation of effector function but also narrow the therapeutic safety window. TCRs generated from human HLA-transgenic mice may be especially problematic since they have not been subjected to thymic selection against the full repertoire of normal human proteins and, thus, may have high affinity for both normal human proteins and cross-reactivity against unintended targets. Furthermore, enhancement of TCR affinity through CDR genetic manipulation should be approached cautiously, since these changes may also enhance cross-reactivity and result in off-target toxicity. Improved methods to define the specificity of engineered TCRs and preclinical models that predict human toxicity will be critical to the success of future clinical investigations.

ACT targetingmutated neoantigens. Although adoptive transfer of TIL has been shown to induce profound and complete clinical responses in patients with metastatic cutaneous melanoma, the specific antigenic targets responsible for the tumor regression have been a mystery. Complicating this analysis is the highly heterogeneous intra-tumoral and inter-tumoral expression of tumor antigens in melanoma metastases (Bartlett et al. 2014; Bartlett and Kammula 2014) and the polyclonal nature of TIL. Early studies of melanoma TIL suspected that shared MDAs, such as gp100 and MART-1/Melan A (Kawakami et al. 1993, 1994, 1995), were the critical targets of T cell attack since these proteins were highly expressed in both melanoma and normal melanocytes. However, an extensive review of ACT trials which selectively targeted either MART-1 and gp100 antigens found an overall objective clinical response rate of only 11.8% with the majority of these responses being partial and transient in nature (Chandran et al. 2015). Complete tumor response (CR) was seen in only 3.7% of patients and typically involved regression of small volume lymph node metastases. This CR rate is significantly lower than the 20% 5-year complete response rate associated with polyclonal TIL therapy in melanoma patients (Rosenberg et al. 2011). Despite the poor antitumor activity with selective MDA targeting, many of these patients developed severe on target-off tumor toxicity in normal tissues in the eye, inner ear, and skin which all harbor populations of normal melanocytes (Johnson et al. 2009). Cumulatively, these clinical studies suggested that the immunologic targeting of MDAs was rarely effective in mediating durable cancer regression in melanoma patients and that alternative tumor antigens might be the targets associated with tumor regression.

Early studies using laborious tumor antigen cloning techniques revealed that T-cell responses could naturally be generated against “neoantigens” derived from gene products of somatic mutations expressed in cutaneous melanoma (Coulie et al. 1995; Wolfel et al. 1995; Robbins et al. 1996). Mutated proteins had long been considered attractive immunologic targets since these antigens would not be expressed in normal host tissues. Further, high-affinity T cells specific for mutant neoepitopes would not have been edited from the endogenous repertoire by central thymic deletion. However, the true biologic significance of immune responses against mutated neoantigens was only recently made possible with the development of rapid and inexpensive next-generation sequencing (NGS) technologies to interrogate the genetic mutations harbored in individual patient tumor samples. Transcriptome and whole-exome sequencing (WES) of tumor DNA and matched normal DNA revealed that cutaneous melanoma was one of the most highly mutated human tumors, presumably due to UV mutagenesis (Lawrence et al. 2013). The clinical importance of tumor mutation load became apparent in correlative studies demonstrating an association between high numbers of somatic mutations and responsive to immunological checkpoint inhibitors targeting the CTLA-4 and PD-1 pathways in patients with metastatic cutaneous melanoma (Snyder et al. 2014; Van Allen et al. 2015; Hugo et al. 2016). Although these associations suggested that tumor neoantigens might represent the immunologic targets for successful immunotherapy, analyses of melanoma TIL reactivity provided direct evidence. Investigators at the NCI retrospectively evaluated TIL infusion samples from metastatic cutaneous melanoma patients who achieved durable and complete clinical responses after ACT. Initial screening studies of autologous tumor cDNA libraries revealed that these TILs had dominant populations of reactive T cells specific for mutated neoantigens (Robbins et al. 1996; Huang et al. 2004; Lu et al. 2013; Zhou et al. 2005). The efficiency of these investigations was enhanced by using WES to rapidly delineate the somatic mutations harbored in patient tumors and epitope prediction algorithms to predict candidate peptides able to bind to autologous MHC class I molecules (Robbins et al. 2013). By employing this focused screening strategy, TIL infusions that had induced complete and durable clinical regression were found to frequently contain multiple neoantigen-reactive CD8+ T-cell populations. In one dramatic example, a single TIL product was found to recognize ten distinct neoantigens (Prickett et al. 2016). Approximately 1 month after infusion, T cells targeting five of the ten neoantigens composed nearly 30% of total peripheral T cells, demonstrating that these T cells could persist and repopulate the repertoire of the host. Independent investigators reported the persistence of neoantigen-reactive CD4+ T cells in a melanoma patient who demonstrated a clinical response after ACT using TIL (Linnemann et al. 2015).

In an effort to more broadly identify candidate neoantigen epitopes that could bind to MHC molecules beyond the common MHC class I alleles, an alternative screening approach was developed that did not employ the bias and limited scope of available peptide prediction algorithms (Lu et al. 2014; Tran et al. 2017). This method employed the individual patient’s antigen presenting cells (APCs) as a personalized tool to present potential neoantigens in the context of all of the patient’s MHC class I and class II molecules. After elucidating all non-synonymous somatic mutations harbored in the patient’s tumor by WES, each of the mutant genes were expressed in the patient’s dendritic cells or B cells by transfection. To enhance efficiency to screen large numbers of mutations, multiple “minigenes” encoding the mutant codon and adjacent amino acids were linked together to form a tandem minigene (TMG) in a single open-reading frame. In vitro-transcribed RNA was synthesized from these TMGs and transferred into the APCs by electroporation. In parallel, pools of synthetic long peptides for each of the mutated neoantigens were pulsed onto the APCs. Autologous TILs were then co-cultured with the transfected and peptide-pulsed APCs to screen for reactivity against the mutant products. This approach allowed the processing and presentation of mutant peptides in the context of the patient’s own MHC class I and II molecules and facilitated the screening of both CD4+ and CD8+ T cells without the need for epitope predictions. This innovative approach was successfully in identifying 75 neoantigens recognized by autologous TIL or peripheral lymphocytes from 29 of 31 melanoma patients in the context of a wide array of MHC restriction molecules (Tran et al. 2017). Interestingly, each neoantigen was unique to the autologous patient with none shared across patients. Collectively, these findings suggested that potentially any mutant protein could serve as an immunologic target in melanoma.

The T-Cell Repertoire in TIL

Interestingly, much of the identification of persistence of TIL in the blood stream is based on predominant clones found in the infused product weeks to months following TIL treatment (e.g., Deniger et al. (2017) a study showing increase in TIL clonality in the peripheral blood in responders following treatment with vemurafenib and TIL). This has allowed some specialized studies and findings focusing on the intrinsic variability within the alpha beta and gamma delta T-cell populations, considered to allow up to 1015 different TCRs to be generated in an individual. This is with as little as 3% of this diversity within the so-called CDR3 region, the peptide/MHC binding region for alpha beta cells, in common between individuals. This suggests that the greatest diversity between individual humans resides not in their genome, not in their microbiome, or, if they have cancer, not in their mutanome but rather in their “adaptome,” defined as the major diversity within the T-cell and B-cell repertoires .

The earliest studies of T-cell clonality in tumors used either PCR to demonstrate diversity of TCR usage in the peripheral blood and tumor (Weidmann et al. 1992) and expansion of specific cells with cell transfer following vaccination and expansion (Weidmann et al. 1993). The so-called spectrotyping allowed facile demonstration (in this instance in renal cancer) that there was specific expansion of T cells in the tumor that differed from the peripheral blood and the lymph node and normal kidney (Puisieux et al. 1996). Subsequent studies demonstrated that one could use either tumor-derived DNA for analysis of T-cell subsets (Emerson et al. 2013) or more facilely with mRNA extracted, reverse transcribed, multiplexed PCR and then deep next-generation sequencing (Sims et al. 2016). This later study done in patients with glioma also was able to demonstrate a signature set of CDR3’s commonly used in normal but lost in the peripheral blood from patients with glioma. Further study of common gains and loss of individual CDR3’s in the peripheral blood will require deep sequencing of large numbers of normal and patient populations.

There does not appear to be sharing of TCR repertoire among Tregs and T conventional cells (Hindley et al. 2011) interestingly. In individual regions of ovarian cancer, spatial homogeneity of T cells was found (Emerson et al. 2013) based on common TCR usage, whereas substantial spatial diversity was found in esophageal cancer (Chen et al. 2016), liver cancer (Shi et al. 2017), renal cancer (Gerlinger et al. 2013), and breast cancer (Kato et al. 2017). This suggests that the emergent notion of screening individual fragments of tumors for TIL reactivity, based on heterogeneity in the local distribution of individual clonotypes, is reasonable.

In breast cancer, use of various physical modalities such as cryoablation with or without a single dose of antibody to CTLA4 allowed demonstration of enhanced clonal diversity in the tumor and in the periphery, thus allowing use of the TCR repertoire as a “biomarker” for immune response (Page et al. 2016). In skin cancers (basal and squamous cancers), expanded clonotypes were found both in the tumor as well as normal skin (Ohmen et al. 1994). In melanoma one could use PD-1 expression on the peripheral blood cells to demonstrate likely antigen-reactive-specific T-cell receptor usage compared to the PD-1-negative cells (Gros et al. 2014). Interestingly, there are some melanoma-reactive clones, based on CDR3 beta chain analysis, in blood and tumor that are unable to express PD-1 (Simon et al. 2016). Using analysis of TCRβ, one could also demonstrate greater number of clonotypes expanded in head and neck cancer when utilizing separation based on double positivity of T cells for CD39 and CD103 (Duhen et al. 2018). Using similar analysis one can demonstrate substantial expansion of TIL in pancreatic cancer (Poschke et al. 2016a, b) and that distinct TCR repertoires from pancreas cancer can be expanded with use of 4-1BB antibody (Sakellariou-Thompson et al. 2017). Reprogramming melanoma TIL to induced pluripotent stem cells (Saito et al. 2016) could convincingly demonstrate maintenance of a diverse repertoire with these strategies.

The future use of TCR repertoire analysis to examine persistence in the peripheral blood following transfer, to enable comparators with the tumor, to identify loss or gain of repertoire in the blood with age and treatment, and to select among various biophysical (such as radiation, chemotherapy, cryoablation, surgery, etc.) approaches and immunotherapies is warranted. The future use of a deeper analysis of the TCR repertoire in individual diseases in the periphery and the tumor to enable earlier selection of relevant populations is also predicted to be useful in therapy, using deep insights derived from deep sequencing.

The Future of ACT

A commercial path has now been realized for highly effective antitumor T cells with several companies approved to deliver CAR-T cells and others in the wings developing TCR-transfected T cells, so-called endogenous T cells, elicited by antigen-pulsed dendritic cells and tumor infiltrating lymphocytes. Indeed, cells as “living drugs” have now been realized with long-lived, “tail of the curve” treatment-free intervals, if not cures. Given the high regulatory burden and requirements for chemistry, manufacturing, and control (CMC) guidelines and oversight, centralized manufacturing with autologous cells has been the primary commercial approach alongside a sea of academic centers manufacturing their own cells. These cumbersome strategies will merge and emerge as a predominantly “site of care” or “bedside” manufacturing at centralized academic medical centers, similarly to what transpires for bone marrow and solid organ transplantation today. This likely will require a common set of manufacturing practices, likely in modular and disposable units capable of the manifold processes within the current cell manufacturing suite including separation, feeding, stimulation, viral transfection, and rapid expansion protocols.

Looming on the horizon are a series of innovations including “backpacking” “deep” T cells to provide suitable stimuli or cytokines for T-cell persistence and proliferation, use of allogeneic cells as off-the-shelf reagents, targeted evaluation of gamma delta non-MHC-restricted T cells, and CRISPR/Cas9 modification of T cells to eradicate unwanted genes or to provide novel genes. The use of vesicular or viral transport to deliver TCRs or other payloads directly in vivo, superseding ex vivo culture approaches or utilizing short Sleeping Beauty transposon strategies to enable very short culture periods and more effective delivery, is currently under evaluation. As is true for most effective public health measures, surveillance of susceptible populations and preventative strategies monitoring the T-cell and B-cell repertoires are in order. This could enable long-lived persistence of diversity and limit emergence of feckless monoclonal expansions of lymphoid clones, sustaining effective surveillance and immune protection from cancer and other diseases emerging from chronic inflammatory conditions.

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Solid Tumor Cell Therapy Program, Division of Surgical OncologyUniversity of Pittsburgh, UPMC Hillman Cancer CenterPittsburghUSA
  2. 2.Department of Surgery, Immunology, and BioengineeringUniversity of Pittsburgh, UPMC Hillman Cancer CenterPittsburghUSA

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