Antiglioma Immunological Memory in Response to Conditional Cytotoxic/Immune-Stimulatory Gene Therapy: Humoral and Cellular Immunity Lead to Tumor Regression

Muhammad, A.K.M. Ghulam; Candolfi, Marianela; King, Gwendalyn D.; Yagiz, Kader; Foulad, David; Mineharu, Yohei; Kroeger, Kurt M.; Treuer, Katherine A.; Nichols, W. Stephen; Sanderson, Nicholas; Yang, Jieping; Khayznikov, Maksim; Rooijen, Nico van; Löwenstein, Pedro R.; Castro, María G.

doi:10.1158/1078-0432.ccr-09-1087

Cited by 63 publications

(42 citation statements)

References 48 publications

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“…Several clinical trials for GMB using DC vaccines have demonstrated cellular and humoral anti-tumor immune responses; and albeit safe, the clinical efficacy of DC vaccination for GBM remains limited (3, 5–10). Our group has shown that i n situ Ad-Flt3L/TK-mediated immunogene therapy elicits an influx of DCs, macrophages, CD4+ T cells, and CD8+ T cells into the brain tumor microenvironment (17) and stimulates effective anti-GBM immune response resulting in tumor regression and long-lasting CD8+ T cell mediated anti-tumor immunological memory in several mouse and rat orthotopic brain tumor models (16, 18, 22–24, 29). Based on these data, a Phase I clinical trial for GBM was recently cleared by the FDA and is slated to commence in 2011.…”

Section: Discussionmentioning

confidence: 99%

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Engineering the Brain Tumor Microenvironment Enhances the Efficacy of Dendritic Cell Vaccination: Implications for Clinical Trial Design

Mineharu

King

Muhammad

et al. 2011

Clinical Cancer Research

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Purpose Glioblastoma multiforme (GBM) is a deadly primary brain tumor. Clinical trials for GBM using dendritic cell (DC) vaccination resulted in anti-tumor immune responses. Herein we tested the hypothesis that combining in situ (intratumoral) Ad-Flt3L/Ad-TK-mediated gene therapy with DC vaccination would increase therapeutic efficacy and anti-tumor immunity. Experimental Design We first assessed the immunogenicity of tumor lysates generated by Ad-TK (+GCV), temozolomide (TMZ) or freeze/thawing cycles (FTC) in a syngeneic brain tumor model. We also assessed phenotypic markers, cytokine release, and phagocytosis of bone marrow derived DCs generated by fms-like tyrosine kinase 3 ligand (Flt3L) + IL-6 or by granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4. Inhibition of tumor progression and production of anti-GBM antibodies was assessed following vaccination with (i) tumor cell lysates, (ii) DCs generated with either Flt3L/IL6 or GM-CSF/IL4 loaded with either Ad-TK/GCV, TMZ, or FTC generated tumor lysates, or (iii) DCs in combination with in situ Ad-Flt3L/Ad-TK gene therapy. Results DCs loaded with tumor cell lysates generated with either Ad-TK/GCV or TMZ led to increased levels of phagocytosis, therapeutic efficacy and humoral immune response. In situ immunogene therapy in combination with DC vaccination led to brain tumor regression and long-term survival in ~90% of animals, a significant increase when compared to either therapy alone. Conclusions Our results indicate that modifying the tumor microenvironment using intra-tumoral Ad-Flt3L/Ad-TK-mediated gene therapy potentiates therapeutic efficacy and anti-tumor immunity induced by DC vaccination. These data support novel Phase I clinical trials to assess the safety and efficacy of this combined approach.

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Section: Discussionmentioning

confidence: 99%

“…Serum levels of anti-CNS1 antibodies were measured by flow cytometry, described previously (29) and in Supplemental Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

Engineering the Brain Tumor Microenvironment Enhances the Efficacy of Dendritic Cell Vaccination: Implications for Clinical Trial Design

Mineharu

King

Muhammad

et al. 2011

Clinical Cancer Research

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“…There are a variety of viral-based anti-cancer approaches being explored today for GBM, ranging from immune-targeting antigen-delivery systems (59–61) to tumor-targeting suicide gene delivery vectors (62) to directly oncolytic viruses (63–65). The latter two strategies classically employ viruses with specific tissue predilections, with the neural preferences for herpes and polioviruses creating roles in glioma (reviewed in (66)).…”

Section: Clinical Applications: Immunotherapeutic Approaches To Gbmmentioning

confidence: 99%

Immunotherapy for Primary Brain Tumors: No Longer a Matter of Privilege

Fecci

Heimberger

Sampson

2014

Clinical Cancer Research

102

106

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Immunotherapy for cancer continues to gain both momentum and legitimacy as a rational mode of therapy and a vital treatment component in the emerging era of personalized medicine. Gliomas, and their most malignant form, glioblastoma, remain as a particularly devastating solid tumor whose standard treatment options proffer only modest efficacy and target specificity. Immunotherapy would seem a well-suited choice to address such deficiencies given both the modest inherent immunogenicity of gliomas and the strong desire for treatment specificity within the confines of the toxicity-averse normal brain. This review highlights the caveats and challenges to immunotherapy for primary brain tumors, as well as reviews modalities that have been currently employed or are undergoing active investigation. Tumor immunosuppressive counter measures, peculiarities of CNS immune access, and opportunities for rational treatment design are discussed.

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“…RG2 cells (20,000 in 3 µl DMEM) were stereotactically implanted in the right striatum of syngeneic Fisher rats (220–250 g; Harlan Laboratories Inc.) at the coordinates of 1.0 mm anterior and 3.2 mm lateral from the bregma and 6.0 mm ventral from the dura as previously described (16, 31). GL26 cells expressing ovalbumin were prepared as before (32).…”

Section: Methodsmentioning

confidence: 99%

Blockade of mTOR Signaling via Rapamycin Combined with Immunotherapy Augments Antiglioma Cytotoxic and Memory T-Cell Functions

Mineharu

Kamran

Löwenstein

et al. 2014

Molecular Cancer Therapeutics

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The success of immunotherapeutic approaches targeting Glioblastomamultiforme demand a robust anti-glioma T cell cytotoxic and memory response. Recent evidence suggests that Rapamycin regulates T cell differentiation. Herein, we tested whether administration of Rapamycin could enhance the efficacy of immunotherapy utilizing Fms-like tyrosine kinase 3 ligand (Ad-Flt3L) and Thymidine kinase/Ganciclovir (Ad-TK/GCV). Using the refractory rat RG2 glioma model, we demonstrate that administration of Rapamycin with Ad-Flt3L + Ad-TK/GCV immunotherapy enhanced the cytotoxic activity of anti-tumor CD8+ T cells. Rats treated with Rapamycin + Ad-Flt3L + Ad-TK/GCV exhibited massive reduction in the tumor volume and extended survival. Rapamycin administration also prolonged the survival of Ad-Flt3L + Ad-TK/GCV treated GL26 tumor bearing mice, associated with an increase in the frequency of tumor-specific and IFN-γ+ CD8+ T cells. More importantly, Rapamycin administration even for a short interval elicited a potent long-lasting central memory CD8+ T cell response. The enhanced memory response translated to an increased frequency of tumor-specific CD8+ T cells within the tumor and IFN-γ release, providing the mice with long-term survival advantage in response to tumor rechallenge. Our data therefore points to Rapamycin as an attractive adjuvant to be used in combination with immunotherapy in a Phase I clinical trial for GBM.

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Antiglioma Immunological Memory in Response to Conditional Cytotoxic/Immune-Stimulatory Gene Therapy: Humoral and Cellular Immunity Lead to Tumor Regression

Cited by 63 publications

References 48 publications

Engineering the Brain Tumor Microenvironment Enhances the Efficacy of Dendritic Cell Vaccination: Implications for Clinical Trial Design

Engineering the Brain Tumor Microenvironment Enhances the Efficacy of Dendritic Cell Vaccination: Implications for Clinical Trial Design

Immunotherapy for Primary Brain Tumors: No Longer a Matter of Privilege

Blockade of mTOR Signaling via Rapamycin Combined with Immunotherapy Augments Antiglioma Cytotoxic and Memory T-Cell Functions

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