Target mediated disposition of T84.66, a monoclonal anti-CEA antibody

Monoclonal antibodies (mAbs) as a class of novel oncology therapeutics are demonstrating clinical efficacy as measured by tumor response (shrinkage in tumor size), and prolongations in progression-free survival (PFS) and overall survival (OS). However, clinical benefits are often limited to when antibodies are used in combination with chemotherapy or radiation modalities, with tumor responses only seen in a fraction of patients, and improvements in PFS and OS are incremental (1). The potential of mAbs and mAb constructs has yet to be fully exploited for maximal clinical benefits. New approaches to further improve the effectiveness of these mAb therapies include (a) selection of patients who may derive the most benefit based on the molecular characteristics of their tumors; (b) improvements in biodistribution to maximize delivery of mAbs to susceptible tumor cells; and (c) optimization of antibody immune effector mechanisms such as antibody-dependent cellular cytotoxicity (ADCC).     

The role of radiation-induced apoptosis as a determinant of tumor responses to radiation therapy

Ionizing radiation is an effective means of killing tumor cells. Approximately 50% of all American cancer patients are treated with radiotherapy at some time during the course of their disease, making radiation one of the most widely used cytotoxic therapies. Currently, much effort is focused on understanding the molecular pathways that regulate tumor cell survival following radiotherapy, with the long term goal of developing novel therapeutic strategies for specifically sensitizing tumors to radiation. At present, there is particular interest in the role of tumor cell apoptotic potential as a regulator of both intrinsic and extrinsic determinants of the response of tumors to radiation therapy. Here we review what is currently known about the role of apoptosis as a mechanism of tumor cell killing by ionizing radiation and the relative contribution of apoptosis to cellular radiosensitivity and the ability to control human cancers using radiotherapy. The following topics will be discussed: (1) radiation-induced apoptosis in normal and malignant cells, (2) clinical findings with respect to apoptosis in human cancers treated with radiotherapy, (3) the contribution of apoptosis to intrinsic radiosensitivity in vitro, (4) the relevance of apoptosis to treatment outcome in experimental tumor models in vivo and (5) the potential of exploiting apoptosis as a means to improve the therapeutic efficacy of radiotherapy.     

Stereotactic Intracranial Implantation and In vivo Bioluminescent Imaging of Tumor Xenografts in a Mouse Model System of Glioblastoma Multiforme

Glioblastoma multiforme (GBM) is a high-grade primary brain cancer with a median survival of only 14.6 months in humans despite standard tri-modality treatment consisting of surgical resection, post-operative radiation therapy and temozolomide chemotherapy ¹. New therapeutic approaches are clearly needed to improve patient survival and quality of life. The development of more effective treatment strategies would be aided by animal models of GBM that recapitulate human disease yet allow serial imaging to monitor tumor growth and treatment response. In this paper, we describe our technique for the precise stereotactic implantation of bio-imageable GBM cancer cells into the brains of nude mice resulting in tumor xenografts that recapitulate key clinical features of GBM ². This method yields tumors that are reproducible and are located in precise anatomic locations while allowing in vivo bioluminescent imaging to serially monitor intracranial xenograft growth and response to treatments ^3-5. This method is also well-tolerated by the animals with low perioperative morbidity and mortality.     

Antibody drug-conjugates targeting the tumor vasculature

Reducing the blood supply of tumors is one modality to combat cancer. Monoclonal antibodies are now established as a key therapeutic approach for a range of diseases. Owing to the ability of antibodies to selectively target endothelial cells within the tumor vasculature, vascular targeting programs have become a mainstay in oncology drug development. However, the antitumor activity of single agent administration of conventional anti-angiogenic compounds is limited and the improvements in patient survival are most prominent in combinations with chemotherapy. Furthermore, prolonged treatment with conventional anti-angiogenic drugs is associated with toxicity and drug resistance. These circumstances provide a strong rationale for novel approaches to enhance the efficacy of mAbs targeting tumor vasculature such as antibody-drug conjugates (ADCs). Here, we review trends in the development of ADCs targeting tumor vasculature with the aim of informing future research and development of this class of therapeutics.     

Antibody drug-conjugates targeting the tumor vasculature: Current and future developments

Reducing the blood supply of tumors is one modality to combat cancer. Monoclonal antibodies are now established as a key therapeutic approach for a range of diseases. Owing to the ability of antibodies to selectively target endothelial cells within the tumor vasculature, vascular targeting programs have become a mainstay in oncology drug development. However, the antitumor activity of single agent administration of conventional anti-angiogenic compounds is limited and the improvements in patient survival are most prominent in combinations with chemotherapy. Furthermore, prolonged treatment with conventional anti-angiogenic drugs is associated with toxicity and drug resistance. These circumstances provide a strong rationale for novel approaches to enhance the efficacy of mAbs targeting tumor vasculature such as antibody-drug conjugates (ADCs). Here, we review trends in the development of ADCs targeting tumor vasculature with the aim of informing future research and development of this class of therapeutics.Key words: tumor, vasculature, immunotherapy, antibody-drug conjugates, monoclonal antibody, cancer, angiogenesis     

Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors

Effective cancer immunotherapy requires the release of a broad spectrum of tumor antigens in the context of potent immune activation. We show here that a cDNA library of normal tissue, expressed from a highly immunogenic viral platform, cures established tumors of the same histological type from which the cDNA library was derived. Immune escape occurred with suboptimal vaccination, but tumor cells that escaped the immune pressure were readily treated by second-line virus-based immunotherapy. This approach has several major advantages. Use of the cDNA library leads to presentation of a broad repertoire of (undefined) tumor-associated antigens, which reduces emergence of treatment-resistant variants and also permits rational, combined-modality approaches in the clinic. Finally, the viral vectors can be delivered systemically, without the need for tumor targeting, and are amenable to clinical-grade production. Therefore, virus-expressed cDNA libraries represent a novel paradigm for cancer treatment addressing many of the key issues that have undermined the efficacy of immuno- and virotherapy to date.     

A global perspective of radiation-induced signal transduction pathways in cancer therapeutics

Radiation is a well established therapeutic modality for the treatment of solid tumors. By merging molecular biological approaches with radiation biology, a significant number of signaling events elicited by ionizing radiation have been delineated. These signaling pathways include events leading to cell cycle arrest, apoptosis or cell survival. There are two major signaling events that affect radiation response. One is the intrinsic/constitutive pro-survival signaling event that is present in proliferating tumor cells while the other is "induced pro-survival event" in response to radiation, both of these events confer resistance to the killing effects of radiation. In this review, signaling pathways that lead to either apoptosis or survival of cells following ionizing radiation are discussed in detail. In addition, mechanisms of action for gene/drug based inhibitors that modulate the expression and function of various genes and gene products involved in pro-survival signaling pathways are described. Further, novel strategies to abrogate the "induced radiation resistance" leading to enhanced therapeutic efficacy of ionizing radiation have been proposed. These novel strategies include the use of radio-gene therapy, low dose fractionated radiation therapy as a chemopotentiator and therapeutic utility of high radiation dose induced bystander effect. The complete understanding of the molecular pathways leading to apoptosis/survival of cells following ionizing radiation will help in tailoring more effective novel strategies and treatment modalities for complete eradication of cancer.     

High-risk estrogen-receptor-positive breast cancer: identification and implications for therapy

The estrogen receptor (ER) has long been recognized as a key discriminative feature of breast cancer, which carries profound implications for management. However, recent advances in the understanding of breast cancer heterogeneity have demonstrated the importance of biologic context to the interpretation of ER as a prognostic and predictive factor. The use of tumor subtyping methods and prognostic indicators based on molecular profiling of tumor tissue is now helping to delineate high-risk ER-positive cancer types that have distinct risk and treatment response profiles. These new approaches to breast cancer classification will have a major impact on the conduct of clinical trials and individual patient assessment in the future.     

Cell- and peptide-based immunotherapeutic approaches for glioma

Glioblastoma multiforme (GBM) is the most common and lethal primary malignant brain tumor. Although considerable progress has been made in surgical and radiation treatment for glioma patients, the impact of these advances on clinical outcome has been disappointing. Therefore, the development of novel therapeutic approaches is essential. Recent reports demonstrate that systemic immunotherapy using dendritic cells (DCs) or peptide vaccines is capable of inducing an antiglioma response. These approaches successfully induce an antitumor immune response and prolong survival in patients with glioma without major side effects. There are several types of glioma, so to achieve effective therapy, it might be necessary to evaluate the molecular genetic abnormalities in individual patient tumors and design novel immunotherapeutic strategies based on the pharmacogenomic findings. Here, we review recent advances in DC- and peptide-based immunotherapy approaches for patients with gliomas.     

Manipulation of cellular redox parameters for improving therapeutic responses in B-cell lymphoma and multiple myeloma

Developing novel combined-modality therapeutic approaches based on understanding of the involvement of redox biology in apoptosis of malignant cells is a promising approach for improving clinical responses in B-cell lymphoma and multiple myeloma. Therapeutic modalities that generate reactive oxygen species (i.e., radiation, photodynamic therapy, and specific chemotherapeutic drugs) have been shown to be selectively cytotoxic to malignant B-cells. In this review, we will discuss agents that induce apoptosis in B-cell tumors by oxidative stress. Subsequently, a novel biochemical rationale (based on fundamental differences in cancer vs. normal cell oxidative metabolism) for combining oxidative stressors with radiotherapy and chemotherapy, that may lead to designing of more effective treatment strategies for B-cell malignancies, will be discussed. Besides providing potential curative benefit, such novel therapies could also selectively target and inhibit the emergence of drug-resistance in tumor cells, which is a major determinant of treatment failure in many B-cell malignancies.     

Angiogenesis in gynecological cancers and the options for anti-angiogenesis therapy

Angiogenesis is required in cancer, including gynecological cancers, for the growth of primary tumors and secondary metastases. Development of anti-angiogenesis therapy in gynecological cancers and improvement of its efficacy have been a major focus of fundamental and clinical research. However, survival benefits of current anti-angiogenic agents, such as bevacizumab, in patients with gynecological cancer, are modest. Therefore, a better understanding of angiogenesis and the tumor microenvironment in gynecological cancers is urgently needed to develop more effective anti-angiogenic therapies, either or not in combination with other therapeutic approaches. We describe the molecular aspects of (tumor) blood vessel formation and the tumor microenvironment and provide an extensive clinical overview of current anti-angiogenic therapies for gynecological cancers. We discuss the different phenotypes of angiogenic endothelial cells as potential therapeutic targets, strategies aimed at intervention in their metabolism, and approaches targeting their (inflammatory) tumor microenvironment.     

A pharmacogenomic method for individualized prediction of drug sensitivity

Identifying the best drug for each cancer patient requires an efficient individualized strategy. We present MATCH (M erging genomic and pharmacologic A nalyses for T herapy CH oice), an approach using public genomic resources and drug testing of fresh tumor samples to link drugs to patients. Valproic acid (VPA) is highlighted as a proof‐of‐principle. In order to predict specific tumor types with high probability of drug sensitivity, we create drug response signatures using publically available gene expression data and assess sensitivity in a data set of >40 cancer types. Next, we evaluate drug sensitivity in matched tumor and normal tissue and exclude cancer types that are no more sensitive than normal tissue. From these analyses, breast tumors are predicted to be sensitive to VPA. A meta‐analysis across breast cancer data sets shows that aggressive subtypes are most likely to be sensitive to VPA, but all subtypes have sensitive tumors. MATCH predictions correlate significantly with growth inhibition in cancer cell lines and three‐dimensional cultures of fresh tumor samples. MATCH accurately predicts reduction in tumor growth rate following VPA treatment in patient tumor xenografts. MATCH uses genomic analysis with in vitro testing of patient tumors to select optimal drug regimens before clinical trial initiation.     

Gene therapy for lung cancer

Lung cancer continues to be the largest killer of Americans due to cancer. Although progress has been made, with advances in chemotherapy, the majority of patients diagnosed with lung cancer ultimately succumb to the disease. A better understanding of the molecular pathogenesis of lung cancer is demonstrating how alterations in oncogenes and tumor suppressor genes control lung cancer initiation, growth, and survival. In this article, attempts to target molecular alterations in lung cancer using gene therapy techniques are reviewed. These include introducing suicide genes into tumor cells, replacement of defective tumor suppressor genes, inactivating oncogenes, and immunotherapy-based approaches using gene therapy technology. The major barrier for these techniques continues to be the inability to specifically target tumor cells while sparing normal cells. Nonetheless, these approaches are likely to yield important biologic and clinical data which will further the progress of lung cancer treatment.     

Therapeutic success of boron neutron capture therapy (BNCT) mediated by a chemically non-selective boron agent in an experimental model of oral cancer: a new paradigm in BNCT radiobiology

The hypothesis of boron neutron capture therapy (BNCT) research has been that the short-range, high-linear energy transfer radiation produced by the capture of thermal neutrons by (10)B will potentially control tumor and spare normal tissue only if the boron compound selectively targets tumor tissue within the treatment volume. In a previous in vivo study of low-dose BNCT mediated by GB-10 (Na(2)(10)B(10)H(10)) alone or combined with boronophenylalanine (BPA) in the hamster cheek pouch oral cancer model that was primarily designed to evaluate safety and feasibility, we showed therapeutic effects but no associated normal tissue radiotoxicity. In the present study, we evaluated the response of tumor, precancerous and normal tissue to high-dose BNCT mediated by GB-10 alone or combined with BPA. Despite the fact that GB-10 does not target hamster cheek pouch tumors selectively, GB-10-BNCT induced a 70% overall tumor response with no damage to normal tissue. (GB-10+BPA)-BNCT induced a 93% overall tumor response with no normal tissue radiotoxicity. Light microscope analysis showed that GB-10-BNCT selectively damages tumor blood vessels, sparing precancerous and normal tissue vessels. In this case, selective tumor lethality would thus result from selective blood vessel damage rather than from selective uptake of the boron compound.     

Targeting apoptosis by hydroxymethylacylfulvene in combination with gamma radiation in prostate tumor cells

Hydroxymethylacylfulvene (HMAF) is a novel agent with alkylating activity and is a potent inducer of apoptosis that is currently undergoing Phase II clinical trials for prostate cancer. This study explored the pro-apoptosis and anti-proliferative potential of HMAF in combination with gamma radiation in human prostate tumor cell lines. Apoptosis was assessed based on the generation of fragmented DNA, a terminal transferase flow cytometry assay, and cell morphology. In each of the tumor cell lines examined, radiation alone induced a marginal level of apoptosis, even after a prolonged 48-h incubation after exposure. In contrast, HMAF alone was a potent inducer of apoptosis in prostate tumor cells but not in normal cells. Marked levels of apoptosis in tumor cells were also observed for the combination of HMAF with gamma radiation. When drug treatment preceded irradiation, at least additive levels of apoptosis were observed in both androgen-responsive and androgen-independent cells. The combined treatment with ionizing radiation and HMAF reduced the radiation dose needed for the same level of clonogenic survival up to 2.5-fold. The potentiation of apoptosis and reduction in the clonogenic survival of tumor cells occurred at HMAF concentrations lower than that which reduced survival to 10% and at doses up to 6 Gy. No potentiation of apoptosis or clonogenic inhibition was noted in normal cells. These results suggest that the combination of HMAF with gamma radiation may have clinical utility for treatments of prostate cancer.     

How can we improve antibody-based cancer therapy?

Monoclonal antibodies (mAbs) as a class of novel oncology therapeutics are demonstrating clinical efficacy as measured by tumor response (shrinkage in tumor size), and prolongations in progression-free survival (PFS) and overall survival (OS). However, clinical benefits are often limited to when antibodies are used in combination with chemotherapy or radiation modalities, with tumor responses only seen in a fraction of patients, and improvements in PFS and OS are incremental.¹ The potential of mAbs and mAb constructs has yet to be fully exploited for maximal clinical benefit. New approaches to further improve the effectiveness of these mAb therapies include (1) selection of patients who may derive the most benefit based on the molecular characteristics of their tumors; (2) improvements in biodistribution to maximize delivery of mAbs to susceptible tumor cells; and (3) optimization of antibody immune effector mechanisms such as antibody-dependent cellular cytotoxicity (ADCC).Key words: monoclonal antibodies, solid tumors, cancer, pharmacogenomics, biodistribution, bioengineeringMonoclonal antibodies (mAbs) as a class of novel oncology therapeutics are demonstrating clinical efficacy as measured by tumor response (shrinkage in tumor size), and prolongations in progression-free survival (PFS) and overall survival (OS). However, clinical benefits are often limited to when antibodies are used in combination with chemotherapy or radiation modalities, with tumor responses only seen in a fraction of patients, and improvements in PFS and OS are incremental.¹ The potential of mAbs and mAb constructs has yet to be fully exploited for maximal clinical benefit. New approaches to further improve the effectiveness of these mAb therapies include (1) selection of patients who may derive the most benefit based on the molecular characteristics of their tumors; (2) improvements in biodistribution to maximize delivery of mAbs to susceptible tumor cells; and (3) optimization of antibody immune effector mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) (Fig. 1).Open in a separate windowFigure 1Efficacy of monoclonal antibodies may be improved by selecting responding patient subpopulations, improving biodistribution and delivery of antibody to the tumor and maximizing antibody-mediated immune responses through application of protein and glyco-engineering.     

Thyroid status is a key modulator of tumor oxygenation: implication for radiation therapy

In normal tissues, thyroid hormones play a major role in the metabolic activity and oxygen consumption of cells. Because the rate of oxygen consumption is a key factor in the response of tumors to radiation, we hypothesized that thyroid hormones may affect the metabolic activity of tumor cells and hence modulate the response to cytotoxic treatments. We measured the influence of thyroid status on the tumor microenvironment in experimental tumors. Hypothyroidism and hyperthyroidism were generated in mice by chronic treatment with propyl thiouracil and l-thyroxine. Thyroid status significantly modified tumor pO(2) as measured with EPR oximetry. Mechanistically, this was the result of the profound changes in oxygen consumption rates. Thyroid status was associated with a significant change in tumor radiosensitivity since the regrowth delay was increased in hypothyroid mice compared to euthyroid mice, an effect that was abolished when temporarily clamped tumors were irradiated. This study provides unique insights into the impact of modulating tumor oxygen consumption and could have implications in the management of cancer patients with thyroid disorders.