Randomized trial of adjuvant therapy for "high risk" primary malignant melanoma

Retrospective pathological classification of 213 patients with malignant melanoma identified a group at high risk of recurrence (25% developed recurrence in 12 months, 50% by 5 years) after resection for apparent cure. Using these criteria, 70 patients were identified after resection of all apparent disease as being at high risk for recurrent melanoma. They were randomly assigned to one of the three adjuvant treatment arms: chemotherapy with dimethyl triazeno imidazole carboxamide (DTIC), immunotherapy with bacillus Calmette-Guerin (BCG), or combined chemoimmunotherapy. Six of 20 patients receiving DTIC developed recurrence (30%) and four died (20%). Five of 28 patients receiving BCG developed recurrence (18%) and two died (7.5%). There have been no recurrences or deaths in 22 patients receiving combined chemoimmunotherapy. In the prevention of early recurrence, the combined therapy arm was significantly superior to both the immunotherapy arm (p less than 0.05) and the chemotherapy arm (p less than 0.01). In terms of survival, combined therapy also was superior to chemotherapy alone (p less than 0.05).     

Limited efficacy and unacceptable toxicity of cyclophosphamide for the induction of mixed chimerism and renal allograft tolerance in cynomolgus monkeys

To induce mixed chimerism and renal allograft tolerance in cynomolgus monkeys, cyclophosphamide (CP) and total body irradiation (TBI) were compared as part of a nonmyeloablative conditioning regimen. CP induced dose-dependent neutropenia and lymphopenia, but hematopoietic recovery was more rapid than that observed in the TBI group. Absolute B cell counts after CP were significantly higher (P<0.01) than those in the TBI group. With CP, a total dose of 200 mg/kg with CD154 blockade regularly induced multilineage chimerism. Nevertheless, the recipients failed to achieve long-term survival because of rejection (3 of 5), posttransplantation B cell lymphoma (1 of 5), and toxicities of CP (1 of 5). As previously reported, 3 Gy of TBI with either splenectomy or CD154 blockade induced mixed chimerism and renal allograft tolerance, with significantly less morbidity and mortality than that produced by CP. Thus, TBI is more effective and less toxic than CP as part of a nonmyeloablative regimen for the induction of mixed chimerism and renal allograft tolerance in cynomolgus monkeys.     

Evolving use of OKT3 monoclonal antibody for treatment of renal allograft rejection

OKT3, a monoclonal antibody reactive with a surface glycoprotein present on all postthymic T cells, was used to treat the initial acute episode of rejection in 30 recipients of cadaveric donor renal allografts. The first 16 patients received 1-5 mg daily for a period of 10-21 days during which the azathioprine and prednisone dosages were sharply reduced. Circulating T cells were eliminated within minutes after the first OKT3 infusion. T cells reactive with OKT3 remained depressed throughout the period of treatment, although a significant number of cells reactive with other T cells subset reagents became detectable after several days of OKT3 treatment. In all instances, the established rejection episode was reversed in 2-8 days without the addition of other immunosuppressive measures. Recurrent rejection occurred in 12 of 16 patients, but with further conventional immunosuppression, 50% of the renal allografts remain functional 20-44 months after transplantation. Fever, chills, and, in some instances, dyspnea following the first dose of OKT3 were the only side-effects observed. Most patients developed antiidiotypic or antimouse immunoglobulin antibodies without apparent clinical sequelae. In the subsequent 14 patients, modifications in the protocol included a steroid bolus prior to the first OKT3 infusion, limitation of therapy to 10 days, resumption of maintenance levels of azathioprine and prednisone prior to discontinuing OKT3, and addition of 3 i.v. doses of cyclophosphamide at the termination of treatment. Respiratory symptoms after the first infusion of the reagent have been eliminated. Antibody responses to OKT3 have been reduced, occurring in 38% as compared with 73% of patients treated previously. Recurrent rejection episodes observed in 8 of 14 patients have been reversible in all but one case. Allograft survival is 86% at 6-17 months posttransplantation. In the entire series of 30 OKT3-treated patients, only 4 grafts (13%) have been lost because of recurrent episodes of rejection.     

Antithymocyte globulin,pretransplant blood transfusion,and tissue typing in cadaver kidney transplantation

Three hundred forty-seven recipients of primary cadaver kidney transplants were analyzed in relation to ATG therapy, pretransplant transfusion, HLA-A, -B and -DR antigen matches, and level of PRA to the panel. Prophylactic ATG treatment increased transplant survival significantly when compared with the non-ATG group. The beneficial effect of pretransplant blood transfusions was not apparent when the recipients received prophylactic ATG treatment. No correlation was noted between HLA-A and -B antigen matches and transplant survival. There was no significant difference in the transplant survival between patients with zero DR antigen match kidneys and those with one DR antigen-match kidney. The number of transplants with two DR antigen-match kidneys was too small to be conclusive. The recipients in whom PRA did not develop despite pretransplant blood transfusions seemed to have better transplant survival than those in whom PRA did develop in response to blood transfusions.     

Monoclonal antibody treatment of human allograft recipients

Antilymphocyte antibody immunosuppression has evolved to the use of therapeutic antibodies which are monoclonal in content. An antibody is termed monoclonal if each immunoglobulin molecule is produced by a single clone of cells and, thus, is identical in both the heavy and light chain structure to every other molecule in the preparation. Monoclonal preparations provide more consistent bioefficacy and predictable toxicity than do polyclonal products. Studies in nonhuman primate allograft recipients have established the immunosuppressive efficacy of several mAb. The results of pilot trial studies using a pan-T-cell mAb, OKT3, either prophylactically or at the time of acute rejection have revealed OKT3 to be remarkably immunosuppressive in man. OKT3 has subsequently been shown in multicenter, randomized trials to be more effective than conventional suppression in reversing renal and hepatic allograft rejection. In uncontrolled trial studies, similar efficacy in reversing cardiac rejection has been reported. Despite these impressive results, several limitations to OKT3 therapy persist. These include febrile and other systemic symptoms after the first or second infusion, a frequency of recurrent rejection episodes and the development of antibodies to the murine protein which may preclude subsequent treatment with the same mAb. Other murine mAb, such as CBL1 and anti-T12, have been noted to produce less side effects; however, these mAb have not been as effective. The next generation of mAb will be selected to minimize these limitations. It is anticipated that future mAb protocols will specifically suppress only selected subsets of T cells, and that these mAb may be chimeric or even human in structure to limit their immunogenicity.