Cytotoxic T-Lymphocytes Reactive to Patient Major Histocompatibility Complex Proteins for Therapy of Brain Tumors

Kruse, Carol A.; Rubinstein, David

doi:10.1007/978-1-59259-035-3_7

Cited by 11 publications

(11 citation statements)

References 55 publications

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“…A unique form of adoptive T cell therapy for brain tumors involves the use of alloreactive cytotoxic T lymphocytes (alloCTL), potent cytotoxic T cell effectors that are trained to recognize non- or aberrant-self class I and II human leukocyte antigens (HLA). They are generated by sensitization of peripheral blood mononuclear cells (PBMC), isolated from a healthy donor, to the HLA of the tumor-bearing host (9–11). The HLA primarily acts as tumor-directed antigen in the brain, since its expression, especially Class I, is absent on normal neuroglia, i.e., neurons, oligodendrocytes, and astrocytes (12–14), but is highly expressed on brain tumor cells (13, 15–18).…”

Section: Introductionmentioning

confidence: 99%

Combined Alloreactive CTL Cellular Therapy with Prodrug Activator Gene Therapy in a Model of Breast Cancer Metastatic to the Brain

Hickey

Malone

Erickson

et al. 2013

Clinical Cancer Research

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Purpose Individual or combined strategies of cellular therapy with alloreactive cytotoxic T lymphocytes (alloCTL) and gene therapy employing retroviral replicating vectors (RRV) encoding a suicide prodrug activating gene were explored for the treatment of breast tumors metastatic to the brain. Experimental Design AlloCTL, sensitized to the human leukocyte antigens of MDA-MB-231 breast cancer cells, were examined in vitro for anti-tumor functionality toward breast cancer targets. RRV encoding the yeast cytosine deaminase (CD) gene was tested in vivo for virus spread, ability to infect, and kill breast cancer targets when exposed to 5-fluorocytosine (5-FC). Individual and combination treatments were tested in subcutaneous and intracranial xenograft models with 231BR, a brain tropic variant. Results AlloCTL preparations were cytotoxic, proliferated and produced interferon-gamma when coincubated with target cells displaying relevant HLA. In vivo, intratumorally-placed alloCTL trafficked through one established intracranial 231BR focus to another in contralateral brain and induced tumor cell apoptosis. RRV-CD efficiently spread in vivo, infected 231BR and induced their apoptosis upon 5-FC exposure. Subcutaneous tumor volumes were significantly reduced in alloCTL and/or gene therapy treated groups compared to control groups. Mice with established intracranial 231BR tumors treated with combined alloCTL and RRV-CD had a median survival of 97.5 days compared with single modalities (50–83 days); all experimental treatment groups survived significantly longer than sham-treated groups (median survivals 31.5 or 40 days) and exhibited good safety/toxicity profiles. Conclusion The results indicate combining cellular and suicide gene therapies is a viable strategy for the treatment of established breast tumors in the brain.

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Section: Introductionmentioning

confidence: 99%

Combined Alloreactive CTL Cellular Therapy with Prodrug Activator Gene Therapy in a Model of Breast Cancer Metastatic to the Brain

Hickey

Malone

Erickson

et al. 2013

Clinical Cancer Research

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“…Responses have been noted with patients given repeated, intratumoral administrations of allospecific cytotoxic T lymphocytes (CTL) generated to the patient's histocompatibility antigens [9,10].…”

Section: Introductionmentioning

confidence: 99%

Tumor antigen precursor protein profiles of adult and pediatric brain tumors identify potential targets for immunotherapy

et al. 2008

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Objectives-We evaluated and compared tumor antigen precursor protein (TAPP) profiles in adult and pediatric brain tumors of 31 genes related to tumor associated antigens (TAA) for possible use in immunotherapy. Antigens were selected based on their potential to stimulate T cell responses against tumors of neuroectodermal origin.Methods-Thirty-seven brain tumor specimens from 11 adult and 26 pediatric patients were analyzed by quantitative real-time PCR for the relative expression of 31 TAPP mRNAs. The age range of adults (4F:7M) was 27-77 years (median 51.5 ± 14.5 years) and for pediatrics (12F:14M) was 0.9-19 years (median 8.3 ± 5.5 years). Histological diagnoses consisted of 16 glioblastomas, 4 low grade astrocytomas, 10 juvenile pilocytic astrocytomas, and 7 ependymomas.Results-The adult gliomas expressed 94% (29 of 31) of the TAPP mRNAs evaluated compared with pediatric brain tumors that expressed 55-74% of the TAPP mRNAs, dependent on tumor histological subtype. Four types of TAPP expression patterns were observed: (1) equal expression among adult and pediatric cases, (2) greater expression in adult than pediatric cases, (3) expression restricted to adult GBM and (4) a random distribution. The pediatric brain tumors lacked expression of some genes associated with engendering tumor survival, such as hTert and Survivin.Conclusions-The potential TAA targets identified from the TAPP profiles of 31 genes associated with adult and pediatric brain tumors may help investigators select specific target antigens for developing dendritic cell-or peptide-based vaccines or T cell-based immunotherapeutic approaches against brain tumors.

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“…Clinical trials in cellular immunotherapy have shown some side effects, ranging from influenza-like symptoms [20] to autoimmune symptoms such as Vitligo and Uveitis [9]. The severity of the symptoms seems to be dose-dependent.…”

Section: Estimation Of the Time To Curementioning

confidence: 99%

“…These HGGs vary in life expectancy, but even with the best-known contemporary care survival does not exceed 1.5 years for GBM and 5 years for the less aggressive forms [15]. A novel cellular immunotherapy using alloreactive CTLs has been suggested [19,20]. The clinical trials showed considerably prolonged survival in some cases in grade III HGG, but were unsuccessful in GBM patients.…”

Section: Introductionmentioning

confidence: 99%

“…In [17] it was shown that HGG grade III and grade IV can be represented by assigning proper values to the parameter representing maximal tumor growth rate. The model successfully retrieved the results of the clinical trial by Kruse et al [19,20], which used donor CTL infusions for brain tumor patients. This model varies from the models studied in the aforementioned studies, by considering the mediator role of MHC receptors and by focusing on the specific type of brain tumors.…”

Section: Introductionmentioning

confidence: 99%

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Cellular Immunotherapy for High Grade Gliomas: Mathematical Analysis Deriving Efficacious Infusion Rates Based on Patient Requirements

Kogan¹,

Foryś²,

Shukron³

et al. 2010

SIAM J. Appl. Math.

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Abstract. To date, no effective cure has been found for high grade malignant glioma (HGG), current median survival for HGG patients under treatment ranging from 18 months (grade IV) to 5 years (grade III). Recently, T cell therapy for HGG has been suggested as a promising avenue for treating such resistant tumors, but clinical outcome has not been conclusive. For studying this new therapy option, a mathematical model for tumor-T cell interactions was developed, where tumor immune response was modeled by six coupled ordinary differential equations describing tumor cells, T cells, and their respective secreted cytokines and immune mediating receptors. Here we mathematically analyze the model in an untreated case and under T cell immunotherapy. For both settings we classify steady states, determine stability properties, and explore the global behavior of the model. Analysis suggests that in untreated patients, the system always converges to a steady state of a large tumor mass. An increase in the patient's pro-inflammatory activity only marginally reduces tumor load at steady state. This result suggests that the patient's own immune system is never sufficient for eliminating HGG. In contrast, infusion of T cells above a certain level, S min , renders a curative tumor-free steady state locally asymptotically stable. When the infusion rate is increased above a higher threshold, Smax, this steady state becomes globally stable, providing a cure from any initial state of the system. These thresholds, as well as the infusion time required for tumor elimination for different doses, are computed explicitly, and can be personalized using patient-specific parameters. Our results suggest that reduction of tumor load and even tumor elimination can be achieved, either by significantly encouraging the endogenous immune response or by T cell infusion. This work provides an insight and practical guidelines for improving the efficacy of brain cancer immunotherapy by T cell infusion, which should be further studied clinically.

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Cytotoxic T-Lymphocytes Reactive to Patient Major Histocompatibility Complex Proteins for Therapy of Brain Tumors

Cited by 11 publications

References 55 publications

Combined Alloreactive CTL Cellular Therapy with Prodrug Activator Gene Therapy in a Model of Breast Cancer Metastatic to the Brain

Combined Alloreactive CTL Cellular Therapy with Prodrug Activator Gene Therapy in a Model of Breast Cancer Metastatic to the Brain

Tumor antigen precursor protein profiles of adult and pediatric brain tumors identify potential targets for immunotherapy

Cellular Immunotherapy for High Grade Gliomas: Mathematical Analysis Deriving Efficacious Infusion Rates Based on Patient Requirements

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