Lessons from past experience in cancer immunotherapy and their application to cancer and AIDS treatment and prophylaxis.
Passive immunotherapy which we attempted in 1957 using polyclonal antibodies from immunized donors aggravated tumor evolution: we suspected that blocking by Ig, tumor cell antigen epitopes which are necessary to enhance or even maintain the T-lymphocyte effector role in anti-cancer immunity could be the reason for this tumor aggravation by "specific" antibodies. Today the very limited results of monoclonal antibodies in cancer treatment favors this hypothesis. The aggravation of HIV by (some) antibodies suggests that the same phenomenon may also happen in this condition. In 1957, on the other hand, we described the therapeutically beneficial cytostatic targetting effect of polyclonal antibodies, an effect which has often been quoted and widely confirmed. Does the reason for the poor results of monoclonal antibody targetting in tumor treatment reside in cancer antigen heterogeneity? This is what an experiment we conducted with Olsson on AkR leukemia indicated, suggesting that several monoclonals should be simultaneously combined for most patients, to be determined by the antigenic study not only of each tumor but of each localisation. We shifted our cancer immunotherapy approach to an adoptive form in 1959; a), after establishing partial and transient, then total and permanent allogeneic marrow graft and chimerism in man; b), after describing the graft versus leukemia (GvL) action of the graft versus host (GvH) effect in leukaemic mice; c), and the same phenomenon in humans. Our observations on human allogeneic grafted bone marrow GvH and GvL were statistically confirmed in 1979 by the Seattle group. In the 1970s we attempted to induce strong GvL with weak GvH by replacing allogeneic bone marrow graft by allogeneic lymphocyte transfusions without host conditioning. Remarkable results were registered in mice, and in patients with acute leukaemia--5 complete remissions out of 7 patients who developed moderate GvH, and only 3 out of 70 in those who did not develop GvH. As we now know that CD4-, CD8+ lymphocytes are not all MHCl-restricted, we consider that the allogeneic CTL approach is worth trying as reinforcement treatment of (at least) severe hematopoietic malignancies. If it is indeed worthwhile in some severe neoplasias to include the adoptive form of immunotherapy in the multi-treatment program, the replacement of the patient's bone marrow by engrafted allogeneic stem cells has not been proven necessary, as the persistence in "ALL cured" chemotherapy patients of abnormally differentiated cells does not reduce the expectancy of cure.(ABSTRACT TRUNCATED AT 400 WORDS)
Mathé
G
G
Institut du Cancer et d'Immunogénétique, Immunitaires et Tumorales, Hôpital Paul-Brousse, Villejuif, France.
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control / Q000601:surgery / Q000628:therapy*; D000818:Animals; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000637:transplantation; D006801:Humans; D007116:Immunization, Passive; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000601:surgery / Q000628:therapy*