Specific immunotherapy of established visceral micrometastases by BCG-tumor cell vaccine alone or as an adjunct to surgery

Hanna, Michael G.; Peters, Leona C.

doi:10.1002/1097-0142(197812)42:6<2613::aid-cncr2820420617>3.0.co;2-k

Cited by 73 publications

(26 citation statements)

References 15 publications

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“…These discrepancies might suggest a lesser significance of innate immunity in the anti-cancer response, but might also be connected to different types of tumors and of BCG, used in clinical studies. Mouse studies (19), as well as clinical observations in patients with bladder cancer confirmed the different therapeutic potential of BCG strains (20).…”

Section: Discussionmentioning

confidence: 83%

Immunotherapy with irradiated autologous leukemic cells in patients with B-CLL in early stages

Hus

Kawiak²,

Tabarkiewicz³

et al. 1994

Oncol Rep

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Abstract. In this study 10 7 peripheral blood mononuclear cells including on average 78.56% CD19 + /CD5 + lymphocytes were irradiated, and then administered intradermally as an anti-cancer vaccine to seventeen patients with B-cell chronic lymphocytic leukemia (B-CLL) at early stages (twelve injections, four at a weekly interval followed by eight vaccines given every two weeks). In eight out of seventeen patients, in the first two injections, irradiated leukemic cells were mixed with Bacillus Calmette-Guerin (BCG) to improve the efficacy of therapy by additional induction of innate immunity. A hematological improvement (as defined by a >25% reduction of leukocyte count) to autologous leukemic cell vaccines was observed in 5/17 patients, stabilisation of disease in 5/17 patients and in 7/17 patients there was no response to immunotherapy. In seven patients significant increase of the lymphocyte doubling time was noted (p=0.02). There was no impact of BCG for immune responses or clinical outcome of vaccinated patients, but there was a significant increase of the absolute counts of CD3 + as well as of CD3 + /CD4 + and CD3 + /CD8 + T cells during the vaccination period. We observed a significant improvement of the phagocytic function of autologous dendritic cells generated from peripheral blood monocytes obtained from patients with B-CLL after the end of immunotherapy (p=0.006). An association between the clinical outcome and the percentage of leukemic cells positive for expression of ZAP-70 and CD38 was noted. In conclusion, our results demonstrated the feasibility and safety of autologous irradiated leukemic cell immunotherapy in patients with B-CLL. As we noted immunological, and to some extent, clinical responses, this approach merits further investigation, including the use of adjuvants other than BCG. IntroductionB-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in western countries. The clinical course of B-CLL can be quite variable. Many patients survive many years with a good quality of life (QOL) without receiving any therapy, whereas others succumb rapidly despite aggressive treatment (1). It was established that treatment of early stage disease carries no benefit over a management of watching and waiting for progression (2). However, ~50% of patients with early stage disease develop a more advanced disease and will die from B-CLL and its complications. Therefore, it might be appropriate to reconsider the strategy of early therapy in B-CLL patients particularly those with high-risk prognostic factors. Most novel treatments, including purine analogues, monoclonal antibodies and combination immunochemotherapy, have significant risks for infectious complications (3,4), which must be carefully weighted against the risks emerging from the underlying disease. Thus, cellular immunotherapies might constitute an advantageous therapeutical option, inhibiting disease progression and delaying the start of chemotherapy in early stage patients with relatively small tumor mass. The purpose of cancer...

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Section: Discussionmentioning

confidence: 83%

Immunotherapy with irradiated autologous leukemic cells in patients with B-CLL in early stages

Hus

Kawiak²,

Tabarkiewicz³

et al. 1994

Oncol Rep

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“…The guinea-pig hepatoma model (31)(32)(33) involved the use of hepatoma induced in a strain of guinea pigs by injection of dimethylnitrosamine. The hepatoma was then converted into an ascites tumor.…”

Section: Lymphatic Metastasismentioning

confidence: 99%

Lymphatic metastasis

Carr

1983

Cancer Metast Rev

114

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Lymphatic metastasis is an important mechanism in the spread of human cancer. During its course, tumor cells first penetrate the basement of membrane of the epithelium, in which they arise, and then the underlying connective tissue, carried partly by hydrostatic pressure. They enter the lymphatic partly by active movement, pass up the lymphatic trunk; they then settle and proliferate in the subcapsular sinus, penetrate its endothelium and proliferate and destroy the node. There are varied forms of immune response in the node and in human nodes often a complex fibrous and vascular response. The degree of lymphocytic response may be important for prognosis. The nodal reaction may be stimulated by release of antigens from the tumor. One of the most studied animal models of lymphatic metastasis is that which occurs in the politeal node after injection of tumor into the footpad. This model has been used to show that tumor cells enter lymphatics through gaps in endothelium, probably between endothelial cells, and that lymph nodes can destroy small numbers of tumor cells. Local immunotherapy and chemotherapy can sterilize a lymph node of tumor cells; the modes of treatment used have included intralymphatic injection and encapsulation of chemotherapeutic agents in liposomes. Prior radiotherapy may accelerate metastasis possibly by making tumor cells shed into lymphatic vessels. Lymph nodes are rather poor barriers to tumor cells. The prognostic significance of lymph node metastasis varies within tumor type; if hematogenous metastasis is early, then the presence of lymph node metastasis is of lesser prognostic significance. Lymph nodes can probably destroy only small numbers of tumor cells. Tumor cell heterogeneity is of importance in many aspects of metastasis; while clonal variation may be of importance in determining lymph node metastasis, it is not yet clear how important this is, nor whether specific clones metastasize specifically to lymph nodes. Lymphography is well established in diagnosis of lymphatic metastasis. A recent interesting development has been to inject antibodies labeled with a radioactive label, and image the label in lymph nodes with a gamma-camera. If anti-tumor antibodies are used in this way it may be possible to detect lymph node metastasis. Within the expanding field of tumor metastasis, lymphatic metastasis needs much more attention, particularly in relation to the diagnosis and treatment of the lymphatic spread of human cancer.

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“…In other studies tumor cells have been injected directly into lymphatic channels (168,169). Experiments using these models have provided useful information on the mechanism by which (174), the diversity of the morphologic and immunologic changes occurring in lymph nodes containing tumor burdens of increasing severity (189) and the efficacy of chemotherapeutic (165,184,185) and immunotherapeutic protocols (172,188) in treating established lymph node metastases. We remain ignorant, however, about many important features of lymph node function in metastasis.…”

Section: Models Of Lymphatic Metastasismentioning

confidence: 99%

Experimental systems for analysis of the malignant phenotype

Poste

1982

Cancer Metast Rev

109

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Identification of the cellular and subcellular alterations responsible for the metastatic behavior of malignant tumor cells and development of reliable screening programs for detecting new therapeutic agents for improved treatment of metastatic disease both depend crucially on the availability of experimental systems that can serve as relevant models of human cancer. Recent advances in our understanding of the pathogenesis of cancer metastasis have raised serious doubts about the usefulness of many of the experimental approaches that have long been used in the study of metastasis. Recent findings showing that metastases are caused by specific subpopulations of metastatic tumor cells, and that not all cells in a malignant primary tumor possess metastatic properties, are of profound importance for experimental efforts to understand the mechanism of metastatic phenotype among cells from the same tumor means that the traditional, and widely used, approach of analyzing primary tumors and cultured cell lines containing multiple, phenotypically heterogeneous, subpopulations of cells may provide little or no insight into the properties of the metastatic subpopulations, particularly if they represent only a minor fraction of the entire population. Similarly, the practice of screening potential therapeutic modalities for their ability to reduce the mass and/or growth rate of a primary tumor may be inadequate in predicting the responsiveness of metastatic lesions. Solution of these problems requires that new methods must be devised to isolate and characterize the specific subpopulations of tumor cells endowed with metastatic potential. In addition, knowledge of how the extraordinary phenotypic diversity found in tumor cell subpopulations from the same tumor is generated and how subpopulation diversity is regulated during progressive growth of both the primary tumor and its metastases are of fundamental importance if we are to design meaningful experimental systems for studying the metastatic process. This article reviews our current understanding of these complex issues and their implications for the experimental analysis of the malignant phenotype. The merits and shortcomings of different experimental systems are discussed in detail together with the identification of areas in which new experimental strategies and models are now needed.'

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Specific immunotherapy of established visceral micrometastases by BCG-tumor cell vaccine alone or as an adjunct to surgery

Cited by 73 publications

References 15 publications

Immunotherapy with irradiated autologous leukemic cells in patients with B-CLL in early stages

Immunotherapy with irradiated autologous leukemic cells in patients with B-CLL in early stages

Lymphatic metastasis

Experimental systems for analysis of the malignant phenotype

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