Critical Review of Previously Reported Clinical Trials of Cancer Immunotherapy With Non‐specific Immunostimulants*

Mastrangelo, Michael J.; Berd, David; Bellet, Robert E.

doi:10.1111/j.1749-6632.1976.tb41693.x

Cited by 65 publications

(15 citation statements)

References 5 publications

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“…Although capable of causing regression of directly injected skin metastases, BCG by itself does not affect distant metastases. 32 Moreover, a number of randomized trials have indicated that BCG is not effective as a postsurgical adjuvant treatment of melanoma. 33 Similarly, the topical application of DNFB that we employed cannot be considered therapeutic.…”

Section: Discussionmentioning

confidence: 99%

Treatment of metastatic melanoma with autologous, hapten‐modified melanoma vaccine: Regression of pulmonary metastases

et al. 2001

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Key words: melanoma; vaccine; immunotherapy; autologous; cyclophosphamideStudies performed and published over the past 30 years have made it clear that immunizing a tumor-bearing patient to his or her own tumor cells is exceedingly difficult. An appealing explanation for this difficulty is that tumor antigens are weakly immunogenic and often induce tolerance, i.e., paralysis of the immune response, rather than effective immunity. 1 Fortunately, advances in basic immunology have disclosed a number of ways of breaking immunologic tolerance. One way is the judicious use of cytotoxic drugs. In 1967, Maguire and Ettore 2 made the surprising discovery that administration of cyclophosphamide to animals prior to an immunization caused the cell-mediated immune response to be augmented rather than suppressed. We have shown that this phenomenon applies to cancer-bearing humans as well. Thus, the administration of low-dose (300 mg/m 2 ) cyclophosphamide prior to an immunization with autologous tumor cells greatly increased the development of cell-mediated immunity to those cells. 3 A second approach to circumventing tolerance is the use of haptens-small molecules that are incapable of inducing an immune response unless they are coupled to a larger molecule. Coupling of a hapten to a protein, i.e., hapten modification, often results in the induction of an immune response to the protein that would otherwise not be possible. For example, Weigle, 4 in a series of now classic experiments, immunized mice with hapten-modified thyroglobulin. This resulted in the induction of an immune response not only to the hapten-modified thyroglobulin, but also to unmodified, i.e., native, thyroglobulin and produced autoimmune thyroiditis. A similar phenomenon was observed more recently by Neurath et al. 5 They found that application of the hapten dinitrophenyl to the colonic mucosa of mice resulted in the development of an autoimmune colitis, similar to human ulcerative colitis. Initially, these mice developed cellular immunity to the haptenmodified mucosa. However, as the chemically modified mucosa cells were shed, a potent immune response to the normal, unmodified mucosa developed, which led to the autoimmune pathology.The immunologic basis of these interesting phenomena is now clear: there are T lymphocytes generated by immunization with hapten-modified cells that are reactive to both modified and unmodified cells. For example, class I MHC-restricted T-cell clones generated from mice immunized with TNP-modified syngeneic lymphocytes respond to MHC-associated, TNP-modified "self" peptides. Furthermore, some TNP-reactive clones respond to certain MHC-binding, unmodified peptides as well. 6 These observations in animal models provide a strong rationale for a human cancer vaccine consisting of autologous tumor cells modified with a hapten, DNP, preceded by the administration of low-dose cyclophosphamide. We have observed that administration of DNP vaccine to patients with metastatic melanoma induces a unique reaction-the development of inflamma...

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Section: Discussionmentioning

confidence: 99%

Treatment of metastatic melanoma with autologous, hapten‐modified melanoma vaccine: Regression of pulmonary metastases

et al. 2001

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“…In many oncology centers, living BCG are used in immunotherapy of human cancer, however, with lim ited success [32] and with detrimental side effects which do occur occasionally in treated patients [33][34][35]. According to the results of immunization therapy in the guinea pig model, living BCG were inferior to nonliving BCG preparations in mineral oil emulsions [2, 6; Bekierkunst, unpublished results].…”

Section: Discussionmentioning

confidence: 99%

Effect of a Single Injection of Cyclophosphamide on Immunization Therapy of Metastases Remaining after Excision of Dermal Primary Tumors in Guinea Pigs

Bekierkunst¹,

Yarkoni²

1984

Oncology

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Guinea pigs with established (7 or 14 days old) syngeneic dermal tumors and metastases in the draining lymph nodes were unsuccessfully treated by excision of the dermal tumors and specific immunization. The vaccines consisted of killed BCG in oil in an emulsified form admixed with mitomycin C treated or irradiated tumor cells. The therapeutic failure to eradicate the metastases was overcome by an additional treatment with a single injection of cyclophosphamide prior to excision of the primary tumor and immunization. It is assumed that cyclophosphamide destroys suppressor elements in the tumor-bearing guinea pigs and, in this way, augments the therapeutic effects of specific immunization.

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“…A number of agents have been used for intratumoral injection: BCG [3], glucan [4] and lymphokines [2], BCG and glucan have been shown to activate the reti culoendothelial system in which macrophages are the central effector cells and to cause tumor regression in animals and humans [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Ultrastructural and Clinical Observations on Skin Metastases from Breast Cancer Patients following Intralesional Treatment with MER/BCG Vaccine

Bar-Sella¹,

Bartal²,

Robinson³

et al. 1981

Oncology

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Ultrastructural and clinical investigations were carried out on skin metastases in patients with advanced breast cancer, following intralesional therapy with MER/BCG vaccine. A total of 65 tumoral lesions in 5 patients were injected with MER. Clinical responses were correlated with light and electron microscopic observations. Regressing tumor lesions showed substantial macrophage and lymphocyte infiltration and severe damage to tumor cells. Activated macrophages with secondary lysosomes and contacts between macrophages and tumor cells were widely observed. In 1 patient with limited cellular immune response, clinical regression was not evident and many tumor cells were ultrastructurally intact.

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Critical Review of Previously Reported Clinical Trials of Cancer Immunotherapy With Non‐specific Immunostimulants*

Cited by 65 publications

References 5 publications

Treatment of metastatic melanoma with autologous, hapten‐modified melanoma vaccine: Regression of pulmonary metastases

Treatment of metastatic melanoma with autologous, hapten‐modified melanoma vaccine: Regression of pulmonary metastases

Effect of a Single Injection of Cyclophosphamide on Immunization Therapy of Metastases Remaining after Excision of Dermal Primary Tumors in Guinea Pigs

Ultrastructural and Clinical Observations on Skin Metastases from Breast Cancer Patients following Intralesional Treatment with MER/BCG Vaccine

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