Impaired immunocompetence has long been recognized clinically in patients with head and neck cancer. The precise immunologic deficiencies and their relation to the development and progression of malignancy have not been completely delineated. Further elucidation of the mechanisms responsible for malignant transformation and the factors that regulate the immune response should generate effective methods of biological therapy. Tumor immunology examines the complex role of the immune system in recognizing and eliminating transformed cells that were once normal constituents of the host's tissues.
Certain risk factors have been associated with the development of head and neck cancer, although the mechanisms for cell transformation have not been determined. The leading etiologic factors consistently implicated in the development of head and neck cancer are tobacco and alcohol consumption. The products produced during the burning of tobacco yield numerous chemical irritants and carcinogens. Such substances, when combined with the effects of radiant and thermal heat, serve to initiate as well as promote the process of carcinogenesis. The alcohol consumption factor provides additional promoter activity in this complicated process. Ancillary consideration must be given to the possible cofactorial and/or etiologic role of viruses in the cause of head and neck cancer. A number of studies have linked the Ebstein-Barr virus to nasopharyngeal carcinoma and implicated herpes simplex virus in the etiology of other types of head and neck cancer. A high degree of variability with the respect to the incidence and demographic distribution of the various types of head and neck cancer may be attributable in part to nutritional status of the host, the immunologic status of the host, and/or biological diversity of the tumor itself in terms of its invasive properties and factors elaborated from the tumor cells.
Ionizing radiation is a carcinogen that can induce thyroid and salivary gland neoplasms as well as skin cancer. The carcinogenic effect of radiation appears to be due to injury to cellular DNA, with the resultant mutations, chromosomal breaks, and gene rearrangements. The effects of these genetic alterations may be related to the location of cellular oncogenes, which can initiate malignant cellular transformation.
Interference with immunity also results in an increased propensity for the development of malignancy. The processes associated with aging represent a natural or involutional interference with immunity, because cellular immune vigor wanes with increasing age. This is shown by the tuberculin skin reactivity of adults which decreases significantly after age 55. Coincidentally, the risk of developing cancer increases with age. Necessary interference with the human immune system in the form of therapeutic or incidental immunosuppression has resulted in an increased incidence of malignancy. This is evident in the increased risk of malignancy in transplant patients. It has also been well documented that many of the modalities used to treat carcinoma of the head and neck are themselves immunosuppressive. There also seems to be an increased incidence of malignancy among patients receiving chemotherapy. Prolonged therapy with cyclophosphamide reduces the circulating amount of lymphocytes and depresses the response to the lymphocyte mitogen phytohemagglutinin. Cyclophosphamide and methotrexate can inhibit the cutaneous response to PPD in experimental animals. It is possible that the immunosuppressive effects of such drugs are contributing to the genesis of the malignancy.
The etiology of immunosuppression in head and neck cancer patients is multifactorial and includes, but is not limited to, alcoholism, malnutrition, viruses, and aging. These patients are frequently elderly, often suffering from alcoholism and malnutrition, and relatively commonly have multiple primary malignancies. Immunosuppression of the delayed hypersensitivity system has been well documented in alcoholic patients even in the absence of carcinoma. Studies of alcoholics have demonstrated abnormalities in peripheral B and T lymphocytes. These abnormalities were found to be reversible following prolonged abstinence from alcohol. Likewise, tobacco has been shown to induce changes in both cellular and humoral immunity. It has been found that prolonged exposure to tobacco smoke is associated with diminished cytotoxicity and reactivity of the immune system. It may be that the immunologic changes noted with tobacco and alcohol reflect underlying malnutrition as opposed to those agents having direct effects. Several studies have noted changes in immune responsiveness following malnutrition. Law et al noted impaired T and B cell responsiveness in malnourished adults with depressed in vitro and in vivo T cell function. These changes could be reversed following nutritional repletion. With all of this in mind, it seems intuitive that correcting the underlying causes of immunosuppression will lead to an improved immune response against malignancy.
Because tumor transplantation experiments are not achievable in humans, little was known about tumor antigens in humans with cancer. A body of data has accumulated suggesting that the immune repertoire of patients with cancer contains B and T cells that recognize antigens expressed by autologous cancer cells. Much of the data about potentially immunogenic tumor antigens came from studies testing sera from cancer patients for antibodies against antigens expressed on autologous tumor cells. Studies employing human monoclonal antibodies derived from patients with cancer have provided further information.
Unique tumor antigens have been difficult to identify in head and neck cancers. Tumor- associated antigens found on normal and malignant cells have been demonstrated, and differentiating between the two types of cells has been possible only by taking advantage of qualitative and quantitative differences in expression. Carey et al found that the surface antigen characteristics of squamous cell carcinoma includes the expression of blood group antigen, beta2-microglobulin, pemphigus antigen, may or may not include pemphigoid antigen, and does not include expression of melanoma antigens or Ia antigens. This characteristic membrane antigen phenotype distinguishes this tumor type from tumors of other histologic origin and draws the thread of unity through all the squamous cell carcinomas.
Serologic techniques have been employed so that in every animal tumor system that has been appropriately studied, tumor-associated antigens have been demonstrated. Burkitt's lymphoma was the first human tumor studied serologically, and at least five distinct antigens are associated with this cancer. Most human tumors that have been rigorously studied appear to possess new antigens foreign to the host but related to the tumor. Human tumors that are demonstrably antigenic include melanoma, neuroblastoma, glioma, uroepithelial carcinoma, ovarian carcinoma, sarcoma, and colon carcinoma.
Monoclonal antibody technology has allowed the development of antibodies that bind to squamous cell carcinomas, although none are specific for the malignant cells. Two such antibodies are E84, which detects antigen in the desmosome region, and A9, which serves as a cell attachment receptor. These antibodies may be useful diagnosis or treatment of squamous cell cancer.
The major histocompatibility complex is a group of genes that encode molecules involved in the immune response. These gene products are grouped into two classes. Class I products are found on all nucleated cells; class II products are found on cells of the immune system. Tumor cells express surface antigens that may play a role in generating immunological signals, and the quantity of these immunologically active antigens may be affected by exposure to cytokines. HLA-DR, a class II MHC molecule that is involved in the processing of antigenic signals, has been demonstrated on the surface of squamous cell carcinomas from the head and neck after induction with interferon gamma. MHC-II molecules are involved in processing foreign antigens and may have a similar role in head and neck cancer.
Immunologic recognition of a foreign or nonself antigen may occur by a more complex mechanism than previously supposed. If unique tumor antigens exist, an explanation is necessary for the inadequate immunologic response to the malignant cell. Mechanisms of immunological escape address the central paradox of tumor immunology which is why neoplasms which are demonstrably immunogenic elude the effector arm of the immune system. Immunological escape may occur when the balance between factors favoring tumor growth and destruction are tilted in the favor of the tumor. The factors that may contribute to immunological escape include tumor kinetics, antigenic modulation, antigen masking, blocking factors, tolerance, genetic factors, tumor products, and growth factors. Tumor cells may not be recognized by the host when they are present in such small amounts until growth is established and beyond recall. Antigenic modulation facilitates escape by removing the target antigens that the immune system's effector cells would recognize, and is known to occur in some instances when administering xenogeneic antibodies for immunotherapy. Tumor escape from effector cells may also occur because certain molecules bind to the surfaces of the tumor cell and mask the tumor antigens which prevents adhesion of attacking lymphocytes. Genetically determined unresponsiveness to tumor antigens occurs when the function of the MHC haplotype causes a failure to induce an effector T cell response. The products of tumors other than antigens can cause a subversion of the immune response. Such products include prostaglandins and other humoral factors that act to impair inflammatory responses, chemotaxis, and the complement cascade. The ability of a tumor to escape from immunological control may depend on a balance between the effectiveness of the immune system and a variety of the factors above that promote escape.
Cell-mediated immunity to tumors is similar to that evoked against T cell-dependent transplantation and other cell surface glycoprotein antigens. T cell activation involves the generation of helper and suppressor subsets as well as cytotoxic lymphocytes. The cytotoxic lymphocytes recognize tumor antigen in association with class I MHC products. Activation also leads to the production of lymphokines by the helper T cells which are important in the recruitment and activation of macrophages, natural killer cells, and lymphokine activated killer cells. Activated T cells then have a cryostatic or cytolytic effect on the tumor cells.
Most studies of the systemic immunity in patients with head and neck malignancies have yielded evidence for decreased immunologic function. Whether these changes are due to the predisposing conditions outlined previously or are a function of the malignancy itself is not known. The bulk of the evidence would support the presence of altered immune function in patients with head and neck cancer as well as other malignancies. Regardless of its etiology, impaired cellular reactivity has been consistently demonstrated in patients with carcinoma of the head and neck. Determination of the peripheral total lymphocyte count appears to correlate quite closely with other measures of cellular immunity. This measure appears to have prognostic implications for patients with carcinoma of the head and neck. By far, the most complex assays of the cell-mediated immune system are those that monitor lymphocyte reactivity. These tests are in vitro assays and consist of exposing the patient's lymphocytes to a variety of stimuli. The stimuli may consist of common recall antigens, specific tumor antigens, or nonspecific stimulants. These tests must be done in the research lab and are quite costly to obtain, so they are not widely used. Therefore, it is more common to determine the peripheral lymphocyte count to determine the status of the cellular immune system. Many studies have attempted to quantitate the number of circulating lymphocytes in the blood of patients with head and neck cancer. These studies have noted a depression in the total number of T lymphocytes. Wanebo et al noted that there was an absolute decrease in T and B cell levels in patients with head and neck cancer. In addition, the absolute T cell counts were noted to decrease with advancing disease. It has also been found that there is a decrease in the stimulation of lymphocytes in patients with head and neck cancer. Wanebo et al also evaluated lymphocyte stimulation in patients with resectable head and neck cancer. Forty percent of the patients were found to have a significant depression of in vitro blastogenic responses. The incidence of depressed mitogenic activity increased with the stage of disease, ranging from 15% in T1N0M0 lesions to 71% in T3N0M0. Depression of mitogenic reactivity was more pronounced in patients with cervical node metastasis but was related more to the size of the primary tumor.
In addition to the evaluation of circulating lymphocytes, attention has also focused on regional immune reactivity. A review of the morphologic changes associated with lymph nodes draining head and neck cancer reported a pattern of lymphocyte predominance. Berlinger et al blindly evaluated the morphologic pattern of lymph nodes from 84 patients with head and neck cancer and correlated their findings with survival. Patients whose lymph nodes demonstrated an active immunologic response, as defined by expanded inner cortices or increased numbers of germinal centers, had a greater 5-year survival. Conversely, no patients whose lymph nodes had a depleted or unstimulated pattern were alive in 5 years. The authors concluded that these results are indicative of a relationship between regional immunoreactivity and survival in head and neck malignancy. Patients whose lymph nodes demonstrated lymphocyte predominance had a better survival than those with germinal center predominance or an unstimulated pattern.
Although there is little doubt that the cellular immune system is the division of the immune system that is most responsible for the destruction of neoplastic cells, it is becoming increasingly apparent that the humoral immune response may, in certain instances, augment the cellular response, such as the phenomenon of antibody-dependent cellular cytotoxicity (ADCC). Central to an understanding of the immune response to cancer is a recognition of the role of the immunoglobulins in the effector mechanism. The immunoglobulins are serum glycoproteins produced by B lymphocytes in response to foreign antigens. The hallmark of the immunoglobulins is their specificity and ability to bind directly to the substance that elicited their production. Each immunoglobulin molecule is composed of two heavy chains and two light chains, each with variable and constant regions. Classification of the heavy and light chains based on differences in the constant regions allows differentiation into two types of light chains, kappa and lambda, and five types of heavy chains, mu, gamma, delta, epsilon, and alpha. The heavy chain classification determines the class of immunoglobulin molecule: IgM, IgG, IgD, IgE, and IgA. The antigen binding site is formed by amino acid sequences located in the variable regions of the heavy and light chains. Much of the immunologic diversity attributable to immunoglobulins occurs through genetic recombinations that change the antigenic determinants of the variable regions. In this way, the immunoglobulins exhibit antigenic specificity and differences in their secondary biologic activities.
The immunoglobulins primarily involved in the immunological response to cancer are IgG and IgA. IgG is the predominant immunoglobulin in the serum, and it appears to play an important role in the cytotoxic assault against malignant cells through two mechanisms. Complement fixation to IgG molecules bound to tumor cells can cause cell death. Molecules in the serum from patients with head and neck cancer have the capacity to bind the first component in the complement cascade. These molecules may be circulating immune complexes made up of tumor antigen bound to immunoglobulin. An alternative and perhaps more efficient mechanism involves ADCC. The immunoglobulin binds to a specific antigenic target on the tumor cell and attaches to an effector cytotoxic cell by means of the Fc receptor. ADCC has functioned in vitro in the immune response to squamous cell carcinoma of the head and neck using peripheral blood lymphocytes directed against pemphigus antigen present on the malignant cells.
The function of IgA in the immunologic response to cancer is less clear. IgA exists as a monomeric circulatory form and a dimeric secretory form. IgA is not capable of binding complement, however, complement can be activated via the alternate pathway by an aggregation of circulatory IgA. It also does not elicit a chemotactic or phagocytic response after binding to an antigen. IgA seems to confer a protective effect for the tumor by isolating malignant cells from cytotoxic mediators. Elevated levels of total serum IgA have been noted to indicate a poor prognosis in patients with carcinoma of the head and neck. IgA levels rise significantly in the presence of metastatic disease and appear to be directly related to total tumor burden. Total serum IgA levels have been correlated with the extent of disease in nasopharyngeal carcinoma, and IgA has been shown to interfere with the destruction of tumor in various types of human malignancies. Tumor regression and temporary restoration of the immune response have been documented in patients who have carcinoma of the head and neck and who have undergone plasmapheresis.
The body fluids of cancer patients frequently contain immune complexes, which have been measured in head and neck cancer patients. Elevated levels of immune complexes in the serum have in some instances been correlated with prognosis and clinical course. Maxim et al measured immune complex levels in head and neck cancer using the Raji cell assay. It was noted that elevated levels of immune complexes were present in greater than 80% of head and neck cancer patients when compared to normal controls. Other studies have confirmed this, however, there has been a marked variability in the incidence of elevated levels of circulating immune complexes. A major question is whether the immune complexes associated with malignancy represent a response to the presence of tumor or are somehow involved with immunosuppression and tumor promotion.
The antitumor responses of the immune system depend on a group of immunomodulatory peptides produced by the mononuclear cells. These cytokines are classified into the categories of interleukins, interferons, growth factors, and colony-stimulating factors. In the immune response to cancer, the cytokines regulate and activate other cellular effectors, affect growth and differentiation of the tumor cells and surrounding tissues, and participate directly as cytotoxic agents. Cloning of the genes for the cytokines has enabled large-scale production of homologous products, fueling the investigative uses of the agents.
The interferons function as immunomodulary, anti-inflammatory, and cytotoxic agents. There are three distinct subclasses of interferon have been identified, two of the subclasses are referred to as type I interferons, interferon alfa and interferon beta. Interferon gamma, a type II interferon, is produced only by T lymphocytes and large granular lymphocytes in response to antigenic stimuli. In addition to their anti-viral effects, the interferons mediate a large range of biologic responses, including antitumor cytotoxicity, inhibition of cell proliferation, gene activation, modulation of cell-surface antigens, immune cell activation, and stimulation of other cytokines and immunomodulators. These effects occur as a result of direct binding of the interferon to specific cell-surface receptors on the target. The exact events responsible for the cytolytic and cytostatic effects of the interferons are not yet resolved. Interferon gamma has shown direct cytotoxic effects against squamous cell carcinoma of the head and neck in vitro. These responses depend on the cumulative interferon gamma dose and duration of exposure. In vivo, interferon gamma can produce cytolysis and increase tumor cell differentiation. It may also enhance the cell-mediated response to head and neck cancer. On the basis of several trials, it appears that interferon has a role in the treatment of squamous cell carcinoma. There is now mounting evidence that the combination of interferon and chemotherapy may have a role to play in the treatment of malignancy. Several trials have been completed revealing that interferon and 5-florouracil or cis- platinum have efficacy in treating certain malignancies. Interferon gamma is also capable of enhancing the antitumor effects of other cytokines, such as tumor necrosis factor.
The interleukins encompass a group of proteins produced by leukocytes and other cells that exert a wide array of overlapping immunologic and nonimmunologic effects. Several interleukins have been identified and are known as interleukin 1 through interleukin 8. Interleukin 1 has a diverse immunologic, inflammatory, and reparative actions. It is produced by most nucleated cell types. The immunologically significant inducers of interleukin 1 include antigens presented in conjunction with class II MHC molecules and other cytokines such as interferon gamma and tumor necrosis factor. Interleukin 1 significantly influences the cells responsible for generating an immune response against tumor. Interleukin 1 enhances T lymphocyte proliferation by inducing interleukin 2 production from other lymphocytes. Interleukin 1 also augments the cytotoxic and antigen-presenting capabilities of the macrophages, stimulates release of other chemoattractant cytokines, stimulates significant osteoclast activation with marked bone resorption, and induces the cellular adhesion molecule on vascular endothelium.
Interleukin 2 which is produced by activated T lymphocytes and has a central role in the immune response. This cytokine is essential for stimulating T cell, B cell, and NK cell proliferation and inducing lymphokine production by these effectors. Interleukin 2 secretion by helper T cells responding to MHC II associated antigens appears to provide the major stimulus for activation of cytotoxic T cells and NK cells directed against tumor cells. The ability of interleukin 2 to generate effective cytotoxic cells has been used in the development of strategies for immunotherapy. Lymphoid cells incubated with interleukin 2 become capable of lysing fresh tumor cells. These activated cells are known as lymphokine-activated killer cells. Interleukin 2 has been administered systematically in a number of phase I clinical trials. A pilot clinical trial of interleukin 2 was reported by Forni et al in patients with recurrent inoperable squamous cell carcinoma of the head and neck. Of the five cases evaluate, partial or complete resolution of tumor was noted in four patients. No responses were noted in patients who had received a previous functional or radical neck dissection. It was postulated that this was due to the removal of draining lymph nodes and the loss of any local lymphoid response. Others have noted antitumor activity in head and neck cancer following treatment with intra- arterially infused LAK cells.
Another lymphokine that participates in the immune response to tumor is interleukin 4. It is produced by activated T lymphocytes. It stimulates B cell immunoglobulin production, immunoglobulin isotype switching, and MHC II and Fc receptor expression. It is also a potent activator of macrophages resulting in enhanced tumor-antigen presentation and cytotoxic ability. Tumor growth factor beta is an immunoregulatory peptide that inhibits many of the effector mechanisms responsible for the antitumor response. It is able to suppress in vitro the mitogenic activity of interleukin 2 on T and B lymphocytes, NK cell cytotoxic function, and interleukin 2 induced LAK cell development.
The complexity of the immune effector interactions responsible for detection and control of malignant cells is evident. Tremendous overlap exists in the regulatory mechanisms generated by the different cells and cytokines involved in tumor-host interaction. A growing understanding of the mechanisms involved in the antitumor response is leading to implementation of therapies directed at augmenting the immune system to improve the results of cancer treatment.
Many of the active therapeutic managements evolved after clinicians observed that some patients with tumor who developed severe postoperative infections exhibited significant tumor regression and increased survival. The infectious agents caused a broad immunologic reaction with cytotoxic cell activation. Tumor vaccine development has been limited by several factors: tumor-specific antigens are difficult to identify; malignant cells express a significant degree of heterogeneity; tumor cells seem capable of altering their antigenic presentation, especially for the MHC antigens; and tumors may produce suppressive factors or augment the function of suppressor T cells, which inhibit the immune response. The effectiveness of the vaccine is inhibited by these factors and it makes it difficult for the host's response mechanisms to identify tumor and differentiate between malignant and normal cells.
Non-specific active immunization employs a diversity of reagents which affect the immune response and are called biological response modifiers (BRM). Of these, the most extensively tested have been BCG, interferon, and interleukin 2. One of the continuing problems of the use of BRMs has been to ensure that the cells which are stimulated are the correct population, that is, it is essential that the treatment does not stimulate cells with suppressive activity. Very little benefit has been found with the use of BCG on patients with various solid tumors, but intralesional injection can cause regression of melanoma lesions. Most of the recent clinical attention has been focused on the use of the interferons and interleukin 2 as single agents and in combination with tumor reactive lymphocytes obtained from the patient's circulating cell pool, LAK cells, or from the tumor itself, tumor-infiltrating lymphocytes (TIL). These agents use has been complicated by difficulties in establishing the appropriate antitumor or immunomodulatory dosages, routes of administration, and the isolated physiologic roles. Systemic administration of interferon gamma has resulted in increased tumor cell differentiation and NK cell activity, suggesting important effects at the local and systemic levels. Similar effects have been found with interferon alfa, although the cytotoxic effect has not been as profound for squamous cell carcinoma as it has been for some hematological malignancies.
Interleukin 2 administered systemically and perilesionally for squamous cell carcinoma of the head and neck has demonstrated antitumor and immunomodulatory activity. Activation of peripheral NK cells after administration of systemic interleukin 2 and interferon alfa has been documented. Systemic interleukin 2 as a single agent therapy has been associated with significant morbidity and few clinical responses. However, immunotherapy with LAK cells in combination with high dose systemic interleukin 2 has produced significant regression of established metastatic disease in animal and human studies by Rosenberg and colleagues. In vivo studies in nude mice have shown significant inhibition of squamous cell carcinoma tumor growth with local or systemic administration of LAK and interleukin 2. Current attempts to generate more homogeneous populations of LAK cells with greater cytotoxic effects may lead to improved clinical outcome with decreased toxicity. Evidence suggests that a significant mononuclear infiltrate in the tumor may be related to improved prognosis and survival in patients with head and neck cancer. Methods have been developed for harvesting the tumor-infiltrating cells (TIL) and clinical trials have been developed to use them for immunotherapy. Treatment with TILs involves their activation by interleukin 2 which results in effectors with significant cytolytic activity against autologous tumor. In vitro studies with head and neck squamous cell carcinoma cultures and TIL therapy demonstrated significant tumor regression, with response rates higher than those achieved with LAK cells and interleukin 2. The cytolytic specificity of TILs for autologous tumor results from MHC restriction. This specificity makes this form of immunotherapy very appealing, but further investigation is needed to determine its effectiveness in head and neck cancer.
Passive immunotherapy using monoclonal antibodies entails the transfer of antitumor antibodies to cancer patients in order to cause tumor regression or to prevent tumor recurrence. The identification of tumor-specific antigens to which antibodies can be produced remains an investigative concern. Many investigative approaches have conjugated a cytotoxic or localizing agent to the monoclonal antibody. The cytotoxic reagents employed include radioisotopes, toxins, chemotherapeutic drugs, and cytokines. However, since many monoclonal antibodies target tumor-associated antigens on malignant and normal cells, some of the antibody conjugates may prove to be too toxic or nonspecific for therapeutic use. Future clinical applications will depend on identification of tumor-specific antigens and refinements in toxic mediators.
Carey TE, et al. Antibodies to human squamous cell carcinoma. Otolaryngology - Head and Neck Surgery 91(5): 482-91.
Collins SL. Controversies in management of cancer of the neck. In: Thawley, Panje, Batsakis, Lindberg, eds. Comprehensive Management of Head and Neck Tumors, Vol. 2. Philadelphia: WB Saunders Co.; 1987: 1286-1443.
Cortesina G, et al. Immunology of head and neck cancer: perspectives. Head and Neck 15(1): 74-7, 1993.
Cortesina G, et al. Immunomodulation therapy for squamous cell carcinoma of the head and neck. Head and Neck 15(3): 266-70, 1993.
Dawson M, Moore M. Tumor immunology. In: Roitt I, Brostoff J, Male D, eds. Immunology 2nd ed. Philadelphia: JB Lippincott Co.; 1989: 18.1-18.18.
Katz AE. Update on immunology of head and neck cancer. In: Josephson JS, ed. The Medical Clinics of North America: Update on Otolaryngology Head and Neck Surgery II. 77(3).Philadelphia: WB Saunders Co.; 1993: 625-34.
Lewis JJ, Houghton AN. Definition of tumor antigens suitable for vaccine construction. Seminars in Cancer Biology 6: 321-27, 1995.
Livingston PO. Introduction: cancer vaccines. Seminars in Cancer Biology 6:319-20, 1995.
Richtsmeier WJ, Scher RL. Immunology of head and neck cancer. In: Bailey BJ, ed. Head and Neck Surgery - Otolaryngology. Philadelphia: JB Lippincott Co.; 1993: 1050- 60.
Schantz SP, et al. The in vivo biologic effect of interleukin 2 and interferon alfa on natural immunity inpatients with head and neck cancer. Archives of Otolaryngology/Head and Neck Surgery 116(11): 1302-8, 1990.
The TH, Leij DE. Search for tumor antigen. In: Veldman JE, ed. Immunobiology, Histopathology, Tumor Immunology in Otorhinolaryngology. Berkeley: Kugler Publication; 1987: 387-92.
Veltri RN. Immune regulation in carcinoma of the head and neck. In: Chretien PB, Johns ME, Shedd DP, Strong EW, Ward PH, eds. Head and Neck Cancer, Vol. 1. Philadelphia: BC Decker, Inc.; 1985: 564-7.
Vlock DR. Immunobiologic aspects of head and neck cancer - clinical and laboratory correlates. In: Vokes EE, ed. Hematology/ Oncology Clinics of North America: Head and Neck Cancer. 5(4); Philadelphia: WB Saunders Co.; 1991: 797-815.
Weiss JF, Chretien PB. Interrelationship of immune response, circulating proteins, and etiologic factors for head and neck cancer. In: Chretien PB, Johns ME, Shedd DP, Strong EW, Ward PH, eds. Head and Neck Cancer, Vol. 1. Philadelphia: BC Decker, Inc.; 1985: 559-63.
Wolf GT. Head and neck tumor immunology. In: Veldman JE, ed. Immunobiology, Histopathology, Tumor Immunology in Otorhinolaryngology. Berkeley: Kugler Publications; 1987: 343-54.