Showing papers on "Tumor antigen published in 1983"

Resistance of human cells to tumorigenesis induced by cloned transforming genes

Abstract: The transformation of human cells was examined by transfection of cloned oncogenic DNAs derived from the tumor virus simian virus 40 and from the human bladder carcinoma cell line EJ into diploid fibroblasts derived from foreskin (FS-2 cells). The simian virus 40 DNA was found to induce a morphologically transformed phenotype, leading to easily detectable focus formation. Tumor antigen was produced, but the transformed cells were not tumorigenic in the nude mouse. The EJ gene, a mutant form of the cellular c-Ha-ras gene, actively transforms NIH/3T3 mouse cells and CHEF/18 hamster cells but is inactive in FS-2 cells. Morphological transformation, focus formation, and tumorigenicity in nude mice were not induced when EJ DNA was transfected into FS-2 cells by using the selectable vector pSVgptEJ. The intactness of the transfected EJ DNA was established by restriction fragment analysis. This result raises the question of what role, if any, the mutated gene derived from the EJ cells played in the origin of the EJ bladder carcinoma.

A pigmentation-associated, differentiation antigen of human melanoma defined by a precipitating antibody in human serum.

Abstract: Antibodies in the serum of melanoma patient AU precipitate an antigen from 125I-labelled extracts of cultured autologous melanoma cells. The antigen, which is probably not a cell surface component, is present in other pigmented melanomas but not in non-pigmented melanomas or other tumor cell types, and the amount of antigen is correlated with the degree of pigmentation. These conclusions are based on absorption experiments with 11 pigmented melanomas, 8 non-pigmented melanomas, 3 astrocytomas, 12 carcinomas of various histological types, 1 leukemia, 2 EB-virus-transformed B lymphocyte lines, and human erythrocytes. The antigen was also detected in cultured human melanocytes. It has a molecular weight of 70,000, an isoelectric point of pH 5.3, and it binds to concanavalin A-Sepharose. Ninety-six sera from other melanoma patients were examined and none of them precipitated this antigen. As described previously, the serum from patient AU also has antibodies to a unique (Class 1) tumor antigen found only on AU melanoma cells. The pigmentation-associated, differentiation antigen and the unique antigen are clearly different in their distribution, but some relationship between these unusual antibody responses is possible.

Recognition by cytotoxic T lymphocytes of cells expressing fragments of the SV40 tumor antigen.

Abstract: Recognition by cytotoxic T lymphocytes (CTL) of syngeneic cells transformed with simian virus 40 (SV40) was examined by using cells expressing known portions of the SV40 early region both as sensitizing cells for stimulation of CTL development and as targets for lysis by CTL LMTK- cells transfected with a plasmid specifying a 33K amino-terminal fragment of the SV40 tumor (T) antigen served both to stimulate syngeneic CTL capable of lysing SV40 transformed cells and as target cells for CTL generated against syngeneic transformants The same is true for cells infected with the adenovirus 2-SV40 hybrid viruses, Ad2+ND1 and Ad2+ND2, which produce proteins homologous with carboxy-terminal regions of the SV40 T antigen These findings indicate that on cells transformed by SV40 virus, and expressing the entire T protein, determinants in both the amino- and carboxy-terminal regions of the molecule are exposed on the cell surface Furthermore, determinants in both these regions are recognized independently in the polyclonal CTL response to SV40

Simian virus 40 tumor antigen: isolation of the origin-specific DNA-binding domain.

Abstract: To localize the origin-specific DNA-binding domain on the simian virus 40 tumor (T) antigen molecule, we used limited proteolysis with trypsin to generate fractional peptides for analysis. A 17,000-Mr peptide was found to be capable of binding not only to calf thymus DNA, but also specifically to the simian virus 40 origin of DNA replication. This approximately 130-amino-acid peptide was derived from the extreme N-terminus of the T antigen and represented less than one-fifth of the entire molecule. The coding sequence for this tryptic peptide was located approximately between 0.51 and 0.67 map units (excluding the intron, which maps between 0.54 and 0.59). Since the first 82 amino acids are shared between large T and small t antigens, and since the latter does not bind DNA, it can be concluded that the sequence between isoleucine 83 and approximately arginine 130 is necessary for origin-specific binding by the T antigen. We also observed that in vivo phosphorylation of the T antigen within this region completely abolished the ability of the 17,000-Mr peptide to bind DNA. This observation is consistent with the idea that DNA binding by the T antigen is regulated by posttranslational modifications.

Selection of macrophage-resistant progressor tumor variants by the normal host. Requirement for concomitant T cell-mediated immunity.

Abstract: The ultraviolet radiation-induced fibrosarcoma 1591 is generally rejected by normal syngeneic mice, but occasionally the tumor succeeds in growing progressively. Analysis of these progressively growing tumors has regularly demonstrated the development of tumor variants that have acquired a heritable progressive growth potential. We have analyzed the phenotypic changes of these variants to determine which kind of selection pressure had occurred during the evolution of the variants, thus giving insight into the relative importance and hierarchy of the different immune defense mechanisms that may be operating in normal individuals as a defense against neoplastic cells. We discovered that all of the host-selected progressor variants had lost not only a strong T cell-recognized and tumor-specific antigen, but also their high sensitivity to cytotoxic macrophages. No selection for macrophage-resistance or loss of the tumor antigen was observed in 1591 tumors reisolated from idiotypically-suppressed mice or from other mice lacking tumor-specific T cell immunity. Analysis of other tumor variants selected in vitro showed that 1591 tumor cells have the potential to lose sensitivity to tumoricidal macrophages without losing the T cell-recognized tumor antigen. Thus the data suggest that T cells and macrophages act together to suppress the outgrowth of potentially malignant cells in vivo.

Suppression of the responsiveness of lymphocytes from cancer patients triggered by co-culture with autologous tumor-derived cells.

Abstract: The question as to whether or not cancer patients have "tumor antigen"-induced suppressor T cells is of considerable interest and importance. As an approach to that question, the effect of addition of autologous irradiated tumor-derived cells (TDC) on the mixed lymphocyte response (MLR) of patients' lymphocytes (Ly) and of healthy donor Ly was tested. The rationale for these experiments was based on the fact that circulating antigen-responsive blood lymphocytes can be reactivated in vitro by exposure to the appropriate antigen. Thus, if there are circulating tumor "antigen"-reactive suppressor Ly, exposure to TDC as a source of the antigen should reactivate those cells. Reactivation of suppressor cells might result in diminished responsiveness to other stimuli such as alloantigens in the mixed leukocyte culture. We found that the addition of TDC to Ly cultures produced four distinct patterns of reaction. In 26 of the 74 different patient-tumor assays, the addition of autologous TDC to the patient cultures inhibited MLR, but the addition of the same TDC to cultures of Ly from healthy donors had no effect or increased their responsiveness (Specific Suppression). In 21 cases, the addition of autologous TDC to the patient cultures suppressed the MLR and the addition of the same TDC to control cultures suppressed the response of some but not all the healthy donors (Selective Suppression). In four cases, the addition of TDC to the cultures suppressed the MLR of the patients and all of the control donors (Nonspecific Suppression). In 23 cases, the addition of autologous TDC resulted in no suppression of the patient MLR or of any of the simultaneously tested normal donors (No Suppression). When TDC of patients with noninvasive bladder cancer were added to their own Ly cultures, only four of 11 produced specific or selective suppression compared to 11 of 12 when TDC came from patients with superficially invasive cancer. These data provide indirect evidence to support the hypothesis that human tumors induce circulating suppressor cells that may be reactivated in vitro by co-culture with TDC.

Human adenovirus 2 E1B-19K and E1B-53K tumor antigens: antipeptide antibodies targeted to the NH2 and COOH termini.

Abstract: The human adenovirus 2 (Ad2) transforming region is located in the left 11.1% of the viral genome and encodes two early transcription units, E1A and E1B. Based on the amino acid sequence deduced from the Ad2 E1B DNA sequence (Gingeras et al., J. Biol. Chem. 257:13475-13491, 1982), we have prepared antibodies against synthetic peptides, 8 to 16 amino acids in length, encoded at the NH2 and COOH termini of the major E1B-19K and E1B-53K tumor antigens. The antipeptide antibodies immunoprecipitated the targeted E1B-19K or E1B-53K tumor antigens from extracts of Ad2-infected cells. The specificity of the peptide competition studies. Antipeptide antibodies directed to the NH2 and COOH termini immunoprecipitated the E1B-19K and E1B-53K tumor antigens from two Ad2-transformed rat cell lines, F17 and F4, providing evidence that identical tumor antigens are synthesized in Ad2-infected and Ad2-transformed cells. These results show that the E1B-19K and E1B-53K T antigens are not processed proteolytically at either the NH2 or COOH terminus. Our data provide strong evidence at the protein level that the E1B-19K and E1B-53K tumor antigens partially overlap in DNA sequence, with the E1B-19K initiating translation at the first ATG at nucleotide 1711 in translation reading frame 1 and the E1B-53K tumor antigen initiating translation at the second ATG at nucleotide 2016 in reading frame 3. This confirms the results of others on the N-terminal amino acid sequence of E1B-19K and theoretical deductions based on the DNA sequence. Our findings prove that the large E1B-53K T antigen initiates translation at the second ATG at nucleotide 2016 and not at equally plausible initiation codons located farther downstream at nucleotides 2202 and 2235. Thus, the E1B-53K T antigen is another example of a protein which initiates translation at an internal ATG rather than at the 5'-proximal ATG.

Purification of biologically active simian virus 40 small tumor antigen.

Abstract: The simian virus 40 small tumor antigen (t antigen) gene has been cloned downstream from a hybrid Escherichia coli trp-lac promoter and a suitable ribosome binding site. A bacterial clone (865i) transformed by such a plasmid (pTR865) expresses this gene and, under optimal conditions, can produce greater than or equal to 5% of its total protein as t antigen. Soluble extracts of such a clone were relatively depleted in t antigen, which was found in the initial pellet fraction. The protein was recovered from this fraction in a significantly purified form by extraction with urea-containing buffer. After gel filtration of such t antigen-enriched solutions, highly purified protein was obtained. When either this fraction (freed of urea) or NaDodSO4 gel-purified 865i t antigen (rendered free of detergent) was injected into untransformed rat cells, dissolution of intracellular actin cable networks was observed.

Simian virus 40 large tumor antigen on replicating viral chromatin: tight binding and localization on the viral genome.

Abstract: Pulse-labeled simian virus 40 (SV40) chromatin as well as uniformly labeled viral chromatin are immunoprecipitable by an SV40-specific tumor antiserum and therefore contain bound tumor antigen (T antigen). Single-stranded calf thymus DNA, immobilized on cellulose, competes effectively for T antigen binding with uniformly labeled nonreplicating, but not with pulse-labeled replicating, chromatin. Furthermore, T antigen dissociates in 0.5 M NaCl from nonreplicating chromatin and from purified SV40 DNA, whereas most T antigen remains associated with replicating chromatin even in the presence of 1.2 to 1.5 M NaCl. We used filtration through DNA-cellulose columns and treatment with high salt to prepare pulse-labeled immunoreactive viral chromatin. The viral DNA was digested before, and in other experiments after, immunoprecipitation with the restriction endonuclease HindIII. We found that SV40 DNA sequences, most probably representing the entire genome, remain in the immunoprecipitate after HindIII digestion, indicating an association of T antigen with origin-distal sections of replicating viral DNA. The results suggest that T antigen in replicating chromatin may be bound to regions close to replicating points. We performed control experiments with in vitro-formed complexes of T antigen and SV40 DNA. When these complexes were immunoprecipitated and HindIII digested we found, in agreement with previous studies, that only the origin containing the HindIII C fragment carried bound T antigen.

Stabilization of the 53,000-dalton nonviral tumor antigen is not required for transformation by simian virus 40.

Abstract: We have isolated a simian virus 40 deletion mutant, F8dl, that lacks the sequences from 0.168 to 0.424 map units. The deleted sequences represent about one-half of the coding region for large T antigen. We present evidence here that F8dl is able to transform mouse cells in a focus assay and that cell lines derived from these foci exhibit fully transformed phenotypes, have integrated mutant genomes, and express mutant-encoded proteins. This result implies that the region of the simian virus 40 genome between 0.168 and 0.424 map units is not essential for the maintenance of transformation. In addition, we have found that cells fully transformed by F8dl produce a 53,000-dalton nonviral tumor antigen (p53) that is as unstable as the p53 of untransformed cells. From this result we infer that transformation by simian virus 40 does not require the stabilization of p53.

Transformation of rodent cells by DNA extracted from transformation-defective adenovirus mutants.

Abstract: Complementation group II host range mutants of adenovirus type 5 which map in early region 1B (E1B, 4.5 to 11.0 map units) have been shown to be defective for the synthesis of the E1B 58,000-dalton (58K) antigen in infections of HeLa or KB cells (Lassam et al., Cell 18:781-791, 1979) and unable to transform cultured rodent cells (Graham et al., Virology 86:10-21, 1978). In this report we show that DNA extracted from group II mutants hr6 and hr50 can transform rat cells with the same efficiency as wild-type DNA. Furthermore, group II mutant-transformed hamster cells were shown to contain no detectable E1B 58K tumor antigen but were capable of inducing tumors in newborn hamsters. Hamster cell lines 1019-3 and 1019-C3, transformed by hr50 DNA, produced no detectable quantities of either the E1B 58K or 19K antigen but nonetheless exhibited a fully transformed oncogenic phenotype. Our results show that the E1B 58K antigen is not absolutely required for oncogenic transformation and suggest that even cells lacking the 19K protein can be oncogenic.

Suppressor mechanisms in tumor immunity.

Abstract: There are many parallels between T cell-mediated suppression of tumor immunity and suppression of immune responses to haptens and polypeptides. We propose a cell interaction model which takes this into account and outlines a regulatory pathway for suppression of immunity to tumor antigens. Free antigen or antigen/antibody complexes trigger an inducer T cell subset, Tsi, which is tumor-specific. This cell activates a non-immune T cell population, pre Ts3, to generate effector suppressor cells, Tse. The Tse are specific for either the idiotype of Tsi or for antigen complexed with a soluble factor made by the Tsi, but the suppression they mediate is antigenically nonspecific. Tumor antigen-specific suppressor factors, TsF, play a major role in the communication between different suppressor cells. Characterization of polyclonal and monoclonal factors produced by Tsi, called TsFi, indicates that they both bind to tumor antigen and contain tumor-specific (idiotypic?) determinants.

Biological Response Modifiers Program

Abstract: The Biological Response Modifiers Program (BRMP) is a comprehensive program of the Division of Cancer Treatment (DCT), National Cancer Institute (NCI), involved in clinical and laboratory research with extramural and intramural components to investigate, develop, and bring to clinical trials potential therapeutic agents that may alter biological responses important in the biology of cancer growth and metastasis. This program was conceived as a focused approach in the DCT to support further basic research in biological response modifiers (BRM) and to rapidly apply these potential leads from that research to the treatment of cancer in man. The classes of agents being investigated in this program include immunoaugmenting, immunomodulating and immunorestorative agents, interferons and interferon inducers, lymphokines, cytokines and growth factors, thymic factors, tumor antigens and modifiers of tumor antigen cell-surface components, antitumor antibodies, antitumor cells, and maturation and differentiation factors. It is recognized that considerable research is underway in each of these areas, but a focused, coordinated approach by the NCI may result in the rapid acquisition of knowledge and a more rapid application of information to the treatment of cancer.

In vitro lyt-1+2-cell proliferative responses to cellbound or subcellular tumor antigen.

Abstract: We investigated the cellular basis of immune reactivity to the S1509a fibrosarcoma in tumor-immune A/J mice. In a Winn assay, immune Lyt-1+2- T cells are capable of retarding S1509a tumor growth in naive A/J mice. In vitro proliferation to S1509a is also mediated by tumor-immune Lyt-1+2- T cells. This response is specific to the immunizing tumor and appears 5 to 7 days after reexposure to the tumor in vivo. Proliferation also requires the presence of a population of adherent cells. In fact, adherent peritoneal exudate cells pulsed with tumor membrane fragments derived from S1509a cells can stimulate proliferation. Proliferation is blocked by the addition of anti-I-Ak monoclonal antibody to the culture medium without complement or by treatment of the responder population with anti-I-Ak and complement. In vitro responsiveness is also inhibited by the presence of tumor-specific suppressor T cells in vivo. These observations suggest in vitro proliferation may provide a potential means of defining tumor antigens and cell-surface structures involved in tumor immunity.

Nonrandom Escape of Tumor Cells from Immune Lysis Due to Intracional Fluctuations in Antigen Expression

Abstract: Considerable heterogeneity in the amount of surface antigen can regularly be demonstrated by cytofluorometric analysis among genetically identical cells in a tumor clone. We have used monoclonal idiotype-specific antibodies to investigate the patterns of change in amounts of an idiotypic tumor antigen and how such changes affect the immune escape of malignant B cells expressing this antigen. By the use of fluorescence-activated cell sorting, we separated cells expressing either very large or very small amounts of the idiotypic target antigen and then analyzed these subpopulations of tumor cells at various times after isolation for expression of idiotype. We found that the differences in amount of antigen expression were not heritable, and that over a period of about 7 days of continuous growth in vitro , the fluorescence-activated cell sorted populations gradually came to express normal amounts of idiotype. The mechanisms regulating the quantity of surface idiotype were independent of those affecting the amounts of other membrane-associated molecules such as H-2 antigen. Furthermore, these nonheritable intraclonal differences in amounts of antigen expression were unrelated to stages of the cell cycle but clearly did affect the susceptibility of the cells from immune lysis. Thus, tumor cells expressing the lowest amount of surface idiotype were much more resistant to the lytic effects of antiidiotypic antibody and complement but had the same cell cycle distribution as did unseparated cells. These results demonstrate that non-heritable, non-cell cycle-related heterogeneity in amount of tumor antigen expression can significantly determine which cells in a cloned malignant cell population preferentially escape monoclonal tumor-specific antibody therapy.

Cancer tests using tumor antigen generated lymphokines and compositions

Abstract: The present invention provides strongly antigenic tumor-specific substances (also cellular material containing said strongly antigenic tumor-specific substances) prepared by radiofrequency or microwave electromagnetic radiation, acting on cancer tissue or cancer cells of known pathohistologic character. Said substances and also cellular material containing said substances are characterized by such sensitizing antigenic qualities that when they are contacted with a composition of naturally cancer-sensitized lymphocytes taken from a host having pathohistologically related cancer, then said lymphocytes produce and exude lymphokine. The invention further provides diagnostic tests for cancer and compositions which contain or utilize said strongly-antigenic cancer-specific substances.

Regulation of the immune response to tumor antigens. IX. In vitro Lyt-1+2- cell proliferative responses to cellbound or subcellular tumor antigen.

Abstract: We investigated the cellular basis of immune reactivity to the S1509a fibrosarcoma in tumor-immune A/J mice. In a Winn assay, immune Lyt-1+2- T cells are capable of retarding S1509a tumor growth in naive A/J mice. In vitro proliferation to S1509a is also mediated by tumor-immune Lyt-1+2- T cells. This response is specific to the immunizing tumor and appears 5 to 7 days after reexposure to the tumor in vivo. Proliferation also requires the presence of a population of adherent cells. In fact, adherent peritoneal exudate cells pulsed with tumor membrane fragments derived from S1509a cells can stimulate proliferation. Proliferation is blocked by the addition of anti-I-Ak monoclonal antibody to the culture medium without complement or by treatment of the responder population with anti-I-Ak and complement. In vitro responsiveness is also inhibited by the presence of tumor-specific suppressor T cells in vivo. These observations suggest in vitro proliferation may provide a potential means of defining tumor antigens and cell-surface structures involved in tumor immunity.

A frameshift mutation affecting the carboxyl terminus of the simian virus 40 large tumor antigen results in a replication- and transformation-defective virus

Abstract: We have constructed a frameshift mutation in the simian virus 40 early region using a novel method of oligonucleotide-directed mutagenesis. The mutated DNA specifies an 84,000-dalton large tumor antigen that consists of approximately equal to 75,000 daltons encoded by the wild-type reading frame and 9,000 daltons, by the alternative reading frame (wild-type large tumor antigen is approximately equal to 82,000 daltons). The frameshifted carboxyl terminus of the protein bears a strong similarity to the same region of polyoma virus middle-sized tumor antigen. We have found that the mutant DNA is unable to replicate when introduced into permissive monkey cells and incapable of transforming nonpermissive mouse cells.

Circulating immune complexes in patients with colorectal cancer

Abstract: We have attempted to better define host humoral immune response in neoplasia by quantitating serial circulating immune complex values before and after surgery in patients with primary or metastatic colorectal cancer. Circulating immune complex levels were correlated with serial carcinoembryonic antigen values and tumor courses in patients with primary resectable colorectal cancer (four patients), resectable liver metastases (three patients), diffuse liver metastases treated with regional chemotherapy (three patients), and untreated intrahepatic (one patient) and extrahepatic metastases (one patient). Circulating immune complex levels, as measured by an antigen-nonspecific assay, which utilized 4 percent polyethylene glycol insolubilization, were increased in all patients at presentation (734 delta OD450 +/- 381) when compared with normal human control sera (202 +/- 4, p less than 0.05). No particular relation was found between presenting circulating immune complex levels and tumor burden. Progressive circulating immune complex increases were demonstrated only in patients whose tumors were either completely removed or dramatically responded to regional therapy (that is, when the tumor antigen load, as reflected by the carcinoembryonic antigen value, rapidly diminished). Serum samples obtained at times of presumed antibody excess in the patients with gastrointestinal cancers were found to contain unexpectedly high concentrations of IgA. We believe these data demonstrate the kinetics of circulating immune complex change during tumor course and they have allowed us to begin to identify circulating immune complex components in patients with colorectal cancer. The results confirm our earlier findings in patients with gestational tumors and differ from accepted relations between immune complexes and tumor growth.

Immunoaffinity chromatography of a cellular tumor antigen from mouse neuroblastoma cells

Abstract: The cellular tumor antigen p53 was isolated from mouse neuroblastoma cells and was found in a form not complexed to another protein. The p53 in these cells was stable, turning over about every 10 h. Its methionine-labelled tryptic peptides were very similar to those of the p53 isolated from SV40-transformed mouse cells. The labelled protein was purified from neuroblastoma cells by immunoaffinity using specific monoclonal antibodies and was about 80% radiochemically pure. Furthermore, the purified p53 sedimented in sucrose gradients with a sedimentation coefficient of approximately 8S. This correlated with the sedimentation coefficient of p53 prior to purification, showing that the purified protein retained its native size.

Identity of HeLa cell determinants acquired by vesicular stomatitis virus with a tumor antigen

Abstract: Growth of vesicular stomatitis virus (VSV) in HeLa cells results in progeny containing non-VSV antigens with a molecular weight around 75,000. The non-VSV antigens were detected by antiserums to HeLa cell determinants. These antiserums precipitate whole virions but do not neutralize them. Because one of the antiserums is directed to a tumor-specific surface antigen of HeLa cells, it appears that VSV specifically acquires such antigens during its passage through human tumor cells.

Differential Expression of Tumor-Associated Antigens in Human Colon Carcinomas Xenografted Into Nude Mice

Abstract: The tumor-associated antigen profile of a number of different human colon carcinomas xenografted into inbred Swiss nude mice was examined to determine whether the tumors could serve as useful models for antigen purification, radioimmunodetection, and immunotherapy. Extreme heterogeneity was observed both by radioimmunoassay and immunohistochemical procedures for the expression of carcinoembryonic antigen (CEA), colon-specific antigens (CSAp), and colonic mucin antigen (CMA) within the tumors. Four of 10 tumors (DLD-2, DLD-3, DLD-5, and HCT-10) were high producers of CEA (greater than 75 micrograms/g wet tissue wt). Two of these (DLD-2 and HCT-10) correlated with a high production of CSAp and CMA, whereas the other 2 produced low quantities of these antigens. Another tumor, HCT-14-OM1, produced large amounts of CMA yet produced moderate amounts of CEA and low quantities of CSAp. Immunohistochemical analyses of CEA gave a mostly diffuse cellular and cell surface staining for all of the tumors. Staining for CSAp was very focal, as in DLD-5 where only a few of the tumor cells were stained. Staining of CMA was limited; however, DLD-2, HCT-10, and HCT-14-OM1 showed intense cystoplasmic and intraluminal staining. A determination of the tumor antigen profile may be useful in characterization and classification of the tumor as well as enabling the selection of the proper antibody or antibodies for immunodetection and immunotherapy.

Immunology of Head and Neck Cancers

Abstract: Despite the ever growing collection of data concerning the function of the immune system in patients with epidermoid carcinoma of the head and neck, the precise mechanism by which these tumors effect the body's surveillance against foreign antigen is as yet unidentified. If these specific immunological characteristics of the cancer cell can be identified, laboratory analysis of these "markers" could lead to detection and treatment of cancer in its earliest stages. Included in this chapter is a review of the embryological development of the immune system, a description of the components of the immune system and their responses to invasion by tumor antigen. Measurements of immuno responsiveness of the individual are important in determining the pretreatment state of immuno-competence and in predicting prognosis following treatment. Measurements of T-lymphocyte functions and their response to immuno-manipulations can also aid in predicting which patients will benefit from immunotherapy. Finally, categorization of the multiple forms of immunotherapy including active, specific and non-specific, and adoptive mechanisms are discussed. More recent methods of related immunotherapy trials will also be mentioned. As of this writing, the trials of immunochemotherapy have not produced any conclusive results due to the lack of multi-institutional trials and limited quantities of immunotherapeutic agents for these clinical trials.

Spontaneous Phenotypic Shifts from Low to High Metastatic Capacity

Abstract: Tumor progression from low to high malignancy is believed to occur in multiple steps (1). Analogous to mutation/selection the process of tumor progression is thought to have its basis in the continuous emergence of successive clones of tumor cell variants, one gradually replacing another, through the intervention of natural or artificial selection pressures (2). Highly malignant metastasizing tumor cells have been shown to differ from low malignant non-metastasizing ones in a number of properties such as plasma membrane enzyme activities (3), cell surface antigen shedding (4), tumor antigenicity and immunogenicity (5). A critical question is whether all these specific properties have been accumulated in the metastatic cell in a stepwise fashion. Is each new property the result of a process of random variation and host selection? How can a random process result in the generation of cells endowed with not just one but a number of very specific properties that enable them to cross the various biological barriers of the host, to survive and grow in different microenvironments?