Mucosally restricted antigens as novel immunological targets for antitumor therapy (original) (raw)
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Cancer Mucosa Antigens a Novel Paradigm in Cancer Immunotherapeutics
BIOforum Europe : trends and techniques in life science research
Employing antigens with expression restricted to normal intestinal mucosa and derivative colorectal tumors - cancer mucosa antigens (CMAs) - represents a novel paradigm in anti-tumor immunotherapy. Immune compartmentalization limits tolerance to CMAs and restricts mucosa-targeted autoimmunity, allowing safe and effective immunotherapy for metastatic colorectal cancer. Guanylyl cyclase C (GCC), an intestine/colorectal cancer-restricted protein, is poised for clinical evaluation as the index CMA.
Colorectal cancer as a model for immunotherapy
Clinical cancer research : an official journal of the American Association for Cancer Research, 1999
Colorectal cancer represents 10% of all cancers and 10% of cancer deaths in the United States with ϳ130,000 new cases diagnosed annually (1). There have been important advances in our understanding of the biology and genetics of this disease, and if diagnosed early, colorectal cancer is highly curable. Patients with Dukes' A colon cancer that invades only the submucosa and Dukes' B1 disease with invasion into the muscularis propria are typically cured with surgery, and no additional therapy is recommended (2). Patients with Dukes' B2 colon cancer with invasion through the muscularis propria or through the serosa, but without lymph node involvement, and Dukes' C colon cancer which includes lymph node involvement, are treated with 5-FU 2 with levamisole or leucovorin with 10-15% improved survival (3-5). Adjuvant immunotherapy with agents such as BCG or methanol extraction residue of BCG have not improved upon these results (discussed below). More recently, a study from Germany in Dukes' C patients who were randomized to a monoclonal antibody, designated 171A, demonstrated improved survival by 30% over patients on the control arm (6). The opportunity to improve results in Dukes' B2, C, and D patients with an immunotherapeutic approach in addition to chemotherapy is excellent. Immune approaches to the therapy of colorectal cancer have substantially evolved over the past years, from treating patients with nonspecific immune stimulants to a focus on the use of TAAs either by passive immune therapy with antibodies targeted directly to tumor cells or by active immune therapy via vaccination with tumor cells, tumor cell lysates, peptides, carbohydrates, gene constructs encoding proteins, or anti-idiotype antibodies that mimic TAAs.
Immunotherapy of colorectal cancer
British Medical Bulletin, 2002
Over the last decade, there has been a rapid expansion in the field of tumour immunology. There is now convincing evidence that both the cellular and humoral arms of the immune system are capable of interacting with tumour cells. The most significant advances have been in our understanding of cellular responses and the complex events that lead to T-lymphocyte activation, as well as in the identification of tumour antigens recognised by T-lymphocytes. This knowledge has led to the development of anticancer immunotherapies designed to produce tumour antigenspecific T-cell responses, adding to the earlier antibody or whole-cell vaccine approaches. In addition, new methods have been developed to quantify antigenspecific T-cell responses, and the emergent field of recombinant gene technology has led to an increasing number of novel methods for vaccine delivery. This review will explore these advances, as well as possible future directions, with an emphasis on colorectal cancer. Anti-tumour immune responses There is now definitive evidence that some patients with established tumours develop spontaneous anti-tumour immune responses. Although the identification of tumour antigens recognised by antibodies dates back to the 1950s, it is only over the last decade that techniques have been developed to identify antigens recognised by T-lymphocytes. Melanoma is the tumour type that has been particularly studied by tumour immunologists. Evidence that melanoma is immunogenic is provided by the association of a lymphocytic infiltrate of the primary tumour with an improved prognosis 1 and, more significantly, by the isolation of tumour antigen-specific T-cells from the blood, tumourinfiltrated lymph nodes and metastases of melanoma patients. These Tcells have been shown to be capable of killing melanoma cells in vitro 2,3. Although a lymphocytic infiltration of primary colorectal carcinoma is similarly associated with improved overall and recurrence-free survival 4 , there is very little data about the antigen-specificity of these lymphocytes. Of interest, a high level of microsatellite instability in colorectal
The Immunogenicity of Colorectal Cancer in Relation to Tumor Development and Treatment
International journal of molecular sciences, 2016
Although most cancer types have been viewed as immunologically silent until recently, it has become increasingly clear that the immune system plays key roles in the course of tumor development. Remarkable progress towards understanding cancer immunogenicity and tumor-immune system interactions has revealed important implications for the design of novel immune-based therapies. Natural immune responses, but also therapeutic interventions, can modulate the tumor phenotype due to selective outgrowth of resistant subtypes. This is the result of heterogeneity of tumors, with genetic instability as a driving force, and obviously changes the immunogenicity of tumors. In this review, we discuss the immunogenicity of colorectal cancer (CRC) in relation to tumor development and treatment. As most tumors, CRC activates the immune system in various ways, and is also capable of escaping recognition and elimination by the immune system. Tumor-immune system interactions underlie the balance between...
Immunotherapy in Colorectal Cancer
Colorectal Cancer - From Pathogenesis to Treatment, 2016
Colorectal cancer (CRC) remains one of the most common malignancies and the second leading cause of cancer-related death worldwide; treatment algorithms include surgery, chemotherapy and targeted therapies. Immunotherapy has recently emerged as an effective treatment approach in several types of cancer, including non-small cell lung cancer, melanoma and kidney cancer. In CRC, novel immune-checkpoint inhibitors such as anti-CTLA4 and PD1/PDL1 monoclonal antibodies have shown limited efficacy, although ongoing trials in mismatch repair-deficient CRC have shown significant and promising results. Here, we review the role of immune-microenvironment in colorectal cancer and current clinical data about therapeutic activity of immunotherapy in the treatment of CRC.
Cancer Immunology, Immunotherapy, 2012
Guanylyl cyclase C (GUCY2C) is the index cancer mucosa antigen, an emerging class of immunotherapeutic targets for the prevention of recurrent metastases originating in visceral epithelia. GUCY2C is an autoantigen principally expressed by intestinal epithelium, and universally by primary and metastatic colorectal tumors. Immunization with adenovirus expressing the structurally unique GUCY2C extracellular domain (GUCY2C ECD ; Ad5-GUCY2C) produces prophylactic and therapeutic protection against GUCY2C-expressing colon cancer metastases in mice, without collateral autoimmunity. GUCY2C antitumor efficacy is mediated by a unique immunological mechanism involving lineage-specific induction of antigen-targeted CD8 ? T cells, without CD4 ? T cells or B cells. Here, the unusual lineage specificity of this response was explored by integrating high-throughput peptide screening and bioinformatics, revealing the role for GUCY2C-directed CD8 ? T cells targeting specific epitopes in antitumor efficacy. In BALB/c mice vaccinated with Ad5-GUCY2C, CD8 ? T cells recognize the dominant GUCY2C 254-262 epitope in the context of H-2K d , driving critical effector functions including interferon gamma secretion, cytolysis ex vivo and in vivo, and antitumor efficacy. The ability of GUCY2C to induce lineage-specific responses targeted to cytotoxic CD8 ? T cells recognizing a single epitope mediating antitumor efficacy without autoimmunity highlights the immediate translational potential of cancer mucosa antigen-based vaccines for preventing metastases of mucosa-derived cancers.
A new mouse model for evaluating the immunotherapy of human colorectal cancer
Cancer research, 2001
A new murine model of human colorectal cancer was generated by crossing human carcinoembryonic antigen (CEA) transgenic mice (H-2K(b)) with adenomatous polyposis coli (Apc1638N) knockout mice (H-2K(b)). The resulting hybrid mice developed gastrointestinal polyps in 6-8 months that progressed to invasive carcinomas with a similar pattern of dysplasia and CEA expression as observed in human colorectal cancer. These animals exhibited incomplete or partial tolerance to CEA as evidenced by delayed growth of CEA-expressing tumors and the inability to inhibit CEA-specific CTL responses. These results have important implications for understanding the role of CEA-specific immunity in human colon cancer patients and suggest that vaccine strategies targeting CEA may be feasible. This model provides a powerful system for evaluating antigen-specific tumor immunity against spontaneous tumors arising in an orthotopic location and permits evaluation of therapeutic vaccine strategies for human color...
Immune landscape and biomarkers for immuno-oncology in colorectal cancers
Journal of Pathology and Translational Medicine
Colorectal cancer (CRC) is the second most commonly diagnosed cancer and the third leading cause of cancer-related death in Korea [1]. Because of rapid spread of colonoscopy screening, there was a general decrease in CRC until 2010. However, recent studies have reported that the decline in CRC incidence has reversed during the last few years, especially in middle-aged persons, and the occurrence of early-onset CRC has rapidly increased [2]. Most patients with CRC are diagnosed at an operable stage; however, approximately 20% of patients with stage III or high-risk stage II CRC relapse within 5 years after curative resection [3]. Moreover, the 5-year relative survival rate for metastatic CRC is 14% [2]. To improve clinical outcomes for patients with CRC, a more effective treatment modality is required to fulfill those unmet needs. Cancer is fundamentally a genetic disease since the accumulation of mutations, fusions, and copy number alterations drives tumorigenesis. However, recent research on the tumor immune microenvironment (TIME) has revealed the importance of interactions between tumor cells and surrounding immune cells in tumorigenesis [4]. Immune checkpoint inhibitor (ICI) treatment , such as anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibodies and anti-programmed death-1 (PD-1) antibodies, has shown marked clinical benefits in many types of cancer [5,6]. CRC also holds promise for cancer immunotherapy use, and the U.S. Food and Drug Administration (U.S. FDA) approved immunotherapeutic agents for microsatellite instability-high (MSI-H) CRC in 2017 (Fig. 1) [7,8]. In this review, we describe the landscape of the immune microenvironment in CRC and summarize the clinical usefulness of several suggested biomarkers in CRC immunotherapy. IMMUNE LANDSCAPE OF COLORECTAL CANCERS Historical use of microscopic evaluation of immune environment in CRCs To our knowledge, Spratt and Spjut [9] published the first study on integrative histologic evaluation of CRCs in 1967. In that study, the authors evaluated histologic grade, mucinous elements, depth of invasion, characteristics of tumor border, lym
Designing effective vaccines for colorectal cancer
Immunotherapy, 2014
Achieving long-term control of colorectal cancers with therapeutic vaccines that generate potent anti-tumor T cell and antibody responses has been a goal for more than two decades. To date, clinical trials of these vaccines have demonstrated induction of immune responses, but clinical benefit has been limited. Improved vector delivery systems with enhanced immunostimulatory properties, decreased immunogenicity against vector and improved antigen presentation are some of the key features of modern tumor vaccines. Furthermore, an improved understanding of the various immunosuppressive factors in the tumor microenvironment and regional lymph nodes, coupled with a burgeoning ability to impair inhibitory immune synapses, highlights a growing opportunity to induce beneficial antigen-specific responses against tumor. The combination of improved antigenic delivery systems, coupled with therapeutic immune activation, represents state-of-the-art colorectal vaccine design concepts with the goal of augmenting immune responses against tumor and improving clinical outcomes.