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Immunotherapy and chemoimmunotherapy of malignant disease with BCG and nonviable mycobacterial fractions

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Abstract

The administration of Bacillus Calmette-Guérin (BCG) has been associated with restoration of general immunocompetence, augmentation of specific tumor immunity, activation of local and regional host defense mechanisms, and stimulation of the reticuloendothelial system. There is evidence that antigens from a variety of unrelated tumors are shared with, or are similar to, antigens in BCG. However, it is uncertain whether this cross-reactivity is the basis for the antitumor activity of BCG. Numerous studies emphasize the importance of regional effects of immunotherapy. They suggest a two-step mechanism for antitumor activity that involves recognition of BCG by host defense mechanisms, followed by activation and mobilization of macrophages by specifically produced lymphokines. The several nonviable derivatives of BCG have activity comparable to BCG without many of the problems associated with viable BCG. An optimal, completely standardized BCG preparation has not yet been produced.

Clinical studies on the immunotherapeutic effects of BCG and its derivatives in cancer patients indicate that in cutaneous malignant melanoma, intralesional injection of BCG causes complete regression of tumor in 65–90% of instances, with long-term remission in patients with purely cutaneous metastatic disease. In patients with disseminated malignant melanoma, studies show prolongation of remission duration and overall survival in patients undergoing chemoimmunotherapy (with BCG + imidazole carboxamide) over those receiving chemotherapy alone. In acute lymphoblastic leukemia, one study has found a greater than 90% probability of survival in patients with the microlymphoblastic type undergoing immunotherapy after 5 years, yet other studies fail to show any therapeutic advantage. In most studies in acute myeloblastic leukemia, immunochemotherapy has given both qualitative and quantitative improvements in remission duration and particularly survival. Increased survival, particularly in stage I patients, has been reported in a trial of adjuvant BCG immunotherapy in lung cancer. Other studies on carcinoma of the colon, breast, and the head and neck, soft tissue sarcomas, and genitourinary cancers, utilizing various combinations of BCG and its derivatives, and chemotherapy, surgery, or radiation therapy indicate enhanced remission duration and survival. However, more research is needed to determine the optimum therapy combination in each case, to make refinements in dose, route, and schedule of administration, to improve product characteristics, and to overcome the complications of BCG immunotherapy.

Résumé

L'administration de BCG s'accompagne d'une restauration de l'immunocompétence générale, d'une augmentation de l'immunité antitumorale, d'une activation des mécanismes de défense locaux et régionaux et d'une stimulation du système réticuloendothélial. Il semble bien que les antigènes de divers types de tumeurs sont comparables, ou mÊme identiques, aux antigènes du BCG. Cependant, il n'est pas certain que cette réactivité croisée soit la base de l'activité antitumorale du BCG. De nombreuses études ont souligné l'importance des effets régionaux de l'immunothérapie. Ces travaux suggèrent que l'activité antitumorale du BCG agit sur deux mécanismes: la reconnaissance du BCG par les mécanismes de défense de l'hÔte suivie d'une activation et d'une mobilisation des macrophages par des lymphokines spécifiques. Les dérivés non viables du BCG ont un effet comparable, sans poser les problèmes du BCG viable. Il n'existe cependant pas encore de préparation complètement standardisée du BCG.

Les études cliniques d'immunothérapie par le BCG ont montré que, dans les mélanomes cutanés malins, l'injection intralésionelle de BCG entraÎne une régression complète de la tumeur dans 65–90% des cas, avec des rémissions à long terme chez les malades ayant uniquement des metastases cutanées. Dans les mélanomes malins disséminés, la chimioimmunothérapie (BCG + imidazole carboxamide) est plus efficace que la chimiothérapie seule. La durée des rémissions est allongée et la survie également. Dans la leucémie lymphoblastique aiquË de forme microlymphoblastique, une étude a obtenu par immunothérapie plus de 90% de survies de 5 ans; mais d'autres travaux n'ont observé aucun effet thérapeutique. Dans la plupart des études sur la leucémie myéloblastique aiguË, l'immunochimiothérapie améliore quantitativement et qualitativement la rémission et la survie. Dans un essai d'immunothérapie adjuvante au BCG dans le cancer pulmonaire, une prolongation de la survie a été observée, surtout dans les cas au stade I.

D'autres travaux sur les cancers du colon, du sein, de la tÊte et du cou, de l'appareil génito-urinaire et sur les sarcomes des tissus mous, ont utilisé des combinaisons variées de BCG et de ses dérivés, de chimiothérapie, de chirurgie et d'irradiation: elles montrent un allongement des rémissions et des survies. Il faudra cependant encore d'autres recherches pour trouver dans chaque cas la combinaison thérapeutique optimale, pour préciser les doses, modes et schémas d'administration, pour perfectionner les caractères du produit et pour prévenir les complications de l'immunothérapie au BCG.

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Author notes

  1. Max A. Schwarz M.B., B.S., F.R.A.C.P.

    Present address: Hematology-Oncology Unit, Alfred Hospital, Victoria, Australia

Authors and Affiliations

  1. Department of Developmental Therapeutics, The University of Texas System Cancer Center, M.D. Anderson Hospital and Tumor Institute, Houston, Texas, USA

    Max A. Schwarz M.B., B.S., F.R.A.C.P., Jordan U. Gutterman M.D., Evan M. Hersh M.D., Stephen P. Richman M.D. & Giora M. Mavligit M.D.

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Supported by Contract NO1-CB-33888 and Grant 05831 from the National Cancer Institute, Bethesda, Maryland. Drs. Gutterman and Mavligit are the recipients of Career Development Awards (CA 71001-03 and CA 00130-02, respectively) from the National Cancer Institute, Bethesda, Dr. Schwarz is the recipient of a Fulbright-Hays Scholarship.

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Schwarz, M.A., Gutterman, J.U., Hersh, E.M. et al. Immunotherapy and chemoimmunotherapy of malignant disease with BCG and nonviable mycobacterial fractions. World J. Surg. 1, 555–579 (1977). https://doi.org/10.1007/BF01556181

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