Immunotherapy for Brain Tumors - BRAINLIFE.ORG

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Immunotherapy for Brain Tumors John H. Sampson, Marcela V. Maus, and Carl H. June Author affiliations and support information (if applicable) appear at the end of this article. Published at jco.org on June 22, 2017. Corresponding author: Carl H. June, MD, University of Pennsylvania, 3400 Civic Center Boulevard, Building 421 Philadelphia, PA. 19104-5156; e-mail: [email protected]. © 2017 by American Society of Clinical

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Glioblastoma (GBM) is the most lethal form of brain tumor and remains a large, unmet medical need. This review focuses on recent advances in the neurosciences that converge with the broader field of immuno-oncology. Recent findings in neuroanatomy provide a basis for new approaches of cellular therapies for tumors that involve the CNS. The ultimate success of immunotherapy in the CNS will require improved imaging technologies and methods for analysis of the tumor microenvironment in patients with GBM. It is likely that combinatorial approaches with targeted immunotherapies will be required to exploit the vulnerabilities of GBM and other brain tumors.

Oncology 0732-183X/17/3599-1/$20.00

J Clin Oncol 35. © 2017 by American Society of Clinical Oncology INTRODUCTION

Recently, cancer immunotherapy has emerged as the first broadly successful strategy for a variety of cancers. The various approaches for cancer immunotherapy that are currently in clinical development or have reached Food and Drug Administration approval are listed in Table 1. Antagonistic antibodies to the cytotoxic T-cell lymphocyte antigen-4 and programmed death 1 pathways have been approved for use in an increasing list of cancers, including melanoma, bladder, kidney, and non–small-cell lung cancers and Hodgkin lymphoma.1 An oncolytic herpesvirus was approved for the treatment of metastatic melanoma in 2016. In 2017, chimeric antigen receptor (CAR) T cells that target CD19 are expected to receive Food and Drug Administration approval for acute lymphoblastic leukemia and diffuse large-cell lymphoma. Here, we discuss the current challenges and opportunities for the development of immunotherapy for brain tumors. We also provide a brief overview of current approaches in the clinic. There are comprehensive reviews of immunotherapy for primary brain cancers.2-4

BIOLOGY OF BRAIN TUMORS: CHALLENGES AND OPPORTUNITIES

DOI: https://doi.org/10.1200/JCO.2017. 72.8089

Until recently, the dogma was that the CNS is immunologically privileged. In the healthy brain, the access of certain chemotherapy agents and antibodies is limited,5 which potentially limits the efficacy of checkpoint antibody therapies.

However, the spontaneous occurrence of multiple sclerosis and other autoimmune syndromes that are mediated by the cellular immune system indicates that immunosurveillance by T cells occurs. Paraneoplastic neurologic syndromes have long been known to clinicians, and they provide one of the clearest examples of naturally occurring tumor immunity and immunosurveillance of the CNS in humans.6 Conversely, severe immunosuppression can lead to viral reactivation in the CNS, as evidenced by the incidence of JC virus– induced progressive multifocal leukoencephalopathy in patients treated with rituximab or natalizumab. Animal models suggest that the breaking of peripheral tolerance and the occurrence of neurotoxicity can be uncoupled.7 The brain was thought to be devoid of lymphatics, but recent studies show that lymphatics exist in the arachnoid meninges and dura, and that lymphocytes exit the brain via this system to deep cervical lymph nodes.8 Thus, antigens and antigen-presenting cells from the brain parenchyma drain via dural lymphatics and from the cribiform plate to the cervical lymphatics.9,10 In the healthy brain, resting T cells do not cross the blood-brain barrier but traffic from meningeal blood vessels into the CSF, where they can gain access to the brain parenchyma via the pia mater or choroid plexus.11 Thus, these studies indicate that, in principle, antigens that arise from tumor mutations should be visible to the immune system in the deep cervical lymph nodes and that T cells administered by systemic infusion would have access to tumors via the CSF and choroid plexus routes. Finally, to the degree to which these barriers limit access of immunotherapy © 2017 by American Society of Clinical Oncology

Downloaded from ascopubs.org by 5.170.29.247 on July 11, 2017 from 005.170.029.247 Copyright © 2017 American Society of Clinical Oncology. All rights reserved.

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Table 1. Types of Cancer Immunotherapy Class of Therapy Adjuvant therapy Adoptive T-cell therapy Checkpoint blockade therapy Cytokine therapy Macrophage activation NK cell therapy Oncolytic virus therapy Vaccines: prophylactic and therapeutic

Example Recombinant Listeria; STING agonists; TLR agonists CAR T cells; TCR transgenic T cells Antagonistic antibody to CTLA-4 or PD-1 IL-2, IFN-g, IL-15, IL-18, TNF-a CD40 agonists; CD47 antagonists NK cell lines; ex vivo expanded NK cells Engineered HSV, measles virus, poliovirus HPV vaccines; Sipeleucel-T vaccine for prostate cancer

Abbreviations: CAR, chimeric antigen receptor; CTLA-4, cytotoxic T-lymphocyte antigen-4; HPV, human papillomavirus; HSV, herpes simplex virus; IFN, interferon; IL, interleukin; NK, natural killer; PD-1, programmed death 1; STING, stimulator of interferon genes; TCR, T cell receptor; TLR, toll-like receptors; TNF, tumor necrosis factor.

to the brain, direct infusion of antibodies and other drugs by convectionenhanced delivery and related methods provides a potential opportunity for direct drug delivery, which may then leverage these barriers to limit egress of these molecules. Although allografts engraft and can avoid rejection for long periods in the rabbit brain,12 the rat brain is highly infiltrated by activated T cells within 12 hours after intravenous infusion.13 As such, T-cell therapies that use activated T cells, such as CAR T cells, should have minimal limitations in access to the brain. However, not all T cells have equal access to the brain. For example, autoreactive CD4+ T cells are first licensed in the lung, where they acquire expression of Ninj1 and very late antigen 4, which facilitates later migration and entrance to the brain.14 Other data indicate that the leptomeninges represent a second checkpoint at which point-activated T cells also are licensed to enter the CNS parenchyma.8 It is clear that the human nervous system is susceptible to lifethreatening toxicity as a result of autoimmune attack.15-18 Historic work demonstrated that rodents and nonhuman primates vaccinated with brain tumor tissue and common adjuvants can succumb to fulminant autoimmune encephalitis.19,20 In these clinical observations and experimental studies, it remains unclear whether these toxicities are due to direct attack that is based on antigen expression or to the spread of the immune responses to other unrelated antigens. This differentiation has importance for the therapeutic approaches selected for this field. However, recent experiments with engineered T cells that have specificity for melanoma-associated antigen 3 show that direct toxicity from T cells in the absence of epitope spreading can be devastating: several patients developed necrotizing leukoencephalopathy as a result of cross-reaction with melanoma-associated antigen 12, an antigen expressed in the normal brain.21 Epitope spreading commonly occurs in autoimmune disorders in the CNS.22 To the degree to which tumor-specific and nonhomogeneously expressed antigens are targeted, a highly specific approach may be safe if epitope spreading does not occur; paradoxically, it also may be ineffective because of antigen heterogeneity. T cells specific for gliomas face a hostile tumor microenvironment in the CNS. Recent work by Chongsathidkiet et al23 suggests that tumors in the CNS prevent T-cell immigration and 2

induce sequestration of T cells in the bone marrow; this may be related to the lymphopenia observed in patients with gliomas even before they start lymphodepleting chemotherapies, such as temozolomide.24 In addition, glioma cells and their exosomes promote interleukin-10 (IL-10) and arginase-1 production and induce monocytes to convert to myeloid-derived suppressor cells.25 C-C motif chemokine ligand 2 produced by gliomas cells also recruits myeloid-derived suppressor cells and regulatory T cells.26 In addition, indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase often are overexpressed in gliomas, and highergrade gliomas express higher levels of indoleamine 2,3-dioxygenase than lower-grade gliomas do.27 These enzymes are part of tryptophan metabolism, and their upregulation results in increased production of the tryptophan catabolite kynurenine. Both tryptophan depletion and kynurenine are thought to be immunosuppressive to cytotoxic T cells. Kynurenine also results in recruitment of immunosuppressive regulatory T cells, perhaps through changes in production of chemokines such as C-C motif chemokine ligand 2228 or through its interaction with the aryl hydrocarbon receptor.29 The PD1 and programmed death ligand-1 axis also is active in gliomas, though results in the preclinical immunocompetent mouse models30 were more encouraging than what has been observed in early clinical trials.49 Gliomas are heterogeneous tumors,31 and identification of the immunologically relevant antigens is challenging. Most of the tumor-specific mutations, or neo-antigens,32 are unique to each individual.33 Gliomas are heterogeneous both among different patients and within each patient. These two forms of heterogeneity make targeted therapies, even immunologically based ones, such as vaccines and engineered T cells, challenging to develop for patient groups and for individual patients. Even in early trials of CAR T cells, antigen escape has occurred in both hematologic34 and solid tumor malignancies.35 The ideal tumor antigen also would be expressed on the cancer stem cell and would have a role in the maintenance of the tumor phenotype. The epidermal growth factor receptor variant III antigen, for example, is a constitutively active oncogenic mutation, but it nevertheless is expressed only in approximately 30% of patients with glioblastoma (GBM), and its expression is heterogeneous subclonal mutations within each tumor. Human epidermal growth factor receptor 2 is expressed more frequently and homogenously, but its expression in other life-sustaining tissues may narrow the therapeutic window. IL-13 receptor a2 (IL13Ra2) also is expressed frequently in GBM (approximately 58%),36 but is not essential for the tumor phenotype, and escape has been noted with both fusion ligands and T cells directed to it. Identification of single targets is difficult, but the reality is that, in the long run, multiple antigens will need to be targeted for most patients to have a reasonable expectation of clinical benefit. Studies of combined antigen-specific CAR T cells have been proposed to avoid antigen escape,37,38 and these studies are expected to enter clinical trials within the year. Checkpoint blockade alone or in combination with engineered T-cell therapies also may effectively overcome tumor heterogeneity, because multiple patient-specific mutations could be targeted at once, which would enhance the breadth of the antitumor immune response.

© 2017 by American Society of Clinical Oncology



Immunotherapy for Brain Tumors

CURRENT STATE OF THE ART FOR IMMUNOTHERAPY OF BRAIN TUMORS

Many clinical trials are being conducted in GBM. Some of these are listed in Table 2.

Checkpoint Inhibitors In preclinical murine models with orthotopic transplanted gliomas, checkpoint inhibitors have worked well individually and in combination with each other or other immunotherapy approaches.39-43 Ipilimumab and pembrolizumab have been shown to have acceptable safety and some efficacy in patients with metastatic brain metastasis from melanoma or non–small-cell lung cancer.44,45 Although recent clinical data suggest that the results with these approaches in patients may have some promise,46-49 the results clearly are not yet as dramatic as those seen in metastatic tumors within the brain or systemic tumors. This may relate to these tumors in general being cold tumors50,51—that is, they lack a considerable amount of intratumoral inflammatory cells52; however, these tumors do have some variability in this regard.53 The underwhelming results also may relate to the relatively low mutational rate of gliomas.54,55 Malignancies with a high burden of clonal neoantigens, such as those induced from chemotherapy,54,56-58 or tumors with high mismatch repair mutations,59 including gliomas,60 do seem to have a high response rate to checkpoint blockade. It would be helpful to have more data about where therapeutic molecules must be located to have beneficial effects. Do the drugs, usually large antibodies that may have limited access to the brain because of the blood-brain barrier, need direct access to the CNS, or can they operate systemically by activating T cells that can then easily penetrate the brain? We still do not know the degree of penetration these molecules have to get into the brain to treat primary tumors, but the amount may be quite low.61 Novel approaches of delivery of these drugs that either deliver them directly into the brain62 or transport them in novel ways from the systemic circulation into the brain may yield more promising results. Vaccines A spectrum of vaccines has been used in preclinical and clinical studies against primary brain tumors.63-74 These vaccines have targeted normal or overexpressed tumor proteins within the tumor,63-69 proteins with specific amino acid changes that resulted from tumor-specific neo-epitopes,72-74 or viral antigens. The approaches used various antigen substrates, including peptides, fulllength proteins, RNA, and DNA. Vaccines have consisted of the antigens alone; antigens in combination with various local71 or systemic adjuvants67; or antigens used in the context of cell-based therapy, such as dendritic cell vaccines. None of these approaches have been optimized, and a comparison of nonoptimized regimens has not been useful to differentiate which approaches might be best. To date, there is no phase III trial to demonstrate the efficacy of vaccines in any cancer except prostate cancer. Preclinical work in this regard, then, generally has failed to predict clinical results. This may be due to the use of heterogeneously expressed antigens, or the need for generation of different immune responses systemically to jco.org

attack antigens within the CNS, or the need to alter the tumor microenvironment differently within the CNS for these vaccine approaches to be successful.75 One example of a study with a single antigen that is heterogeneously expressed in GBM as a target is the recent phase III ACT IV trial, although the study failed to support use of the single antigen. It is possible that vaccine approaches against tumor-specific antigens, which are more homogeneously expressed, such as the IDH1 or IDH2 mutations, may be more favorable. More recently, vaccines that target epitopes that may be recognized by CD4+ T cells in the context of major histocompatibility complex class II presentation seem to have shown some promise in preclinical studies.76,77 However, the mechanism by which these would work in malignant gliomas, which may not express major histocompatibility complex class II (at least not de novo),78 is yet to be determined.

Cellular Therapies The presence of lymphocytes within malignant gliomas can be a positive prognostic indicator of survival for patients with these tumors.79,80 However, such naturally existing T-cell responses are insufficient to mediate regression of gliomas and may be related to the lack of high-affinity T-cell receptors specific to glioma antigens, to checkpoint molecules, and to limitations in antigen presentation in the CNS. Synthetic Biology With Engineered T Cells Engineered T cells are part of a broad explosion in immunooncology. What perhaps makes these therapies most revolutionary, though, is the concept of use of a living cell as the therapeutic platform. Living T cells after genetic modification are radically different from inanimate platforms, such as small molecules or antibodies, in that the cells are capable of intelligent sensing and response behaviors. At the same time, these cells are more challenging to manipulate, manufacture, and control. In theory, the combination of a living platform that is capable of complex sensing and response behaviors with the ability to genetically reprogram these behaviors is what generates the disruptive therapeutic potential of this approach. Adoptive immunotherapy with redirected T cells obviates the need for antigen presentation and stimulation of a primary immune response and can be directed to specific antigens with wellcharacterized, high-affinity antigen receptors. T cells redirected with CARs that target the B-cell marker CD19 have shown remarkable and durable efficacy in acute lymphoblastic leukemia, chronic lymphocytic leukemia, and B-cell lymphomas.81-87 Most CARs are designs to target surface proteins or antigens independent of HLA. One of the principal challenges in the development of new CARs is identification of an appropriate cell surface antigen to target. The principal antigens that have been targeted with such HLA-independent CARs include human epidermal growth factor receptor 2/neu,88 IL-13Ra2,35,89 and epidermal growth factor receptor variant III90,91; there is also interest in ephrin-A2– targeted CAR development, but these CARs have not yet entered clinical trials.92 In addition to targeting multiple antigens, there are many other variables to consider in the design and administration of © 2017 by American Society of Clinical Oncology


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Table 2. Examples of Clinical Trials for Brain Tumors Immunotherapy Approach and Agent Vaccine CMV pp65-LAMP mRNA-pulsed DCs Autologous Wilms tumor 1 mRNA-loaded DCs Tumor lysate-loaded DCs BTSC mRNA-loaded DCs Tumor lysate-loaded DCs Epitope enhanced peptides corresponding to IL-13Ra2 and surviving Poly-ICLC peptide vaccine Attenuated Listeria monocytogenes encoding EGFRvIII and NY-ESO-1 Personalized peptide vaccine plus Poly-ICLC and GM-CSF IDH1 peptide vaccine Checkpoint Pembrolizumab

Anti–LAG-3 and/or anti-CD137 Anti–PD-1 and/or IL-15 Anti–PD-1 and/or ipilimumab and/or bevacizumab

Combination DC and T cells HSCs, DC, and CTLs DC and nivolumab DC and nivolumab

TGF-b -RI inhibitor and nivolumab

Anti-CD27 and anti–PD-1 Anti–PD-L1 and radiation Anti–PD-L1 and radiation Anti–PD-1 and oncolytic adenovirus Adoptive T cell CAR T EGFRvIII CAR T IL-13Ra2 CAR T CD133 CMV CAR T HER2 CMV CTL T cells PD-1:CD28 switch receptor Donor NK cells

Title Vaccine therapy for the treatment of newly diagnosed glioblastoma multiforme Adjuvant dendritic cell-immunotherapy plus temozolomide in glioblastoma patients DCVax-L to treat newly diagnosed GBM brain cancer Vaccine therapy in treating patients undergoing surgery for recurrent glioblastoma multiforme Dendritic cell vaccine with imiquimod for patients with malignant glioma SL-701, a glioma-associated antigen vaccine to treat recurrent glioblastoma multiforme Personalized neoantigen cancer vaccine with radiotherapy for patients with MGMT unmethylated, newly diagnosed glioblastoma Phase I study of safety and immunogenicity of ADU-623

Clinicaltrials.gov Identifier NCT02465268 NCT02649582 NCT00045968 NCT00890032 NCT01792505 NCT02078648 NCT02287428 NCT01967758

GAPVAC phase I trial in newly diagnosed glioblastoma patients

NCT02149225

Phase I trial of IDH1 peptide vaccine in IDH1R132H-mutated grade III-IV gliomas

NCT02454634

Pilot surgical trial to evaluate early immunologic pharmacodynamic parameters for the PD-1 checkpoint inhibitor, pembrolizumab (MK-3475) in patients with surgically accessible recurrent/ progressive glioblastoma Anti–LAG-3 or urelumab alone and in combination with nivolumab in treating patients with recurrent glioblastoma Phase I/II study of BLZ945 single agent or BLZ945 in combination with PDR001 in advanced solid tumors A study of the effectiveness and safety of nivolumab compared with bevacizumab and of nivolumab with or without ipilimumab in glioblastoma patients

NCT02852655

DC + ex vivo expanded autologous lymphocyte transfer (xALT) Proteome-based personalized immunotherapy of glioblastoma Nivolumab with DC vaccines for recurrent brain tumors Autologous dendritic cells pulsed with tumor lysate antigen vaccine and nivolumab in treating patients with recurrent glioblastoma A study of galunisertib (LY2157299) in combination with nivolumab in refractory NSCLC, hepatocellular carcinoma, or glioblastoma A dose escalation and cohort expansion study of anti-CD27 (varlilumab) and anti–PD-1 (nivolumab) in advanced refractory solid tumors Avelumab with hypofractionated radiation therapy in adults with isocitrate dehydrogenase (IDH) mutant glioblastoma MK-3475 in combination with MRI-guided laser ablation in recurrent malignant gliomas Combination Adenovirus + Pembrolizumab to Trigger Immune Virus Effects (CAPTIVE)

NCT01326104 NCT01759810 NCT02529072 NCT03014804

Autologous T cells redirected to EGFRVIII-negative with a chimeric antigen receptor in patients with EGFRVIII-positive glioblastoma Genetically modified T cells in treating patients with recurrent or refractory malignant glioma Treatment of relapsed and/or chemotherapy refractory advanced malignancies by CART133 CMV-specific cytotoxic T lymphocytes expressing CAR targeting HER2 in patients with GBM Autologous cytomegalovirus (CMV)-specific cytotoxic T cells for glioblastoma (GBM) patients Pilot study of autologous chimeric switch receptor modified T cells in recurrent glioblastoma multiforme Haploidentical transplant and donor natural killer cells for solid tumors (STIR)

NCT02209376

NCT02658981 NCT02829723 NCT02017717

NCT02423343

NCT02335918 NCT02968940 NCT02311582 NCT02798406

NCT02208362 NCT02541370 NCT01109095 NCT02661282 NCT02937844 NCT02100891

NOTE. Identifiers and titles obtained from clinicaltrials.gov access on February 1, 2017. Abbreviations: BTSC, brain tumor stem cells; CAR, chimeric antigen receptor; CART133, CAR T cell CD133; CMV, cytomegalovirus; CTLs, cytotoxic T lymphocytes; DCs, dendritic cells; DCVax-L, Dendritic Cells Pulsed With Tumor Lysate Antigen; EGFRvIII, epidermal growth factor receptor variant III; GBM, glioblastoma; GM-CSF, granulocyte-macrophage colony-stimulating factor; HER2, human epidermal growth factor receptor 2; HSCs, hematopoietic stem cells; ICLC, polyinosinic-polycytidylic acid and poly-L-lysine double-stranded RNA; IDH1, isocitrate dehydrogenase 1; IDH1R132H, IDH1 R132H point mutation; IL-13Ra2, interleukin-13 receptor a2; LAG-3, lymphocyte-activation gene 3; LAMP, lysosome-associated membrane glycoprotein; MGMT, methyl-o-guanine-methyl-transferase; MRI, magnetic resonance imaging; NK, natural killer; NSCLC, nonsmall-cell lung cancer; NY-ESO-1, cancer testis antigen CTAG1B gene product; PD-1, programmed death 1; PD-L1, programmed death ligand-1; STIR, Solid Tumor Immunotherapy Response; TGF-b-RI, transforming growth factor b receptor 1; xALT, ex vivo expanded autologous lymphocyte transfer.

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cellular therapy with engineered T cells. The CARs may contain different signaling domains, which can affect their long-term proliferation and survival; they may be cultured differently during the ex vivo manufacturing process; and the vectors used to introduce and maintain CAR expression may affect the T-cell biology.93 Brown et al35 recently reported a striking response in a patient with a poor prognosis of multifocal GBM after multiple intraventricular infusions of IL-13Ra2 CAR T cells.94 This raises the possibility that local delivery of CAR T cells may enhance response in GBM and that the route of administration is important, as suggested by preclinical studies in mesothelioma.94 In conclusion, the advances in general oncology coupled with the recent fundamental advances in the understanding of neuroimmunology have created opportunities for the development of effective immunotherapy for malignant brain cancer. It is likely that combinatorial regimens with complementary mechanisms of action will be required to achieve a broad and durable antitumor

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benefit. Previous experience indicates that there are considerable challenges in the translation of early-stage trials to trials that change the standard of care. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the authors are available with this article at jco.org.

AUTHOR CONTRIBUTIONS Conception and design: All authors Manuscript writing: All authors Final approval of manuscript: All authors Accountable for all aspects of the work: All authors

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Affiliations John H. Sampson, Duke University, Durham, NC; Marcela V. Maus, Massachusetts General Hospital and Harvard Medical School, Boston, MA; and Carl H. June, University of Pennsylvania, Philadelphia, PA. nnn

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Sampson et al

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Immunotherapy for Brain Tumors The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. John H. Sampson Stock or Other Ownership: Celldex, Annias Immunotherapeutics, ISTARI Oncology, Neuronium Consulting or Advisory Role: Bristol-Myers Squibb, Medicenna Patents, Royalties, Other Intellectual Property: Celldex (licensed IP, royalties); Annias Immunotherapeutics (licensed IP); ISTARI Oncology (licensed IP); Neuronium (optioned IP) Marcela V. Maus Consulting or Advisory Role: Neon Therapeutics, Adaptive Biotechnologies, Agenus, Bluebird Bio, Cell Design Laboratories, Intellia Therapeutics, Precision Therapeutics, Unum Therapeutics, TCR2 Therapeutics, Windmil, Cellectis Research Funding: Agenus, TCR2 Therapeutics, Kyn, Unum Therapeutics Patents, Royalties, Other Intellectual Property: Inventor on patents held by University of Pennsylvania with and without Novartis

Carl H. June Honoraria: Novartis Consulting or Advisory Role: Celldex, Immuine Design Research Funding: Novartis, Tmunity Therapeutics Stock or Other Ownership: Celldex, Immune Design, Tmunity Therapeutics Patents, Royalties, Other Intellectual Property: IP licensed to Novartis; royalties paid to University of Pennsylvania; Office of Naval Research IP and patent royalties; IP licensed to Tmunity Therapeutics (Inst)





Acknowledgment C.H.J. is a member of the Parker Institute for Cancer Immunotherapy, which supports the University of Pennsylvania Cancer Immunotherapy Program. We apologize to colleagues for work that we were unable to cite because of space constraints.

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