Immunotherapy in Cancers Prof. M.C.Bansal MBBS,MS,MICOG,FICOG Professor OBGY Ex-Principal & Controller Jhalawar Medical College & Hospital Mahatma Gandhi Medical College, Jaipur.
Tumor cell proliferation andimmunotheray of cancers Professor M. C. Bansal M.B.B.S. M.S. F.I.C.O.G M.I.C.O.G
Cell Cycle Information on growth patterns and doubling times relates to the growth of the tumor mass as a whole. The kinetic behavior of individual tumor cells has been well described, and a classic cell cycle model has been produced . M phase (mitotic phase) of the cell cycle is the phase of cell division. G1 phase (postmitotic phase) is a period of variable duration when cellular activities and protein and RNA synthesis continue. These G1 cells can differentiate or continue in the proliferative cycle.
S phase (DNA synthetic phase) is the period in which new DNA replication occurs. G2 phase (postsynthetic phase) is the period in which the cell has a diploid number of chromosomes and twice the DNA content of the normal cell. The cell remains in this phase for a relatively short time and then enters the mitotic phase again. G0 phase (the resting phase) is the time during which cells do not divide. Cells may move in and out of the G0 phase.
The generation time is the duration of the cycle from M phase to M phase. Variation occurs in all phases of the cell cycle, but the variation is greatest during the G1 period. The reasons for this variation are complex and not completely understood.
These cell cycle events have important implications for the cancer therapist. Differential sensitivities to chemotherapy and radiation therapy are associated with different proliferative states. Dividing cancer cells that are actively traversing the cell cycle are very sensitive to chemotherapeutic agents.
Cells in a resting state (G0) are relatively insensitive to chemotherapeutic agents, although they occupy space and contribute to the bulk of the tumor.
Cell Kinetics In cell kinetic studies performed on human tumors, the duration of the S phase (DNA synthesis phase) is relatively similar for most human tumors, ranging from a low of 10 hours to a high of approximately 31 hours. The length of the cell cycle in human tumors varies from slightly more than half a day to perhaps 5 days. With cell cycle times in the range of 24 hours and doubling times in the range of 10 to 1,000 days, it is clear that only a small proportion of tumor cells are in active cell division at any one time.
Two major factors that affect the rate at which tumors grow are the growth fraction and cell death. The growth fraction is the number of cells in the tumor mass that are actively undergoing cell division. There is a marked variation in the growth fraction of tumors in human beings, ranging from 25% to almost 95%.
In the past, it was thought that human tumors contained billions of cells, all growing slowly. In actuality, only a small fraction of cells in a tumor mass are rapidly proliferating; the remainder are out of the cell cycle and quiescent. Cancer “stem cells” are a very small population of cells that appear to be relatively chemoresistant; these play a major role in the development and progression of cancers.
Tumor growth may be altered by the following: cytotoxic chemotherapy, which alters both the generation time and the growth fraction of a tumor hormones, which appear to alter the growth fraction without changing the generation time radiation therapy, which alters both the generation time and the growth fraction alterations in oxygen tension and vascular supply, which alter the growth fraction without altering generation time immunologic therapies, which seem to alter both generation time and growth fraction
INTRODUCTION Cancer is caused by a series of events that include the accumulation of successive molecular lesions and alterations in the tumor microenvironment . Molecular lesions include overexpression, amplification, or mutations of oncogenes; deletion of tumor suppressor genes; and the inappropriate expression of growth factors and their cellular receptors. In addition to these molecular changes, the formation of new blood vessels (angiogenesis) and the lack of effective host antitumor immune responses create a microenvironment that supports the growth of cancer .
Our improved understanding of these mechanisms presents an opportunity for the development of novel therapeutic approaches . This presentation provides an overview of biologic, targeted, and immunotherapeutic strategies for gynecologic cancers.
Biologic and Targeted Therapies The growth of cancer cells is crucially dependent on oncogenic signal transduction pathways. Extracellular signals are transmitted to the cancer cell via transmembrane receptors. Activation of the epidermal growth factor receptors (EGFR, HER2, HER3, and HER4), for example, stimulates a cascade of intracellular proteins that ultimately lead to changes in gene expression. Novel therapeutics are targeted to modulate these signal transduction pathways by blocking the extracellular transmembrane receptors or interfering with intracellular proteins such as tyrosine kinases further downstream.
This novel therapeutic approach is also termed molecular targeting . It is accomplished by either monoclonal antibodies that bind to transmembrane receptors and serum proteins such as vascular endothelial growth factor (VEGF) or chemical, small-molecule inhibitors that prevent activation of signal transduction proteins. Targeting the signaling cascade inhibits the proliferation of cancer cells, induces apoptosis, and blocks metastasis.
The specificity of these molecules is based on the assumption that cancer cells are overexpressing various proteins in the signal transduction pathways, therefore presenting a preferred target compared to normal cells. Conceptually, this should result in more cancer cell- specific therapy and less clinical side effects because of sparing of normal tissue
Angiogenesis The formation of new blood vessels (neoangiogenesis) is a normal process during embryonic development, tissue remodeling, and wound healing . Malignant tumors are able to induce angiogenesis by secreting paracrine factors that promote the formation of new blood vessels. Angiogenesis is a complex process that is influenced by various pro-and antiangiogenic factors, including VEGF, interleukin 8, platelet-derived endothelial cell growth factor, and angiopoietins. Overexpression of these angiogenic factors leads to neovascularization and increased supply of nutrients and oxygen to the tumor.
Three main therapeutic strategies that target angiogenesis are currently being explored for the treatment of cancer patients . One group of agents targets VEGF (e.g., bevacizumab, VEGF-Trap), the second group prevents VEGF from binding to its receptor (pertuzumab), and a third group of agents inhibits tyrosine kinase activation and downstream signaling in the angiogenesis signaling cascade (valatanib, sunitenib).
Vascular Endothelial Growth Factor VEGF is overexpressed in gynecologic malignancies, therefore presenting an excellent target for therapy . Inhibition of VEGF-induced angiogenic signaling decreases tumor microvascular density and causes death of solid tumors in various preclinical models. Several agents are now available for clinical use; all target the VEGF signaling pathway. The most widely used agent at this time is bevacizumab, a humanized, recombinant monoclonal antibody that binds to all isoforms of VEGF-A.
In ovarian carcinoma, various clinical trials have demonstrated the efficacy of bevacizumab treatment. In a study by the Gynecologic Oncology Group, 62 patients received single agent bevacizumab 15 mg/kg intravenously every 21 days . Thirteen patients (21%) showed clinical responses with two complete and 11 partial responses. The median response duration was 10 months, and 25 patients (41.3%) survived progression free for at least 6 months.
Bevacizumab has also been used in combination with other agents. In a phase II study of 13 patients with recurrent ovarian or primary peritoneal carcinoma, combination treatment with bevacizumab (15 mg/kg i.v. every 21 days) and erlotinib (150 mg/day orally) resulted in one complete response and one partial response for a total response rate of 15% . Seven patients had stable disease. Another trial investigated the combination of bevacizumab (10 mg/kg every 14 days) and oral cyclophosphamide (50 mg/day orally) in 70 patients with recurrent ovarian cancer.
The Gynecologic Oncology Group has initiated a clinical trial that will evaluate the addition of bevacizumab to first-line chemotherapy after primary tumor debulking. A similar trial by the Gynecologic Cancer InterGroup is designed to evaluate the safety and efficacy of adding bevacizumab to standard chemotherapy (carboplatin and paclitaxel) in patients with advanced epithelial ovarian or primary peritoneal cancer .
Epidermal Growth Factor ReceptorInhibitors The epidermal growth factor receptor family consists of four members including EGFR (HER1), HER2, HER3, and HER4 . EGFR overexpression has been reported in 35% to 70% of patients with epithelial ovarian cancer . In endometrial cancer, EGFR is overexpressed in 43% to 67% of tumors and is associated with shortened disease-free and overall survival . In addition, amplification of the HER2 gene is commonly found in endometrial carcinoma.
Various agents directed against epidermal growth factor receptors are available . Trastuzumab is a humanized monoclonal antibody that binds to the extracellular domain of HER2 . Blockade of HER2 affects various molecules that ultimately decreases cell proliferation. Pertuzumab is another humanized monoclonal antibody that binds to a different epitope of HER2 compared to trastuzumab. Binding to HER2 prevents dimerization of the receptor, which is required for its function .
Epidermal Growth Factor Receptor Inhibition of EGFR signaling is accomplished by using either monoclonal antibodies against the extracellular receptor or small-molecule inhibitors against the intracellular kinase domain. Both strategies results in inhibition of phosphorylation or receptor activation. Erlotinib is a potent reversible inhibitor of EGFR tyrosine kinase that blocks receptor autophosphorylation and has been used for the treatment of ovarian carcinoma.
Erlotinib has been used in combination with docetaxel and carboplatin as first-line treatment after surgical cytoreduction in patients with ovarian, fallopian tube, and primary peritoneal cancers . Cetuximab (C225, Erbitux) is a chimerized monoclonal antibody against EGFR. Cetuximab in combination with carboplatin resulted in three complete (10.7%) and six partial (21.4%) responses in 28 patients with recurrent ovarian cancer. Twenty-six of these 28 patients (92.8%) had EGFR-positive tumors.
The combination of paclitaxel, carboplatin, and cetuximab for first-line chemotherapy of stage III ovarian cancer patients resulted in progression-free survival of 14.4 months and was therefore not significantly prolonged compared to historical data.
Gefitinib (ZD1839 Iressa) is a low molecular weight quinazoline derivative that inhibits the activation of EGFR tyrosine kinase via competitive binding of the ATP-binding domain of the receptor. Treatment of patients with recurrent ovarian cancer using the combination of gefitinib, carboplatin, and paxitaxel resulted in a high overall response rate of 63% . Interestingly, antitumor responses were observed in 35% of patients with platinum-resistant disease compared to a 73% response rate in patients with platinum-sensitive disease.
Gefitinib has also been used in combination with tamoxifen. In squamous and adenocarcinoma of the cervix, gefitinib (500 mg/day) treatment resulted in disease stabilization in six of 28 patients (20%) but no clinical responses . Lapatinib is a small-molecule inhibitor of both the HER2 and EGFR tyrosine kinase receptor. The rationale for using lapatinib in endometrial carcinoma is supported mainly by studies in human cancer cell lines. Its efficacy in endometrial cancer is being investigated currently in clinical trials .
HER-2/neu The HER-2/neu receptor is activated by homo- or heterodimerization, resulting in tyrosine phosphorylation and subsequent activation of various downstream signals that among other functions control cellular proliferation, migration, and invasion. Trastuzumab is a recombinant, humanized IgG1 monoclonal antibody that is specific for the extracellular domain of HER-2/neu. Binding of the antibody to HER-2/neu prevents activation of the receptor with a subsequent increase of apoptosis in vitro and in vivo, impaired DNA damage repair, and inhibition of tumor neovascularization.
The HER-2/neu oncogene is overexpressed in several gynecologic malignancies, including 20% to 30% of ovarian cancers. HER2/neu overexpression is infrequent in cervical cancer. In uterine papillary serous carcinoma, 12 of 68 (18%) tumors showed HER2/neu overexpression; this was associated with a worse overall prognosis .
Mitogen-Activated Protein Kinase Pathways The mitogen-activated protein (MAP) kinase cascades are activated by various cofactors, inflammatory cytokines, and stress. Sorafenib is among the first of the agents with clinically proven efficacy. Sorafenib is a competitive inhibitor of raf that has been approved for treatment of renal cell carcinoma and hepatocellular carcinoma. Besides targeting raf, sorafenib also inhibits VEGFR2 and VEGFR3, FT3, c-kit, and PDGFR-β.
The PI3-kinase/Akt/mTOR Pathway The phosphoinositide3-kinase (PI3-kinase)/Akt/mTOR pathway is a major oncogenic signaling pathway in various cancers. Activation of this pathway can be demonstrated in more than 80% of endometrial cancers, 50% to 70% of epithelial ovarian cancers, and approximately 50% of cervical cancers. Several inhibitors of PI3-kinase/Akt/mTOR signaling are currently in clinical trials. Rapamycin or rapamycin analogues, for example, block the activity of mTOR, a protein complex responsible for increasing protein synthesis and cellular proliferation.
Several mTOR inhibitors, including RAD001 and CCI779, and specific PI3-kinase inhibitors are currently under development in preclinical models and clinical trials. PI3-kinase/Akt/mTOR inhibitors have been used in endometrial cancer with limited benefit.
Immunotherapy Failure of functional immunity contributes to the genesis of virus-associated cancers, such as those caused by human papilloma virus (HPV) or Epstein- Barr virus. The greatest success story involving the enhancement of immunity to combat gynecologic cancer is the development of vaccines against HPV, which are highly effective for the prevention of cervical dysplasia and cancer .
Some researchers suggest that immune responses are mainly involved in protection from virus-associated cancers but not other forms of cancer . Cancer is a common disease, and overt immune deficiency certainly is not necessary for its development. However, recent studies have shown that many cancers, including those that are not known to have a viral etiology, are seen with increased frequency in patients who have dysfunctional immunity.
In a recent metaanalysis of cancer incidence in populations known to be immune deficient (e.g., organ-transplant recipients, patients with HIV infection), Grulich and co-workers found an increased incidence of several common cancers, suggesting that impaired immunity can contribute to the development of cancer.
Components of the Immune SystemInvolved in Antitumor Responses Various types of human immune responses can target tumor cells. Immune responses can be categorized as humoral or cellular, a distinction based on the observation in experimental systems that some immune responses could be transferred by serum (humoral) and others by cells (cellular). In general, humoral responses refer to antibody responses; antibodies are antigen-reactive, soluble, bifunctional molecules composed of specific antigen-binding sites associated with a constant region that directs the biologic activities of the antibody molecule, such as binding to effector cells or complement activation .
Cellular immune responses generally refer to cytotoxic responses mediated directly by activated immune cells rather than by the production of antibodies . Nearly all immune responses involve both humoral and cellular components and require the coordinated activities of populations of lymphocytes operating in concert with each other and with antigen-presenting cells. These activities result in various effector functions such as antibody production, cytokine secretion, and the stimulation and expansion of cytotoxic T cells.
Cellular interactions involved in immune responses include direct cell-cell contact, as well as cellular interactions mediated by the secretion of, and response to, cytokines. The latter are biologic messenger molecules that play important roles in the genesis, amplification, and effector functions of immune responses. T lymphocytes play a pivotal role by acting as helper cells in the generation of humoral and cellular immune responses and by acting as effector cells in cellular responses.
Cytotoxic T cells are effector T cells that can directly interact with, and kill, target cells by the release of cytotoxic molecules and the induction of target cell apoptosis. T-lymphocyte precursors mature into functional T lymphocytes in the thymus, where they learn to recognize antigen in the context of the major histocompatibility complex (MHC) molecules of the individual. Most T lymphocytes with the capability of responding to self-antigens are removed during thymic development.
T lymphocytes are distinguished from other types of lymphocytes by their biologic activities and by the expression of distinctive cell surface molecules, including the T-cell antigen receptor and the CD3 molecular complex. T lymphocytes recognize specific antigens by interactions that involve the T-cell antigen receptor .
There are two major subsets of T lymphocytes: T helper/inducer cells, which express the CD4 cell surface marker; and T suppressor/cytotoxic cells, which express the CD8 marker. CD4 T lymphocytes can provide help to B lymphocytes, resulting in antibody production, and also can act as helper cells for other T lymphocytes. Much of the helper activity of T lymphocytes is mediated by the production of cytokines. CD4 T cells have been further subdivided into TH1 (cellular immunity/proinflammatory) and TH2 (antibody response- promoting) subsets, based on the pattern of cytokine production and the biological properties of these cells.
Recent studies have identified a subset of T cells that inhibit autoreactive cells, perhaps acting to prevent autoimmune responses . This subset of T cells has been called regulatory T cells. Other recently described T-cell subsets include TH17 cells, which are important in driving immune responses to bacteria and fungi . The CD8 T-lymphocyte subset includes cells that are cytotoxic and can directly kill target cells. A major biologic role of such cytotoxic T lymphocytes is the lysis of virus-infected cells. However, cytotoxic T lymphocytes can directly mediate the lysis of tumor cells.
Effector T cells also can contribute to antitumor immune responses by producing cytokines, such as tumor necrosis factor (TNF), that induce tumor cell lysis and can enhance other antitumor cell effector responses. Both CD4 and CD8 T cells respond to antigen only when it is presented in the context of MHC molecules on antigen- presenting cells or target cells or both. The T-cell receptor on CD4 T cells is restricted to responding to antigen plus MHC class II molecules; the receptor on CD8 T-cells is restricted to responding to antigen plus MHC class I molecules.
Therefore, provision of effective costimulatory signals is necessary for the induction of effective antitumor responses by activated T cells. B lymphocytes are the cells that produce and secrete antibodies, which are antigenbinding molecules . B lymphocytes develop from pre-B cells and, after exposure to antigen and appropriate activation signals, differentiate to become plasma cells—cells that produce large quantities of antibodies. Mature B lymphocytes use cell-surface immunoglobulin molecules as antigen receptors.
In addition to producing antibodies, B lymphocytes play another important role: They can serve as efficient antigen-presenting cells for T lymphocytes. Although the production of antitumor antibodies does not appear to play a central role in host antitumor immune responses, monoclonal antibodies reactive with tumor-associated antigens have proved to be very useful in antitumor therapy, as well as in the detection of tumors or of tumor-associated molecules.
Macrophages and dendritic cells also play key roles in the generation of adaptive, lymphocyte-mediated immune responses by acting as antigen-presenting cells. Helper/inducer (CD4) T lymphocytes, bearing a T-cell receptor of appropriate antigen and self-specificity, are activated by antigen-presenting cells that display processed antigen combined with self-MHC molecules.
Antigen-presenting cells also provide costimulatory signals that are important for the induction of T- lymphocyte activation. In addition to serving as antigen-presenting cells, macrophages can ingest .and kill microorganisms and act as cytotoxic antitumor killer cells. These cells also produce various cytokines, including IL-1, IL-6, chemokines, IL-10, and TNF, which are involved in many immune responses
These monocyte-produced cytokines can have direct effects on tumor cell growth and development, both as growth-inducing and growth-inhibiting factors. Natural killer (NK) cells are cells that have large granular lymphocytic morphology, do not express the CD3 T-cell receptor complex, and do not respond to specific antigens. NK cells can lyse target cells, including tumor cells, unrestricted by the expression of antigen or self-MHC molecules on the target cell. Therefore, NK cells are effector cells in an innate (non- antigen-restricted) immune response and may play a vital role in immune responses to tumor cells. The cells that can effect antibody-dependent cellular cytotoxicity (ADCC) are NKlike cells.
Cytokines are soluble mediator molecules that induce, enhance, or effect immune responses. Cytokines are produced by various types of cells and play critical roles not only in immune responses but also in biologic responses outside of the immune response, such as hematopoiesis or the acute-phase response. T helper 1(TH1) and TH2 cells, which control the nature of an immune response by secreting characteristic and mutually antagonistic sets of cytokines (9,10,11), are defined by the cytokines they produce.
TH1 clones produce IL-2 and IFN-, whereas TH2 clones produce IL-4, IL-5, IL-6, and IL-10. TH1 cytokines promote cellmediated and inflammatory responses, whereas TH2 cytokines enhance antibody production. Most immune responses involve both TH1 and TH2 components. Research has identified CD4-positive T cells that participate in the maintenance of immunologic self- tolerance by actively suppressing the activation and expansion of self-reactive lymphocytes.
These cells are called regulatory T cells, or Treg cells. Treg cells are characterized by the expression of CD25 (the IL-2 receptor-chain) and the transcription factor FoxP3. Treg cell activity is thought to be important in preventing the development of autoimmune diseases. Removal of Treg also may enhance immune responses against infectious agents or cancer. Although much remains to be learned about the role of Treg activity in antitumor immunity, it is clear that such cells may play a role in modulating host responses to cancer.
Therapeutic Strategies There is great interest in developing effective biologic and immune therapies for gynecologic malignancies. For example, patients with small-volume or microscopic residual peritoneal ovarian cancer are attractive candidates for immunotherapy or biologic therapy, especially approaches based on regional peritoneal immunotherapy or biotherapy. Also, many patients with advanced disease are immunocompromised, suggesting a role for immuneenhancing therapeutic approaches.
Dysplastic and cancerous cervical epithelial cells infected with HPV, an oncogenic virus, also present an attractive target for immune enhancement-based therapeutic strategies, including the development of therapeutic vaccines for HPV. Advances in molecular biology, biotechnology, immunology, and cytokine biology have resulted in the availability of many new, promising immunotherapeutic approaches for gynecologic cancers.
Monoclonal Antibodies andAntibody-Based Immunotherapy Monoclonal antibodies have played an important role in both the development of immunotherapeutic agents and tumor markers. Monoclonal antibodies also have been used for radioimmunodetection and are being used for treatment. Monoclonal antibodies can potentially induce antitumor responses in various ways: (i) by complement activation and subsequent tumor cell lysis; (ii) by directly inducing antiproliferative effects, perhaps by interaction with tumor cell surface signaling molecules; (iii) by enhancing the activity of phagocytic cells, which can interact with immune complexes containing monoclonal antibodies; and (iv) by mediating ADCC via interactions of the Fc portion of monoclonal antibodies with Fc receptors on cells that mediate ADCC .
In addition, monoclonal antibodies can be labeled with either radioactive particles or antitumor drugs and used to focus these agents onto tumor cells . In fact, some monoclonal antibody-based drugs are currently approved and being used for the treatment of cancer with great success.
Several clinical trials have utilized monoclonal antibodies directed against ovarian cancer antigens, including CA125, folate receptor, MUC1 antigen, and tumor- associated glycoprotein 72 . Evidence that CA125 can act as a tumor antigen that stimulates humoral and cellular immune responses is derived from various in vitro studies and clinical trials. Oregovomab (B43.13) is a murine monoclonal antibody to CA125 that has been used for the treatment of ovarian cancer. The antibody binds to circulating CA125, resulting in the formation of immune complexes (antibody-antigen complexes).
These immune complexes are recognized as foreign, mainly because of the murine component. They are taken up by antigen-presenting cells, allowing the processing of the autologous CA125 antigen, ultimately leading to induction of CA125- specific antibodies, helper T cells, and cytolytic T cells.
the velocity of the rise in CA125 levels at relapse was found to be a highly significant predictor of postrelapse outcome. Another antibody network-based strategy has employed anti-idiotype vaccines in patients with relapsed ovarian cancer. ACA125 is a murine anti-idiotypic antibody that mimics an antigenic epitope on CA125. Therefore, antibodies generated to ACA125 have the potential to react with antigenic epitopes on CA125, with ACA125 serving as an antiidiotype vaccine that would enhance immune responses to CA125 .
Treatment with ACA125 resulted in both humoral and cellular responses, and those patients who had detectable anti-ACA125 responses showed a longer mean survival time than those who did not develop responses . Abagovomab is an anti-idiotypic antibody that mimics the CA125 antigen. The initial results of abagovomab treatment in patients with ovarian cancer were reported by Sabbatini et al. and showed that all patients developed an anti-idiotypic antibody response (Ab3).
In addition, the generation of T-cell immunity to CA125 was demonstrated in five patients. While patients had measurable serum CA125 levels in both trials, neither trial analyzed CA125 expression in tumor tissue. A large international, multicenter trial is underway to investigate the effect of abagovomab as consolidation treatment in patients with ovarian cancer.
Adoptive lmmunotherapy Adoptive immunotherapy involves the ex vivo expansion of antitumor immune cells followed by the administration of such effector cells. It has provided another immune system-based approach for antitumor therapy. Adoptive immunotherapy, involving the infusion of large numbers of autologous ex vivo-activated immune effector cells, has been shown to produce tumor regression in various animal and human tumors.
Early approaches used peripheral blood mononuclear cells exposed to IL-2 ex vivo to lead to the generation of lymphokine-activated killer (LAK) cells that are cytotoxic for a variety of tumor cells . adoptive immunotherapy with LAK cells does not appear to be a practical option for the treatment of ovarian cancer. The use of immunotherapy based on ex vivo- stimulated tumor-infiltrating lymphocytes or tumor- associated lymphocytes from ascites, with or without added IL-2, also has been examined in ovarian cancer .
Dendritic Cell and Tumor VaccineTherapy Various tumor-associated antigens are potential immunogens for tumor vaccines, including (i) differentiation antigens, (ii) new antigens created by mutation of genes encoding host cell proteins, (iii) molecules that are overexpressed on tumor cells (i.e., HER2, NY-ESO-1, CA125), and (iv) viral antigens from oncogenic viruses (i.e., HPV-encoded antigens) . Experimental tumor vaccine therapy in ovarian cancer has been carried out using the NY-ESO-1 antigen. Nearly half of epithelial ovarian cancers are NY-ESO-1 positive .
Vaccination with a peptide from NY-ESO-1 resulted in the generation of both cellular and humoral immunity to this antigen, in most vaccinated patients . Vaccines based on HER2 also have been tested in ovarian cancer patients, with such treatment resulting in the induction of specific T-cell responses in most patients . Human papilloma virus—specifically, HPV subtypes 16, 18, 31, and 45—has been implicated as the major etiologic agent in cervical cancer.
HPV-infected dysplastic and cancerous cervical epithelial cells consistently retain and express two of the viral genes, E6 and E7, that respectively interact with and disrupt the function of the p53 and retinoblastoma tumorsuppressor gene products. Factors other than infection with HPV, such as cellular immune function, play an important role in determining whether the infection of cervical epithelial cells regresses or progresses to cancer.
This has led to the development of prophylactic and therapeutic vaccines to HPV, as well as treatment approaches based on the enhancement of host immune function. Human papilloma virus vaccines have been shown to have an exceptional level of efficacy , clearly reducing the incidence of both HPV-16 and -18 infections and HPV-16 and -18-related cervical intraepithelial neoplasia. The HPV vaccines Gardasil and Cerverix use HPV-like particles as immunogens to generate neutralizing antibodies for HPV.
These findings suggest that HPV-based therapeutic cancer vaccines may also be effective for the control of cervical cancer . HPV E6 and E7 are attractive antigens for use in therapeutic vaccines because these HPV-encoded proteins are involved in cellular transformation and therefore are consistently expressed in HPV-positive tumor cells.
Dendritic cells are highly effective antigen-presenting cells and play a central role in the induction of both CD4 and CD8 T-cell responses. Dendritic cells can be pulsed with tumor antigen peptides or bioengineered to express tumor antigens, allowing them to be used in experimental therapies that aim to enhance antitumor immunity. Exposure of T cells to dendritic cells pulsed with ovarian cancer-derived antigenic preparations resulted in the generation of cytolytic effector T cells that could kill autologous tumor cells in vitro .
In a phase I clinical trial, Hernando and co-workers showed that patients with advanced gynecological malignancies could be effectively vaccinated with dendritic cells pulsed with a nontumor test antigen, keyhole limpet hemocyanin (KLH), and autologous tumor antigens. Lymphoproliferative responses to KLH and to tumor lysate stimulation were noted. The treatment was safe, well tolerated, immunologically active, and generally devoid of significant adverse effects.
Biologic Response Modifier andCytokine Therapy: Modulation of HostImmunity Most early experimental biologic therapies for metastatic ovarian cancer involved biologic response modifiers such as Corynebacterium parvum (a heat- killed, gram-negative anaerobic bacillus), bacillus Calmette-Guérin (BCG), or modifications of these agents . Exposure to C. parvum resulted in the nonspecific enhancement of host immune responses, including the induction of an acute inflammatory response .
Biologic response modifier therapy for ovarian cancer, including treatment with C. parvum and BCG, was examined in several studies. IP treatment with IL-12 in patients with carcinomatosis from mesotheliomas, müllerian or gastrointestinal carcinomas, showed a 10% complete response rate and disease stabilization in nearly half of the treated patients . In a recent phase II trial, treatment with subcutaneously administered IL-2 and oral retinoic acid was reported to improve survival in patients who had ovarian cancer responding to chemotherapy .
The recent identification of T-cell subpopulations that have potent immunoregulatory properties, such as Treg cells and TH17 cells, provides new opportunities for the design of host immune system-modulating therapies with the aim of enhancing immune responses to cancer. TH17 cells are another recently identified regulatory T- cell subpopulation, characterized by the secretion of IL-17. They have the ability to modulate Treg activity .