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Basic and Translational Investigations |
Gene Therapeutics Research Institute, Cedars Sinai Medical Center, and Departments of Molecular and Medical Pharmacology, and Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
Address correspondence to Maria G. Castro, Gene Therapeutics Research Institute, Cedars-Sinai Medical Center and the Departments of Molecular and Medical Pharmacology, UCLA, 8700 Beverly Blvd., Davis Building 5090, Los Angeles, CA 90048, USA (castromg{at}cshs.org).
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionGReferences |
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Key Words: Flt3L • glioblastoma • HSV1-TK • immunotherapy • multiple tumor
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Introduction |
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Immunotherapy is another promising approach for treating disseminated GBM in human patients. Several immunotherapeutic approaches have used tumor vaccines to stimulate a highly specific and targeted immune response directed against tumor-specific antigens. These approaches require the recruitment and activation of antigen-presenting cells (APCs) within the tumor mass.11 Since dendritic cells (DCs) are the most efficient APCs,12,13 many preclinical and clinical trials employ DCs loaded with tumor lysates or specific tumor antigens14-18 to induce an immunotherapeutic antitumor effect.
Flt3L (human soluble FMS-like tyrosine kinase 3 ligand) stimulates maturation and proliferation of DCs19-21 and natural killer (NK) cells.22 Treatment of solid tumors with recombinant Flt3L protein slows disease progression in models of breast cancer and leukemia and decreases the number of metastases in models of colon adenocarcinoma, sarcoma, and melanoma.23-25 Also, in sarcoma models, the administration of recombinant Flt3L protein induces significant tumor regression and immunological memory.26-28 However, Flt3L recombinant protein has not been efficacious in the treatment of sarcoma and melanoma tumors when implanted in the brain.23 This has been attributed to the dose, short half-life, or distribution of the cytokine, as well as to tumor antigen availability.
We have recently demonstrated that injection of an adenoviral (Ad) vector expressing Flt3L (AdFlt3L) into the brain of rats induces a specific increase in the number of interferon alpha (IFN
)-secreting plasmacytoid dendritic cells (pDCs) within the parenchyma.19 In a syngeneic intracranial glioma model in rats, we found that AdFlt3L improves survival when tumors are treated within 3 days of tumor implantation.29 However, the efficacy of this treatment inversely correlates to tumor volume. Thus, we combined AdFlt3L with an Ad vector expressing herpes simplex virus type 1-thymidine kinase (AdTK), which prolonged survival in more than 70% of treated animals by inducing an antitumor immune response.30 In this experimental paradigm, TK in the presence of the prodrug ganciclovir (GCV) kills glioma cells,31,32 inducing the release of antigens that can be taken up by Flt3L-recruited DCs.
Although preclinical models of GBM share many pathological features with human GBM,33 they do not fully mimic the disseminated nature of the human disease. In this study, we aimed to determine whether the antitumor response generated by combined treatment with AdFlt3L and AdTK would be effective in a multifocal intracranial GBM model in rat. Thus, we implanted CNS-1 rat glioma cells bilaterally in both brain hemispheres and administered AdFlt3L combined with AdTK unilaterally, leaving the second tumor untreated. The results of this study demonstrates that the antitumor response generated by AdFlt3L and AdTK is effective at eliminating both the primary treated and the secondary, distant untreated tumor. Our results suggest that this gene therapeutic approach would be effective in eliminating glioma cells that disseminate from the main tumor mass throughout the normal brain parenchyma, and support further development of TK in combination with Flt3L for translation into a phase I clinical trial.
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Materials and Methods |
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Syngeneic Intracranial Rat Tumor Models
Intracranial GBM model; single tumor mass. Male Lewis rats (220-250 g; Harlan, Indianapolis, IN, USA) were unilaterally injected into the striatum (+1 mm bregma, +3 mm lateral, and -4 mm from the dura) with 5,000 CNS-1 cells stably transfected with firefly luciferase. Ten days later, utilizing the same drill hole, saline, taAdflt3L and AdTK (5 x 107 IU each) were delivered within the tumor mass using the same coordinates as those used for implantation of CNS-1 cells. Twenty-four hours after delivery of viral vectors, animals that received AdTK began treatment with GCV (25 mg/kg, intraperitoneal [IP] injection), twice daily for 7 days. Animals were monitored daily and euthanized at the first signs of moribund behavior or at predetermined time points for neuropathological analysis and ELISA. Euthanasia was conducted under deep anesthesia by terminal perfusion. Animals were housed in a humidity- and temperature-controlled vivarium on a 12-h light/12-h dark cycle (lights on 07:00) with free access to food and water. All experimental procedures were carried out in accordance with the NIH Guide for the Care and Use of Laboratory Animals.
Multifocal tumor models. Rats were injected with 5,000 CNS-1 cells followed 10 days later by intratumoral injection of either saline or AdFlt3L and AdTK (5 x 107 IU each). Following saline or AdFlt3L and AdTK injection, 5,000 CNS-1 cells were injected into the contralateral striatum. Twenty-four hours later, animals were treated with GCV (25 mg/kg, IP) twice daily for 7 days. In the second multifocal GBM model used, animals were injected at the same time with 5,000 CNS-1 cells bilaterally, followed 4 days later by unilateral, intratumoral injection of saline or AdFlt3L and AdTK (5 x 107 IU each). Twenty-four hours later, all animals were treated with GCV (25 mg/kg, IP) twice daily for 7 days. Animals were monitored daily and euthanized at the first signs of moribund behavior or at day 4, 9, or 45 for neuropathological analysis. Results shown are representative of two independent experiments.
Human Soluble Flt3L ELISA
Human soluble Flt3L was assessed within homogenized tumor or striatal extracts taken day 15 or 22 after tumor cell implantation and from serum collected prior to perfusion (n = 4-10/group). Samples were measured utilizing a specific human soluble Flt3L ELISA system (R&D Systems, Minneapolis, MN, USA) following the manufacturer's instructions.19,29,31
Immunocytochemistry
Following perfusion, brains to be used for immunocytochemistry (ICC) were fixed in 4% paraformaldehyde (n = 4/group). Sixty-micrometer serial coronal sections were cut through the striatum. Free-floating ICC was performed to detect inflammatory and immune cell markers. Briefly, endogenous peroxidases were inactivated with 0.3% hydrogen peroxide, followed by blocking in 10% horse serum/phosphate-buffered saline. Sections were incubated overnight with primary antibody: anti-CD68 (clone ED1 to identify macrophages/activated microglia; 1:1,000), anti-major histocompatibility complex II (anti-MHC II; to identify immune cells; 1:1,000), and anti-CD8 (to identify cytotoxic T cells; 1:1,000), obtained from Serotec (Raleigh, NC, USA). Antivimentin (1:1,000; Sigma, St. Louis, MO, USA) was used to detect CNS-1 cells. To assess brain neuropathology, myelin basic protein (MBP; 1:1,000; Chemicon, Billerica, MA, USA) and tyrosine hydroxylase (TH; 1:1,000; Calbiochem, San Diego, CA, USA) immunoreactivity was evaluated. Binding of biotinylated secondary antibody against either mouse or rabbit immunoglobulins (1:1,000; Jackson Immunochemicals, West Grove, PA, USA) was detected using the Vectastain Elite ABC horseradish peroxidase method (Vector Laboratories, Burlingame, CA, USA). After developing with diaminobenzidine and glucose oxidase, sections were mounted on gelatinized glass slides and dehydrated through graded ethanol solutions. Tissues were analyzed and photographed using a Carl Zeiss Optical Axioplan microscope (Carl Zeiss, Chester, VA, USA).
Nissl staining was used to determine the histopathological features of the brains. Brain sections were mounted and incubated in cresyl violet (0.1%; Sigma). Sections were passed through destain solution (70% ethanol, 10% acetic acid) and dehydrated (100% ethanol and xylene). Sections were analyzed and photographed using a Zeiss Axioplan microscope.
Ad-expressed transgenes were detected utilizing custom-generated rabbit antibodies specific to TK35,44,45 or human soluble Flt3L19,30,31,44 (developed in rabbit; 1:1,000) combined with the mouse antivimentin antibody. Alexa 488 directly conjugated fluorescent secondary antibodies (1:1,000) were used to detect transgenes (Invitrogen, Carlsbad, CA, USA). Sections were mounted with ProLong Antifade mounting media (Invitrogen, Carlsbad, CA, USA).
Confocal Microscopy
Confocal micrographs were obtained using a Leica TCS SP2 confocal microscope with an acousto-optical beam splitter, equipped with a 405-nm violet diode ultraviolet laser, 488-nm argon laser, and 594- and 633-nm helium-neon lasers and using an HCX PL APO x 63 1.4 numerical-aperture oil objective (Leica Microsystems Heidelberg, Mannheim, Germany).
Statistical Analysis
Statistical analyses were performed using Graphpad Prism (version 3.03; Graphpad Software, San Diego, CA, USA). Flt3L ELISA measurements were compared by one-way analysis of variance tests followed by the Bonferroni multiple comparison test. Survival curves were compared using the Mantel-Haenszel log-rank test; p < 0.05 was considered significant. All experiments were performed at least twice.
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Flt3L and TK Expression within the Intracranial GBM Mass: Widespread Therapeutic Gene Expression within the Tumor and Levels of Flt3L in the Peripheral Circulation
Animals implanted with CNS-1 glioma cells succumb to tumors within 3 weeks if AdFlt3L and AdTK treatment does not eradicate the tumor.29,30 Flt3L and TK delivered by Ad vectors are hypothesized to induce high levels of tumor regression by infecting CNS-1 cells and inducing a systemic antitumor immune response.30 Male Lewis rats were unilaterally implanted with 5,000 syngeneic CNS-1 glioma cells into the striatum. Ten days later saline, Ad 0 (control virus expressing no transgene), or AdFlt3L and AdTK were intratumorally delivered, followed by the administration of GCV twice daily for 1 week. Animals either were euthanized at day 15 and day 22 postimplantation for analysis of transgene expression and tumor regression or were evaluated for long-term survival (Fig. 1B). At day 15 after tumor implantation, untreated animals began to succumb to tumors. At day 22, after the cessation of GCV, tumor regression, if successful, had been fully initiated.
Neither saline nor Ad 0 treatment induced detectable levels of human soluble Flt3L in CNS or serum (Fig. 1C,D). At both time points, animals treated with AdFlt3L and AdTK showed high levels of Flt3L, detectable both locally in the CNS (Fig. 1C) and in the peripheral circulation in serum (Fig. 1D). Brain levels of Flt3L expression diminished between day 15 and day 22 (Fig. 1C; p < 0.05), as the tumor regressed.
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Combined GBM Treatment with AdFlt3L and AdTK: Tumor Regression, Neuropathology, and Immune Infiltrates
To assess tumor progression in control and AdFlt3L/AdTK-treated animals, neuropathological analysis was conducted at days 15 and 22 after CNS-1 cell implantation and in long-term survivors at days 60 and 240 postimplantation. Vimentin staining clearly delineated the tumor area encompassing most of the left striatum in saline- or Ad 0-treated tumors at day 15 (Fig. 2A,B). Conversely, vimentin staining at day 15 in AdFlt3L/AdTK-treated animals showed a smaller tumor mass that was absent by day 22 and was likewise not detectable 60 or 240 days after GBM implantation (Fig. 2A,B). Treated tumor-bearing animals euthanized at days 22, 60, and 240 after CNS-1 cell implantation showed vimentin staining consistent with reactive astrocytes, not CNS-1 tumor growth, both at the injection site and in adjacent areas (Fig. 2A). Positive vimentin staining for reactive astrocytes was limited to the ipsilateral hemisphere and corpus callosum, as shown in higher magnification images of treated animals euthanized 60 days after tumor implantation (Fig. 2B).
In the presence of a lesion, astrocytes become activated, up-regulating synthesis of a number of structural proteins, such as glial fibrillary acidic protein and vimentin.52,53 Up-regulation of vimentin expression indicates the existence of astrocyte hypertrophy and gliosis, which is a typical response to a brain lesion.54 CNS-1 tumors, regardless of the treatment modality, are heavily infiltrated with immune cells (MHC II, Fig. 2C) absent from the normal brain parenchyma. Notably, CNS-1 tumors are highly infiltrated with macrophages/activated microglia (CD68, Fig. 2C). Both CD68- and MHC II-immunoreactive cells decreased by day 22 in AdFlt3L/AdTK-treated animals, indicating a gradual decrease in immune cell infiltration as tumor regression occurred (Fig. 2C).
Elimination of Multifocal Disease by Combined Flt3L and TK Expression
Considering that human glioblastoma is a disseminated disease, we aimed to test whether AdFlt3L and AdTK administration within a large single tumor mass would induce an effective antitumor response that would eliminate tumor cells located at a distant site in relation to the primary treated tumor. Thus, we determined whether AdFlt3L and AdTK would be effective in eliminating tumor cells implanted at the contralateral hemisphere from the primary treated lesion in a multifocal glioma model. CNS-1 cells were implanted into the striatum, followed 10 days later with injection of either saline or AdFlt3L and AdTK into the primary tumor mass. A second tumor was implanted in the contralateral hemisphere (Fig. 3A) on the same day the treatment was delivered to the primary tumor. As a control for treatment efficacy, single tumors were implanted and treated 10 days later with either saline or AdFlt3L and AdTK to evaluate long-term survival and therapeutic efficacy. All saline-treated animals implanted with either single or multifocal GBMs succumbed to tumors by day 22 (Fig. 3B) and showed tumors in one or both hemispheres, respectively. Approximately 50% of animals bearing multifocal GBM treated with AdFlt3L and AdTK survived to 60 days (Fig. 3B), and we observed >70% long-term survival of the animals bearing a single GBM mass treated with AdFlt3L and AdTK (Fig. 3B). Both treatments were statistically different from the saline-treated control group (p < 0.05). No significant difference in survival was found between unifocal and multifocal GBM-bearing animals treated with AdFlt3L and AdTK.
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Untreated multifocal tumors were evaluated on the day of treatment (day 10) for the presence of primary and secondary tumor masses (Fig. 4A) and for tumor appearance and tumor-infiltrating immune cell markers (Fig. 4B,C). Both primary (Fig. 4B) and secondary tumors (Fig. 4C) were readily visible by Nissl and vimentin staining. They were profusely infiltrated with immune cells (Fig. 4B,C), as determined by MHC II staining, some of which were macrophages/activated microglia (CD68, Fig. 4B,C).
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To evaluate tumor regression and immune cell infiltration into the tumor mass in control and AdFlt3L/AdTK-treated animals, groups of animals were euthanized 5 days after treatment, on day 9 after GBM implantation (Fig. 7A,B). In all saline-treated animals examined, large tumors were evident in both hemispheres (Fig. 7A). Although tumors were evident in AdFlt3L/AdTK-treated animals 5 days after treatment, they were much smaller than in the saline-treated animals (Fig. 7B). In all tumors, immune infiltration was detected by ICC using specific antibodies for macrophages/activated microglia (CD68), T cells (CD8), and APCs (MHC II) (Fig. 7A,B). Animals treated with AdFlt3L and AdTK and surviving to day 45 after GBM implantation were similarly evaluated for neuropathology and immune cell infiltration. Nissl staining revealed a scar at the injection site in both hemispheres and ventriculomegaly with no other gross alterations to the brain parenchyma (Fig. 7C). While CD68, MHC II, and CD8 were detected in both hemispheres as at earlier time points during the tumor regression process (Fig. 7B), immune infiltration was limited to the area immediate to the injection site 45 days after tumor implantation (Fig. 7C).
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We previously demonstrated that alterations to the local brain tumor microenvironment by TK-mediated tumor cell killing and Flt3L-induced recruitment of antitumor macrophages and CD4 cells30 are critical to mounting an effective antitumor response. In the CNS-1 syngeneic intracranial tumor model of glioma, untreated or saline-treated animals begin to succumb to tumor as early as 15 days after tumor implantation.29,30,35 Animals succumb to the disease because of compression of the brainstem caused by the growing tumor. When the combination of AdFlt3L and AdTK is used to treat intracranial syngeneic GBM in Lewis rats, the efficacy of the treatment decreases with increased tumor burden. If a single large tumor is treated 6 days postimplantation, 100% of the animals survive up to 2 months; if treatment is delivered 10 days postimplantation, the treatment rescues around 70% of the tumor-bearing rats.30 By implanting a second tumor on day 10 postimplantation and delivering the therapeutic vectors only into the original tumor, we have increased tumor burden at the time of treatment, which could reduce treatment efficacy. Also, the host immune system plays a critical role in eliminating the tumor, establishing a battle between activating an effective antitumor immune response and tumor progression.30
Our treatment is effective in approximately 80% of the treated, multifocal GBM-bearing animals in which both tumors were implanted at the same time and only one tumor mass was treated 4 days after tumor implantation. In the multifocal tumor model in which the secondary tumor was implanted 10 days after implantation of the primary tumor and at the time of treatment, the efficacy of the combined therapy is approximately 50%. The delayed death of some of the tumor-bearing, treated animals attests to the effects of the combined therapy in inducing a delay in tumor growth. This is a result of individual variability in the therapeutic responses, as was observed by us and other groups implementing anti-GBM therapies in vivo.29,30,59-64
Elimination of secondary untreated tumors located in a different area of the brain could have relevance for a wider application of AdFlt3L and AdTK in brain cancer treatment. Our results could have implications for leptomeningeal tumors and tumors metastasizing to the brain from primary lung, breast, and melanoma cancers,65-67 as well as tumors that often disseminate through the cerebrospinal fluid (CSF), such as those seen in pediatric medulloblastoma.68 Novel strategies for these cancers have utilized replication-deficient adenovirus,69,70 replication-competent reovirus,68,71 herpes simplex virus,6-10,72 and immunotoxin73 approaches to slow but not eliminate tumor growth at therapeutically efficacious levels. Only the use of a replication-competent herpes simplex virus vector resulted in long-term survival in a 9L model of disseminated glioma.8,9 Similar effects have been observed in multifocal tumor models outside of the CNS, including models of melanoma, colorectal carcinoma, prostate cancer, and gallbladder carcinoma, where treatment with replication-competent herpes simplex virus resulted in an antitumor immune response to eliminate tumors never directly transduced by virus.74-77
Multifocal brain tumor models are preclinically useful in at least two contexts: to develop novel treatments that address the disseminated nature of gliomas,6-9,78 and to treat metastatic brain tumors.10 The majority of studies to date have utilized oncolytic replication-competent herpes simplex virus vectors to target multiple tumor foci in the brain6,7,10 or the brain and CSF.8,9,78 In models of disseminated disease, treatment using intraarterial delivery of oncolytic viruses is more effective in short-term immunosuppressive environments where innate immune responses to virus have been disabled.6,7,10 We have demonstrated that the antitumor effects mediated by expression of Flt3L in combination with TK plus GCV30 within the intracranial brain tumor is able to eliminate a distant tumor mass and prolong the survival of the tumor-bearing immune-competent rodents.
Regardless of tumor treatment, CNS-1 tumors such as human GBMs are highly infiltrated with macrophages. AdFlt3L/AdTK-mediated tumor regression requires both macrophages and CD4 cells.30 Whether the macrophages critical for tumor elimination are new infiltrating cells or are resident cells that shift phenotypically depending on the microenvironment of the tumor remains to be determined. The high levels of survival with AdFlt3L and AdTK suggest a synergy between altered microenvironment and systemic immune activation that eliminates the tumor. While AdTK alone has been shown to trigger immune activation preclinically,79-83 in clinical trials the strength of AdTK alone was insufficient to provide more than modest survival improvements.55,57 AdFlt3L alone has been shown to induce influx of IFN-secreting plasmacytoid DCs into the brain19 and improves survival in small brain tumor models.29 The combination therapy of AdFlt3L with AdTK is effective against large, intracranial syngeneic GBMs,30 providing very long-term survival. Importantly, long-term survivors do not exhibit any noticeable neuropathological changes beyond ventriculomegaly. We conclude that this ventriculomegaly would be a consequence of tumor regression in response to the treatment rather than induced by the combined Ad delivery and therapeutic transgene expression, since non-tumor-bearing animals receiving AdFlt3L and AdTK and treated with GCV did not exhibit any structural or neuropathological changes. This indicates that this treatment, which upon GCV administration induces death only of actively dividing cells, does not induce damage to the normal brain parenchyma.
In summary, we have demonstrated that treatment with AdFlt3L and AdTK/GCV can induce tumor regression of the primary, treated tumor mass and also of tumor foci growing at distant sites in the contralateral hemisphere without any long-term neuropathological adverse side effects. These results suggest that this gene therapeutic approach would be effective in eliminating cells that disseminate from the main tumor mass throughout the normal brain parenchyma, and provide a strong rationale for further developing these therapeutic targets in order to implement this approach in a phase I clinical trial for GBM.
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Acknowledgments |
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Received for publication July 19, 2006. Accepted for publication February 26, 2007.
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