Recent Advances in Cancer Research and Therapy

Xin-Yuan Liu, Sidney Pestka, Yu-Fang Shi, Yu-fang Shi

• Publisher: Elsevier
• Year: 2012
• eBook ISBN: 9780123978363
• Topic: Medicine
• Subtopic: Epidemiology

Cancer continues to be one of the major causes of death throughout the developed world, which has led to increased research on effective treatments. Because of this, in the past decade, rapid progress in the field of cancer treatment has been seen. Recent Advances in Cancer Research and Therapy reviews in specific details some of the most effective and promising treatments developed in research centers worldwide. While referencing advances in traditional therapies and treatments such as chemotherapy, this book also highlights advances in biotherapy including research using Interferon and Super Interferon, HecI based and liposome based therapy, gene therapy, and p53 based cancer therapy. There is also a discussion of current cancer research in China including traditional Chinese medicine. Written by leading scientists in the field, this book provides an essential insight into the current state of cancer therapy and treatment. - Includes a wide range of research areas including a focus on biotherapy and the development of novel cancer therapeutic strategies. - Formatted for a broad audience including all working in researching cancer treatments and therapies. - Discusses special traits and results of Chinese cancer research.

1

Cancer Biotherapy

Progress in China

Zhen-Yu Ding and Yu-Quan Wei*

Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, People’s Republic of China

1.1 Introduction

Public health problems in China have never been so seriously considered as they are today. Acquired immune deficiency syndrome (AIDS), SARS, avian flu, and swine flu (H1N1) have all posed great threats to the nation. However, the most critical public health problem still comes from chronic (noncontagious) diseases, including cancer, cardiovascular disease, and diabetes mellitus. A report from the World Health Organization (WHO) warned that chronic diseases were becoming the most lethal “killer” of people worldwide. Due to the deterioration of the environment and widely prevalent but uncontrolled smoking, the morbidity of cancer is still on a rapid rise. A retrospective survey that investigated the cause of death in citizens from both urban and rural areas was conducted by the Ministry of Health in 2008. This survey reported that the mortality associated with malignancy increased eightfold over the past three decades. Cancer moved ahead of respiratory disease to become the most deadly disease for rural citizens, while it is the number two killer of people in urban districts (http://61.49.18.102/newshtml/21698.htm).

Cancer has emerged as a great burden for the Chinese health care system. Liver cancer (hepatocellular carcinoma, HCC), gastric cancer, and esophageal cancer still remain the most common causes of death in patients with cancer. However, the prevalence of lung cancer is increasing dramatically.

The past century has witnessed rapid progress in the field of cancer treatment. Surgery and radiotherapy have become mainstays for the treatment of locoregional disease, followed by increasingly effective chemotherapy for disseminated disease. However, despite the great effort that has been devoted, many believe the war against cancer is “being lost,” and cancer continues to exert a great threat to humankind. In clinical practice, the prognosis is still discouraging for most cancer patients. In addition, radiotherapy and chemotherapy kill tumor cells in a nonspecific way and inevitably cause toxicities while reducing patient tolerance. Therefore, there is a high but unmet need to develop and implement innovative approaches to cure cancer. Fortunately, in recent years, our treatment armamentarium has expanded beyond conventional treatment modalities to include biotherapy, which acts against cancer in a more specific way.

Chinese scientists in oncology, immunology, biochemistry, chemistry, biology, and pharmacology have conducted significant levels of both basic and translational research, advancing our knowledge in these fields. The focus of this chapter will be on selected topics in which substantial progress has been made by Chinese scientists, especially tumor biotherapy.

The discovery of biotherapy dates back one century and was possibly due to chance. The observation of a relationship between infection and cancer regression led Dr. Coley to establish the so-called Coley toxin, which was a mixture of bacterial toxins for the treatment of patients with cancer. Biotherapy, sometimes referred to as biological therapy, biological response modifier (BRM), or immunotherapy, is a treatment used to boost or restore the ability of the host body to fight cancer, infections, and other diseases (http://www.cancer.gov/templates/db_alpha.aspx?CdrID=44483). It is also used to lessen certain side effects that may be caused by other cancer treatments. Agents used in biotherapy include monoclonal antibodies, growth factors, and vaccines. In our opinion, biotherapy also includes gene therapy and targeted therapy, as well as immunotherapy. Cancer biotherapy can be mainly categorized into the following: immunotherapy, gene therapy, antiangiogenesis therapy, and targeted therapy. In this chapter, we will discuss the progress of biotherapy with respect to these categories.

1.2 Immunotherapy

1.2.1 Cancer Vaccine

A vaccine is an active immunogen that can induce protective immunity. Effective vaccines have drastically reduced the incidence of many infectious diseases such as smallpox, poliomyelitis, and diphtheria. Researchers are working hard to make use of this modality to treat cancer, hoping to translate the success of antimicrobial therapy to cancer therapy. A cancer vaccine is a therapeutic vaccine that is usually administered to patients already suffering from cancer. The dream of developing a cancer vaccine has been partially realized only recently. In this area, Chinese researchers are able to remain current with the progress of those abroad who are at the frontiers of investigation.

The identification of cytotoxic T lymphocyte (CTL) epitopes from tumor antigens is very important for the development of peptide-based, cancer-specific immunotherapy. Heparanase is broadly expressed in various advanced tumors and can serve as a universal tumor-associated antigen. Although several epitopes of the heparanase antigen are known in humans, the corresponding knowledge in mice is still rather limited. Chinese researchers conducted a study to predict and identify the CTL epitopes in the mouse heparanase protein. The results showed that of the tested peptides, effectors induced by peptides of mouse heparanase at residue positions 398–405 (LSLLFKKL; mHpa398) and 519–526 (FSYGFFVI; mHpa519) lysed three types of carcinoma cells that expressed both heparanase and H-2K(b) (B16 melanoma cells, EL4 lymphoma cells, and Lewis lung cancer cells). In vivo experiments indicated that mHpa398 and mHpa519 peptides offered the possibility of not only immunizing against tumors but also successfully treating tumor-bearing hosts. The authors suggested that mHpa398 and mHpa519 peptides are novel H-2K(b)-restricted CTL epitopes capable of inducing heparanase-specific CTLs in vitro and in vivo.¹

Gastrin-releasing peptide (GRP), a bombesin-like peptide, is an autocrine growth factor that can stimulate the growth of various cancer cells. A novel protein vaccine HSP65-(GRP-10)(6) (HG6) that consists of six copies of a 10-amino acid residue epitope of GRP C-terminal fragment carried by mycobacterial 65 kDa HSP65 was constructed and then used to immunize mice via subcutaneous injection. Strong humoral and cell-mediated immune responses were induced. High titers of anti-GRP antibodies were detected in the immunized mice sera by ELISA and verified by Western blot analysis. The activity of CD4+ T lymphocytes, especially the high levels of interferon (INF)-gamma, was observed in mice immunized with HG6 when compared with HSP65 or PBS. Immunogenic tumor therapy with a vaccine based on GRP was effective in both protective and therapeutic antitumor immunity in breast tumor models in mice. The purified GRP monoclonal antibody (McAb) was proven to be potent in inhibiting EMT-6 tumor cell proliferation in vitro. The attenuation induced by active immune responses on tumor-induced angiogenesis was observed within an intradermal tumor model in mice. This result showed that immune responses elicited by a novel chimeric protein vaccine targeting GRP can suppress the proliferation of the EMT-6 breast tumor cell line in mice, and that it may be of importance in the further exploration of the applications of other autocrine growth factors identified in humans and in other animals in cancer therapy.²

1.2.2 Cell Therapy

The field of cancer immunotherapy has been recently invigorated by the discovery that vaccination with dendritic cells (DCs) pulsed with tumor antigens is a potent strategy to elicit protective and therapeutic immunity in tumor-bearing hosts. DCs are considered to be the most potent and efficient professional antigen-presenting cells (APCs) identified to date and are capable of activating both resting and naïve T-cells. In fact, most active immunotherapeutic strategies do not stimulate a direct immune response, but rather, they recruit or improve the delivery of antigens to the APCs, mostly DCs. It is well known that DCs express high levels of both class I and II MHC molecules on their cell surfaces in addition to CD28 and intercellular adhesion molecules, which are two of the most critical co-stimulatory molecules for T-cell activation. Their extraordinary capacity to capture, process, and present exogenous antigens also makes DCs the most powerful APCs for the generation of antitumor immunity. The ability to isolate DCs from patients’ peripheral blood and expand them in vitro can help overcome the initial obstacles associated with production. Chinese scientists have made great contributions to the exploitation and application of DCs for cancer biotherapy, gaining recognition from peers abroad.

Tumor-derived exosomes have been proposed as a new type of cancer vaccine. Heat shock proteins (HSPs) are potent Th1 adjuvants. Heat stress can induce HSP and MHC-I expression in tumor cells, leading to the increased immunogenicity of these cells. To improve the immunogenicity of exosomes as a cancer vaccine, Chinese researchers have induced more efficient HLA-A*0201-restricted and carcinoembryonic antigen (CEA)-specific CTL responses by immunization with exosomes prepared from heat-stressed CEA-positive tumor cells. In this study, the researchers identified the composition of CEA+/HS-Exo and observed their effects on human DC maturation. CEA+/HS-Exo contained CEA as well as more HSP70 and MHC-I, while significantly inducing DC maturation. They later evaluated the DCs’ ability to induce a CEA-specific immune response in vivo in HLA-A2.1/Kb transgenic mice, as well as a CEA-specific CTL response in vitro in HLA-A*0201+ healthy donors and HLA-A*0201+CEA+ cancer patients. The immunization of HLA-A2.1/Kb transgenic mice with CEA+/HS-Exo was more efficient in priming a CEA-specific CTL, while the CTL showed antitumor effects when adoptively transferred to SW480-bearing nude mice. Moreover, the in vitro incubation of lymphocytes from HLA-A*0201+ healthy donors and HLA-A*0201+CEA+ cancer patients with CEA+/HS-Exo-pulsed autologous DCs induced HLA-A*0201-restricted and CEA-specific CTL responses. This study showed that CEA+/HS-Exo had a superior immunogenicity than did CEA+/Exo in inducing CEA-specific CTL responses and suggested that exosomes derived from heat-stressed tumor cells be used as efficient vaccines for cancer immunotherapy.³

In another report, researchers from the same group used Hsp70-like protein-1 fusion protein to enhance the induction of a CEA-specific CD8+ CTL response via a DC vaccine. HSPs have been shown to interact with APCs and have a potent adjuvant capability to induce antigen-specific CD8+ CTL and Th1 responses. Hsp70-like protein-1 (Hsp70L1), a new member of the Hsp70 subfamily, acts as a potent Th1 adjuvant. In this report, a tumor antigen-specific immune response was induced by DCs pulsed with a recombinant fusion protein of Hsp70L1 and the CEA(576–669) fragment of CEA containing CAP-1 (an HLA-A2-restricted CTL epitope). The fusion protein CEA(576–669)-Hsp70L1 can promote DC maturation and activate DCs to produce cytokines such as interleukin-12 (IL-12), IL-1beta, and tumor necrosis factor-alpha (TNF-alpha), as well as chemokines such as macrophage inflammatory protein-1alpha and macrophage inflammatory protein-1beta, indicating the adjuvant ability of Hsp70L1 in the fusion protein. CEA-specific HLA-A2.1-restricted CD8+ CTLs, either from patients with CEA+/HLA-A2.1+ colon carcinoma or from splenocytes of immunized HLA-A2.1/Kb transgenic mice, can be generated more efficiently after stimulations or immunizations with DCs pulsed by CEA(576–669)-Hsp70L1 than with DCs pulsed by CEA(576–669) alone, resulting in increased secretions of the Th1 cytokine IFN-gamma and the more potent killing of target cells in an antigen-specific and HLA-A2.1-restricted manner. The adoptive transfer of splenocytes from transgenic mice immunized with CEA(576–669)-Hsp70L1-pulsed DCs can more markedly inhibit tumor growth and prolong survival in nude mice bearing CEA+/HLA-A2.1+ human colon carcinoma. Therefore, Hsp70L1 has a potent adjuvant effect in the form of a fusion protein, indicating that Hsp70L1 may be widely used as a Th1 adjuvant to prepare antigenic fusion proteins for treatment of cancer or infectious diseases.⁴

It is noteworthy that the efficacy of DC therapy was confirmed not only in preclinical studies but also in pivotal clinical trials. A phase II trial has just been completed, which confirmed the efficacy of antigen-pulsed DC (APDC) for the treatment of metastatic colon and rectal cancer (mCRC). APDC has entered into a phase III trial, and once it passes the phase III trial, the agent will soon enter into clinical testing.

The tumoricidal efficacy of chemotherapy agents for a panel of solid and hematological tumors has been established, although recently accumulating evidence has shown that an immunological effect was also present for at least some of the agents.⁵ Chinese scientists have also played a role in this area. In a recently published paper, they provided the “proof-of-principle” that low-dose paclitaxel is able to change the tumor microenvironment and improve the outcome of treatment with an intratumoral DC vaccine in a murine lung cancer model.

Their data showed that low-dose paclitaxel, which induced apoptosis in approximately 10% of tumor cells, was not toxic to bone marrow cells or DCs while it stimulated DC maturation and function in vitro. Although the tumor cells inhibited DC differentiation in vitro, this immunosuppressive effect was abrogated by the pretreatment of tumor cells with low-dose paclitaxel. They tested whether the pretreatment of tumor-bearing mice with low-dose paclitaxel in vivo would improve the antitumor potential of a DC vaccine administered intratumorally, and they found significant inhibition of tumor growth in mice treated with low-dose paclitaxel plus intratumoral administration of the DC vaccine, as observed by increased tumor infiltration by CD4+ and CD8+ T-cells and elevated tumor-specific IFN-gamma production by the draining of lymph node cells. These data indicated that low-dose chemotherapy before intratumoral delivery of DCs might be associated with beneficial alterations of the intratumoral microenvironment, thus providing support for antitumor immunity.⁶

Researchers from China have also focused on defining the mechanism and modifying the therapeutic strategy associated with DC therapy. It is...

Table of contents

• Cover Image
• Title Page
• Table of Contents
• Copyright
• Preface
• List of Contributors
• 1. Cancer Biotherapy: Progress in China
• 2. Cancer Targeting Gene–Viro–Therapy and its Promising Future: A Trend in Both Cancer Gene Therapy and Cancer Virotherapy
• 3. Relationship Between Antiproliferative Activities and Class I MHC Surface Expression of Mouse Interferon Proteins on B16-F10 Melanoma Cells
• 4. Mitotic Regulator Hec1 as a Potential Target for Cancer Therapy
• 5. Advances in Liposome-Based Targeted Gene Therapy of Cancer
• 6. Rewiring the Intracellular Signaling Network in Cancer
• 7. Research and Development of Highly Potent Antibody-Based Drug Conjugates and Fusion Proteins for Cancer Therapy
• 8. Cancer Stem Cell
• 9. p53: A Target and a Biomarker of Cancer Therapy?
• 10. Recombinant Adenoviral-p53 Agent (Gendicine®): Quality Control, Mechanism of Action, and Its Use for Treatment of Malignant Tumors
• 11. Three-Dimensional Tumor Model and T-Lymphocytes Immunotherapy for Cancer
• 12. Advances in Cancer Chemotherapeutic Drug Research in China
• 13. Doxorubicin Cardiotoxicity Revisited: ROS Versus Top2
• 14. Biochemistry and Pharmacology of Human ABCC1/MRP1 and Its Role in Detoxification and in Multidrug Resistance of Cancer Chemotherapy
• 15. The Role of Traditional Chinese Medicine in Clinical Oncology
• 16. Effect of Arsenic Trioxide on Acute Promyelocytic Leukemia and Glioma: Experimental Studies, Clinical Applications, and Perspectives
• 17. Recent Advances in Nasopharyngeal Carcinoma Research and Its Pathogenesis
• 18. Esophageal Carcinoma
• 19. Research on Colorectal Cancer in China
• 20. Molecular and Cellular Characteristics of Small Cell Lung Cancer: Implications for Molecular-Targeted Cancer Therapy
• 21. Possibility to Partly Win the War Against Cancer
• About the Editors