Biology of Blood and Marrow Transplantation
Volume 16, Issue 1, Supplement , Pages S75-S81, January 2010

Immunotherapy for Pediatric Central Nervous System Tumors

  • Sharon L. Gardner

      Affiliations

    • Division of Pediatric Hematology/Oncology, Steven D. Hassenfeld Children's Center for Cancer and Blood Disorders, New York University, New York, New York
    • Corresponding Author InformationCorrespondence and reprint requests: Dr. Sharon L. Gardner, Steven D. Hassenfeld Children's Center for Cancer and Blood Disorders, 160 E. 32nd Street, 2nd Floor, New York, NY 10016.
    • ,
  • Nabil Ahmed

      Affiliations

    • Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas
    • ,
  • Hideho Okada

      Affiliations

    • Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania

published online 06 November 2009.

Article Outline

Key Words: Immunotherapy, Central nervous system tumor, Monoclonal antibody, Adoptive T cell, Vaccine

 

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Introduction 

Despite significant advances in surgical techniques, irradiation, and chemotherapy, central nervous system (CNS) tumors are the second-leading cancer-related cause of death in children [1]. Many of those fortunate enough to survive their CNS tumors are left with life-long deficits resulting from their treatments [2]. Thus, investigators are exploring new therapeutic approaches more specifically targeted against the tumors, resulting in better tumor kills with fewer long-term side effects.

Immunotherapeutic approaches to treating CNS tumors are currently of significant interest. These approaches include passive immunotherapy through the use of monoclonal antibodies (mAbs), adoptive immunotherapy through the use of ex vivo expanded tumor-specific T cells, and active immunotherapy through the use of tumor lysate and peptide vaccines.

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Passive Immunotherapy (Sharon L. Gardner) 

mAbs offer the advantage of attaching specifically to tumor antigens causing cell death through antibody-dependent cell-mediated cytotoxicity, complement-dependent lysis, and possibly tumor antigen inhibition [3]. In addition, mAbs can be used as vehicles to deliver cytotoxic agents, such as irradiation and toxins directly to the tumor cells.

Several mAbs, including rituximab (anti-CD20), myelotarg (anti-CD33), and alemtuzumab (anti-CD52), are used to treat leukemia and lymphoma [4]. mAbs also have produced responses in children with metastatic neuroblastoma [5]. Although several trials incorporating monoclonal antibodies are underway, the role of these antibodies in treating pediatric CNS tumors has not yet been definitively established.

Similar to other malignancies, CNS tumors offer the challenge of identifying unique antigens for the antibodies to target. Epidermal growth factor receptor (EGFR) is a target that has been studied in both adult and pediatric brain tumors. Studies have shown that EGFR is overexpressed, amplified, or mutated in a significant proportion of high-grade gliomas [6]. Nimotuzumab, a humanized IgG1 antibody directed against the extracellular ligand-binding domain of EGFR, is one of several mAbs developed to target abnormal signaling through EGFR. In a phase II study of nimotuzumab in children and adolescents with refractory high-grade gliomas, 12 of 34 patients had a partial response or stable disease after 2 months of therapy, including 9 of 14 patients with diffuse intrinsic brainstem gliomas [7].

mAbs have been used to deliver toxins and irradiation directly to tumor cells. The use of toxin or irradiation-conjugated mAbs precludes the need for complement-mediated lysis, which can be difficult in the CNS. Radiation-conjugated mAbs can be used for diagnostic purposes as well as to deliver radiation therapy.

Tenascin is one of the most widely used targets for radioimmunotherapy. Tenacin-C, an extracellular matrix glycoprotein, is expressed several-fold greater in high-grade gliomas than in normal brain tissue [8]. In a phase II trial of I131-labeled anti-tenacin antibody, median survival in patients with newly diagnosed high-grade glioma exceeded that exceeded in historical controls treated with irradiation and chemotherapy [9].

Radiolabeled mAbs also have been used to treat patients with refractory primitive neuroectodermal tumors (PNETs) with leptomeningeal dissemination. in 19 patients with refractory PNET with measurable disease, mAbs labeled with I131 were chosen from a panel of antibodies based on binding with each individual tumor and absence of binding on normal CNS tissue. The overall response rate was 64% (complete response [CR], 37%; partial response [PR], 16%; stable disease [SD], 11%) [10].

Targeted therapy also has been explored through the use of toxins conjugated to ligands, such as transforming growth factor (TGF)-α and transferrin, which bind to receptors overexpressed on brain tumors. Pseudomonas exotoxin conjugated with TGF-α enables delivery of the exotoxin to glioma cells through binding to EGFRs [11]. A diphtheria-transferrin conjugate has been used to treat glioma by exploiting the enhanced expression of transferrin receptors on glioma cells [12].

Along with directly targeting tumor cells, many investigators are examining the environment surrounding the tumors as well. More than 30 years ago, Judah Folkman hypothesized that tumors could be contained with drugs that prevent the development of new blood vessels to feed the tumors [13]. Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor [14]. Investigators at Duke combined bevacizumab with irinotecan in adults with recurrent malignant glioma, and found an objective response rate of 57% and a 6-month progression-free survival (PFS) of 46% [15]. Although some small preliminary studies in children with refractory high-grade gliomas have not shown a benefit with bevacizumab, there is a suggestion that it may be efficacious in children with low-grade gliomas. In a small pilot study of 10 children with low-grade gliomas with refractory disease after exhausting all conventional treatments, 7 of 9 evaluable patients had a minor, partial, or complete radiographic response, as well as clinical improvement, following 2 courses of bevacizumab and irinotecan [16]. At the time of the report, 6 children remained on therapy for between 3 and 22 months, and 8 children were progression-free survivors. The therapy was well tolerated; only 2 patients suffered a dose-limiting toxicity, with transient leukoencephalopathy in one and grade 3 proteinuria in the other.

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Adoptive Cellular Therapies for Brain Tumors (Nabil Ahmed) 

Immunotherapy with T cells has been most successful in hematopoietic stem cell transplantation (HSCT) recipients, in whom the T cell source is normal marrow donors. Adoptive immunotherapy with donor lymphocyte infusion (DLI) has been used to effectively augment the graft-versus-leukemia (GVL) response and to treat Epstein-Barr virus (EBV)-associated lymphoproliferative disease after HSCT; however, DLI is associated with a high risk of graft-versus-host disease (GVHD) and is not always effective 17, 18, 19, 20. Selectively activated and/or expanded cytomegalovirus (CMV)- or EBV-specific cytotoxic T lymphocytes (CTLs) have been successful in restoring immune response and preventing diseases associated with these viruses without causing GVHD [21].

Factors Limiting the Application of Antigen-Specific T Cell Therapy 

The broader use of antigen-specific CTLs for tumor therapy is currently limited by several factors, including (1) the reliable generation of tumor-specific T cells; (2) decreased major histocompatibility (MHC) class I expression on tumor cells or defects in the antigen-processing machinery; (3) the presence of inhibitory T cells, such as T helper type 2 (Th2) cells and/or T regulatory cells (Tregs), at the tumor site; and (4) limited in vivo expansion of adoptively transferred T cells. One strategy for overcoming many of these limitations is the genetic modification of T cells to express chimeric antigen receptors (CARs). CARs are synthetic molecules consisting of an extracellular receptor domain (ectodomain) that contains the heavy-chain and light-chain variable regions of an mAb joined to a transmembrane and a cytoplasmic-signaling domain (endodomain) derived from the CD3-ξ chain and costimulatory molecules such as CD28, OX40, and 4-1BB (Figure 1) 22, 23. CARs provide T cell activation in a non-MHC-restricted manner and thereby circumvent some of the major mechanisms by which tumors avoid MHC-restricted T cell recognition, such as downregulation of HLA class I molecules and defects in antigen processing. Moreover, expressing CARs with multiple signaling domains in T cells renders them resistant to the inhibitory effects of regulatory Tregs [24]. Finally, CAR-expressing T cells can be readily prepared in large quantities ex vivo for clinical applications. Indeed, our preliminary results indicate that T cells expressing CARs specific for the human epidermal growth factor receptor 2 (HER2) could overcome several of the current limitations of malignant glioma-specific T cell therapies.

  • View full-size image.
  • Figure 1 

    CARs consist of an extracellular antigen-recognition domain (ectodomain), a transmembrane domain, and an intracellular signaling domain (endodomain). A CAR with a CD3-ξ signaling domain is shown. Additional signaling domains derived from costimulatory molecules can be introduced into the endodomain to enhance CAR-mediated T cell activation.

Human epidermal growth factor receptor 2 (Her2) has been used as a T cell therapy target in malignant gliomas. The ideal target for biological therapies is one that distinguishes tumor cells from normal surrounding tissue, thereby avoiding unwanted bystander effects. In addition, the therapeutic target should be essential to the malignant phenotype of cancer cells, so that it cannot be lost by mutation or deletion. HER2 satisfies these criteria in malignant gliomas. HER2 protein is present in up to 80% of glioblastoma multiformes (GBMs) 25, 26, but not in the normal postnatal brain [27]. HER2 signaling deregulates cell proliferation, inhibits apoptosis, and increases the metastatic potential of cancer cells 28, 29, 30. Moreover, HER2 expression increases with the degree of anaplasia in glial tumors 26, 28, 29, 31, 32. The median survival for GBM patients with HER2-overexpressing tumors was 4 months, compared with approximately 14 months for patients whose tumors lacked overexpression [26]. This observation, along with the fact that HER2 is not expressed by normal postnatal human brain cells [33], makes HER2 an attractive target for biological therapies for malignant glioma.

HER2 is a validated target for breast cancer immunotherapy 28, 34, 35, 36; however, the HER2 expression is low on GBM, making HER2 mAbs like trastuzumab less effective 37, 38, 39. Our preliminary results suggests that genetic modification of T cells with HER2-specific CARs effectively overcomes this limitation, because the overall avidity of receptors arrayed on a T cell is greater than that of a bivalent antibody, and engagement of a limited number of T cell receptor molecules is sufficient to trigger a cytotoxic effector response [37].

CMV and Glioblastoma Multiforme: An Evolving Association 

Cytomegalovirus (CMV) is a ubiquitous beta-herpes virus that produces a minor mononucleosis-like syndrome in the immunocompetent host. Several recent reports have identified immunoreactivity for the CMV proteins pp65 (CMVpp65) and IE1-72 by immunohistochemistry (IHC) in 80% to 100% of GBM samples studied, as well as CMV RNA by in situ hybridization (ISH) in all IHC-positive samples 40, 41. In addition, CMV DNA as well as viral particles were detected in pp65 and IE1-72 immunoreactive cells. It is likely that CMV promotes the malignant phenotype of GBM cells by enhancing cell invasiveness and activating telomerase [42]. Although the presence of CMV antigens in GBMs is controversial, recent results of phase II clinical studies with dendritic cell (DC) vaccines unequivocally support their presence. Patients with newly diagnosed GBM vaccinated with CMVpp65-RNA-transfected DCs have a longer PFS than nonvaccinated controls, and 1 patient enrolled on the DCVax study (DC pulsed with autologous tumor lysate) developed a strong CMV-specific T cell response after vaccination [43].

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Enhancing the in vivo Expansion and Persistence of Adoptively Transferred CAR T Cells 

Full T cell activation requires that receptor engagement be accompanied by a sequence of costimulatory stimuli. Such a sequence is usually lacking when a synthetic CAR is engaged. To overcome this limitation, investigators have grafted CARs into CTLs with defined antigen specificity, including CTLs specific for EBV 44, 45. These cells not only provide antitumor activity through their CAR component, but also receive appropriate costimulation following native T cell receptor engagement by EBV-latent antigens presented by APCs. For GBM-targeted T cell therapies, we explored using CTLs specific for a different latent herpes virus, CMV. This may be a superior proposition, because CMV antigens are present not only in latently infected leukocytes, but also in most GBMs.

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Molecularly Targeted Vaccine Strategies for Adult and Pediatric Patients with Glioma (Hideho Okada) 

Introduction 

Brain tumors, like other malignancies, are able to overcome host immune defenses through various mechanisms that have become increasingly well characterized over the past decade [46]. Immunologic tolerance of brain tumors may result in part from the absence of conventional draining lymphatics, which limits primary immune responses initiated within the CNS. Furthermore, the normal and neoplastic brain tissues elaborate a variety of immunosuppressive factors, including TGF-β2, Fas ligand (CD95L), and programmed death ligand-1 (PDL-1). This “immunologically privileged” status of the brain is not absolute, however. Systemic activation of T cell responses against brain-specific antigens induces immune responses that are manifested in the CNS, such as experimental allergic encephalomyelitis [47] and paraneoplastic cerebellar degeneration [48].

For more than a decade, we have been dedicated to developing novel immunization approaches for patients with CNS tumors, such as gliomas. Early-phase clinical trials by us 49, 50 and others of more than 100 patients with malignant glioma have demonstrated the safety and preliminary therapeutic benefits of peripheral vaccinations using autologous glioma tissue-derived bulk antigens [46]. To develop tumor-specific (ie, safer) and effective glioma vaccines, we have focused our research efforts on identifying and characterizing human glioma-associated antigen (GAA)-derived CTL epitopes, such as those in the interleukin-13 receptor (IL-13R)α2 [51] and EphA2 [52].

But, the rejection of tumors by GAA-specific vaccines is the final outcome of a series of events initiated by an immune or inflammatory response at the site of vaccination. Vaccine-induced GAA-specific T cells are required to traffic into the tumor sites in sufficient numbers, retain their functionality, and exert their antitumor activities. Given the unique immunologic environment of the CNS and CNS tumors, we propose that the systemic induction of GAA-specific responses by peripheral vaccines must be followed by therapeutic interventions that enhance the attraction and promote the functionality of vaccine-induced effector cells within the CNS tumor site for optimal efficacy.

Type-1 CTL Response for Anti-CNS Tumor Immunotherapy 

Our previous preclinical studies have indicated that efficient CNS tumor homing is a characteristic of CTLs with type 1 phenotype (Tc1) as opposed to those with type 2 phenotype (Tc2), and appears to be mediated by a type 1 chemokine, CXCL10/IP-10 [53]. Further characterization of the expression of a panel of homing receptors on Tc1 and Tc2 cells showed that only very late antigen (VLA)-4 (a heterodimer of CD49d and CD29) was expressed at significantly higher levels on Tc1 cells than on Tc2 cells [54]. VLA-4 expression on T cells was downregulated in an IL-4 dose-dependent manner but not by other type 2 cytokines (eg, IL-10, IL-13), suggesting that IL-4 uniquely downregulates VLA-4 expression on these T cells . The efficient trafficking of Tc1 cells into intracranial tumors in vivo was efficiently blocked by administration of mAbs against CD49d or VCAM-1 or small interfering RNA-mediated silencing of CD49d on Tc1 cells, supporting the critical role of VLA-4 in the effective intracranial tumor homing of antigen-specific Tc1 cells. These data also suggest that effective vaccine and/or ex vivo T cell activation regimens may be developed by promoting the generation of VLA-4+ antitumor Tc1 cells.

Poly-ICLC as an Attractive Adjuvant to Promote Type-1 Antiglioma Immunity 

A clinically relevant type 1 polarizing regimen may be achieved by poly-ICLC, a natural type 1 interferon (IFN) inducer. Poly-ICLC is a synthetic complex of carboxymethylcellulose, polyinosinic-polycytidylic acid, and poly-L-lysine double-stranded RNA that has been extensively investigated in clinical trials and found to stimulate the release of type 1 cytokines and chemokines by dendritic cells, thereby increasing the tumoricidal activities of various immune effector cells via stimulation of TLR3 and MDA5 [55] (also see the National Cancer Institute website: http://www.cancer.gov/Templates/drugdictionary.aspx?CdrID=39559).

TLR3 is involved in the recognition of viral components, such as viral double-stranded (ds)RNA [56]. The CNS requires rapid, innate immune responses by resident brain cells to effectively fight infectious agents in the CNS. Recent studies have analyzed the expression and function of TLRs in microglia [57] and astrocytes 58, 59. In human astrocytes, TLR3 had the highest relative expression level among TLRs 1-10, whereas mouse and human microglia expressed mRNA for all of the recently identified TLRs [57]. It also has been noted that poly-IC is capable of efficiently inducing the production of proinflammatory cytokines, such as IFN-β, IL-6, and TNF-α, and chemokines, such as CCL2/MCP-1, CCL5/RANTES, CCL20/MIP-3α, and CXCL10/IP-10, from astrocytes and microglia 58, 59. These data demonstrate that stimulation of TLR3 pathway may be key for expanding and directing systemic immunity into the CNS.

Poly-ICLC has been extensively evaluated in patients with gliomas. In the first pilot study [60], 38 patients with malignant gliomas received i.m. injections of poly-ICLC. Minimal toxicity was associated with the treatment. Antitumor response was associated with activation of 2',5'-oligoadenylate synthetase (OAS), type 1 IFN-induced proteins with antiviral properties, suggesting a biological activity of this regimen in humans. Recently, the North American Brain Tumor Consortium (NABTC) sponsored 2 phase II trials of poly-ICLC. In one trial, 30 adults with newly diagnosed GBM received poly-ICLC in combination with, and after, radiation therapy (RT) [61]. The study suggested a survival advantage compared with historical studies using RT without chemotherapy, but no survival advantage compared with RT with adjuvant nitrosourea or non-temozolomide chemotherapy. However, the other phase II study failed to show clinical efficacy of poly-ICLC as monotherapy in 45 patients with recurrent GBM or anaplastic glioma (AG) compared with an historical database [62]. These 2 studies, based on the association of antitumor response with activation of 2',5'-OAS, suggest that better clinical outcomes may be achieved by using poly-ICLC in combination with other modalities, such as glioma vaccines.

Using mouse brain tumor models, we have demonstrated that i.m. administration of poly-ICLC enhances the effect of peripheral vaccinations with GAA-derived CTL epitopes [63]. Specifically, this combination strategy can promote induction of GAA-specific CTLs and survival of glioma-bearing mice without CNS autoimmunity, and CNS-tumor infiltration of GAA-specific CTLs expressing VLA-4, a critical homing receptor to CNS tumors [54].

Early-Phase Evaluation of Vaccinations Using Type-1 Polarizing DCs Loaded with GAA-Derived CTL Epitopes and Poly-ICLC In Patients with Recurrent Malignant Glioma 

Based on these inventions by our laboratory, we recently implemented a novel phase I/II vaccine trial designed to maximize the induction of type 1 anti-GAA CTL responses in patients with recurrent malignant glioma (UPCI 05-115). Patients with recurrent GBM or anaplastic glioma are vaccinated with 1-3 × 107 type 1 polarizing DCs (αDC1) [64] loaded with synthetic peptide encoding GAA-derived HLA-A2-binding CTL epitopes (EphA2 883-891, IL-13Rα2 345: 1A9V, YKL-40 201-210, and GP100 209-217:M2) once every 2 weeks (minimum 4 vaccinations) by ultrasound-guided injection into lymph nodes. These patients also receive i.m. injections of poly-ICLC twice a week (20 μg/kg). This study was designed to evaluate the safety (primary objective) and induction of anti-GAA immunity and clinical response (secondary objectives) of the regimen. αDC1s have been shown to be more potent than conventional DCs in induction of antigen-specific CTL responses [64].

To date, we have enrolled a total 21 patients and completed 4 scheduled vaccinations in 18 participants. No Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher adverse events were reported. None of the patients enrolled in this trial have demonstrated any clinical indices, radiologic signs, or laboratory data suggesting autoimmunity. Immune responses have been evaluated in participants who received at least 4 vaccinations, using ELISPOT and/or tetramer assays. These interim data demonstrate for the first time induction of specific reactivity against novel IL-13Rα2- and EphA2-derived epitopes in vaccine recipients. Interestingly, Fisher's exact test indicated an association between positive tetramer response and 6-month PFA (P = .040 [1-sided] and .048 [2-sided]), suggesting a possible correlation between tetramer-detected immune responses and clinical response.

Conclusion 

Several different immunotherapy strategies for treating CNS tumors are currently under investigation. CNS tumors pose multiple challenges that must be overcome for these therapies to be effective. Obstacles include the inability to obtain tumor tissue from many patients, the need for steroids to decrease swelling, and the inability of many large molecules to cross the blood-brain barrier. Several different approaches including those presented in this paper are being explored in order to overcome these obstacles. More work is needed to better understand how to increase the efficacy of these strategies and how best to incorporate them into the overall treatment plan for these patients.

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Acknowledgments 

Financial disclosure: Dr. Okada created a peptide used in his vaccine which has just been licensed with Stemline.

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 Financial disclosure: See Acknowledgments on page S79.

PII: S1083-8791(09)00520-5

doi:10.1016/j.bbmt.2009.11.003

Biology of Blood and Marrow Transplantation
Volume 16, Issue 1, Supplement , Pages S75-S81, January 2010

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