Immunologic approach to cancer.
01 Mar 1970-Vol. 2, Iss: 1, pp 92-103
About: The article was published on 1970-03-01 and is currently open access. It has received 92 citations till now. The article focuses on the topics: Cancer.
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TL;DR: The adoptive secondary response of mice to conjugates of NIP and DNP is used to elucidate the mechanism of cellular cooperation and shows that helper cells serve a role as handlers or concentrators of antigen, thus enabling AFCP which would otherwise be incapable of reacting to initiate antibody synthesis.
Abstract: The adoptive secondary response of mice to conjugates of NIP (4-hydroxy-5-iodo-3-nitro-phenacetyl-) and DNP (2,4-dinitrophenyl-) is here used to elucidate the mechanism of cellular cooperation. The framework into which the experiments fit can be formulated as follows. Priming immunization raises a crop not only of specific antibody-forming-cell-precursors (AFCP) but also of specific helper cells. Upon secondary stimulation the helper cells serve a role as handlers or concentrators of antigen, thus enabling AFCP which would otherwise be incapable of reacting to initiate antibody synthesis. In this act of cooperation both cells recognise antigen; in the system examined here the helpers recognise carrier determinants and the AFCP recognise either the hapten or other carrier determinants.
The first aim of the experiments was to raise populations of helpers and AFCP of distinguishable specificity. Mice were primed with NIP-Ovalbumin (OA) mixed with chicken γ-globulin (CGG) and bovine serum albumin (BSA); in comparison with controls primed with unmixed NIP-OA, their cells after transfer were relatively more sensitive to secondary stimulation with NIP-CGG or NIP-BSA and similar findings were obtained in cross-checks of these carriers. For reasons which are not entirely clear, non-transferred cells did not show the same effect. In further experiments cells primed with one conjugate (e. g. NIP-OA) were mixed with cells primed with another protein (e. g. BSA), transferred and challenged with the hapten conjugated to the second protein (i. e. NIP-BSA). In comparison with controls lacking the protein-primed cells, the mixture regularly showed greater sensitivity to stimulation. NIP and DNP were tested in many of the possible combinations with BSA, OA and CGG with the same result. The mixture system was used in the further analysis.
Tests with allotype-marked protein-primed cells showed that these cells did not participate in the production of the anti-hapten antibody and could therefore properly be regarded as helpers. Tests of specificity showed that physical union of the hapten and carrier were required: cells primed with BSA, for example, would not help NIP-OA-primed cells to make a response to NIP-HSA even when stimulated at the same time with BSA. Transfer of less than one-tenth of the spleen gives a maximum helper effect, whereas AFCP activity continues to rise as larger numbers of cells are transferred. Helper cells are therefore normally present in excess.
Helper activity is more resistant than AFCP activity to irradiation, drugs and semi-allogeneic cell transfer across an H-2 barrier. This suggests that helper cells play a relatively passive role in the immune response.
Several observations indicate that helper cells are thymus-derived mediators of cellular immunity. Passively transferred antibody did not substitute for helper cells. After immunization helper activity developed faster than AFCP activity. Spleen cells obtained from lethally-irradiated, thymocyte-repopulated, immunized donors provided help. Cells from the thymus-derived fraction of thymus/marrow chimeras also appear to provide help.
Thus, the hapten-carrier cooperative response maps onto the well-established synergy of thymus and marrow in the response to foreign erythrocytes.
642 citations
TL;DR: By the end of the treatment period, total tumor size is smaller than that achieved through traditional pulsed therapy, and the normal cell population suffers nearly no oscillations.
Abstract: We present a competition model of cancer tumor growth that includes both the immune system response and drug therapy. This is a four-population model that includes tumor cells, host cells, immune cells, and drug interaction. We analyze the stability of the drug-free equilibria with respect to the immune response in order to look for target basins of attraction. One of our goals was to simulate qualitatively the asynchronous tumor-drug interaction known as “Jeffs phenomenon.” The model we develop is successful in generating this asynchronous response behavior. Our other goal was to identify treatment protocols that could improve standard pulsed chemotherapy regimens. Using optimal control theory with constraints and numerical simulations, we obtain new therapy protocols that we then compare with traditional pulsed periodic treatment. The optimal control generated therapies produce larger oscillations in the tumor population over time. However, by the end of the treatment period, total tumor size is smaller than that achieved through traditional pulsed therapy, and the normal cell population suffers nearly no oscillations.
325 citations
TL;DR: A carrier effect is obtained typically when a hapten‐protein conjugate is injected into an animal which has previously been primed with the same haptan conjugated to another carrier protein.
Abstract: A carrier effect is obtained typically when a hapten-protein conjugate is injected into an animal which has previously been primed with the same hapten conjugated to another carrier protein. Under these circumstances the anti-hapten secondary response is usually less than that which would have been obtained had the animal been injected with a conjugate prepared with the same carrier as that originally used for priming. Attempts have been made to account for the phenomenon in terms of the local environment hypothesis, which assumes that the receptor on immunologically competent cells recognises the hapten jointly with the area on the complete antigen which surrounds it. Alternatively the phenomenon can be accounted for by the hypothesis of cooperation, which assumes that the antigen is recognised by two receptors, one directed to the hapten and the other to a determinant on the carrier protein.
Methods are described which enable carrier effects to be studied quantitatively in mice. They involve a cell transfer system in which cell suspensions prepared from large numbers of donors are distributed among irradiated syngeneic recipients. In these recipients the transferred cells can be made to perform a secondary response by appropriate antigenic stimulation. The response is monitored by binding tests in which the capacity of serum to bind highly radioactive haptens or proteins is measured. The haptens employed in this system are NIP (4-hydroxy-5-iodo-3-nitro-phenacetyl-) and DNP (2,4-dinitrophenyl-) and the proteins comprise chicken γ-globulin, bovine serum albumin, human serum albumin, ovalbumin, bovine γ-globulin, keyhole limpet hemocyanin and mouse γ-globulin.
A carrier effect was regularly obtained when the proteins were tested against one another as carriers, for priming and for the secondary response. The effect could best be measured by comparing the relative potencies in the secondary response of the homologous conjugate (i. e. one with the carrier which had originally been used for priming) with heterologous conjugates (i. e. ones with new carriers). In this way the intrinsic potency of the individual protein could also be measured and allowance made for it in calculating the magnitude of the carrier effect. An average carrier effect of one thousand-fold relative potency was obtained. Priming by NIP-ovalbumin or NIP-chicken γ-globulin with secondary stimulation by NIP-bovine serum albumin (or the corresponding DNP conjugates) could be identified as the combination best suited to further study.
Support for the cooperation hypothesis, particularly for that version of the hypothesis which postulates that recognition of carrier determinants allows an antigen-concentrating mechanism to operate, could be found in the parallel slopes of the dose-response curves obtained with homologous and heterologous conjugates. On the other hand the local environment hypothesis failed to pass either of the tests to which it was subjected. One, the weaker, was to compare haptens with and without spacer groups inserted between themselves and the carrier protein, in the expectation that spacers might reduce the local environment contribution: no difference could in fact be detected. The other, the stronger, was to attempt to inhibit the response with an excess of carrier protein even though the anti-hapten antibody had no detectable affinity for the carrier: such inhibition could regularly be obtained.
291 citations
TL;DR: Evidence that mutagenic treatment may represent an additional way to increase the immunogenicity of tumor cells is reviewed, suggesting that significant tumor inhibition may be obtained by specific removal of the relevant suppressor T cells by anti-idiotypic immunization.
Abstract: Publisher Summary This chapter reviews evidence that mutagenic treatment may represent an additional way to increase the immunogenicity of tumor cells. For human cancer, extensive serological analysis of melanomas and other tumors has revealed antigens whose presence appears to be restricted to single tumors. It appears, therefore, that some human tumors carry tumor-specific antigens. Large number of reports has described stimulation of antitumoral responses with nonspecific immunostimulatory agents such as Bacillus Calmette-Guerin (BCG) and Corynebacterium parvum . There is no doubt that for a number of experimental tumors that elicit some degree of a rejection response, these agents often improve the response significantly. However, a large number of clinical trials have failed to show indisputable therapeutic benefit, perhaps because in most instances of human cancer there is little rejection response to be amplified. The recent advances in the understanding of the regulatory mechanisms of the immune system have lead quite logically to attempts at increasing the antitumoral responses by manipulating regulatory lymphocytes. Inhibition of tumor growth has been observed after the treatment of tumor-bearing mice with anti-I-J antibodies reported to affect preferentially suppressor T cells. Other results suggest that significant tumor inhibition may be obtained by specific removal of the relevant suppressor T cells by anti-idiotypic immunization.
162 citations
TL;DR: Investigating whether immunotherapy with a vaccine prepared from vaccinia melanoma cell lysates over a 2-year period after definitive surgery would improve relapse-free survival (RFS) and overall survival (OS) in patients with high-risk melanoma compared with a control group treated only with surgery found it was not associated with a statistically significant improvement in OS or RFS.
Abstract: PURPOSE: Patients with high-risk melanoma treated by immunotherapy with vaccinia viral lysates were found in phase II studies to have improved survival compared with historical controls. We therefore elected to test this therapy in a phase III study. PATIENTS AND METHODS: A prospective, randomized, multicenter trial to determine whether immunotherapy with a vaccine prepared from vaccinia melanoma cell lysates (VMCL) over a 2-year period after definitive surgery would improve relapse-free survival (RFS) and overall survival (OS) in patients with American Joint Committee on Cancer stage IIB and III melanoma compared with a control group treated only with surgery. RESULTS: A total of 700 patients were randomized: 353 to VMCL and 347 to no immunotherapy. Seventy-seven percent had lymph node (LN) metastases and 66% had clinically detected LN metastases. Analysis on the basis of all eligible, randomized patients (n = 675) found, after a median follow-up period of 8 years, a median OS of 88 months in the control...
146 citations