The role of high dose chemo-radiotherapy with autologous bone marrow transplantation in the treatment of neoplasia remains to be clearly defined. Because of the iatrogenic morbidity, mortality and high cost of the supportive care required during the post-transplantation period of prolonged marrow aplasia, intensive therapy remains a sophisticated procedure lacking proper evaluation in clinical trials. We report here that when autologous bone marrow cells are supplemented with a small number of peripheral blood nucleated cells collected after prior myelosuppressive chemotherapy, complete hematological recovery is so prompt that myeloid toxicity appears no longer the major limiting factor of high-dose chemo-radiotherapy. The increased therapeutic index made possible by the procedure will allow us to address the issue of whether intensive cytoreductive therapy can be useful as initial treatment of selected tumors with curative intent.

BACKGROUND:  The wide diffusion of multicomponent collection in donor apheresis has led to the yielding of different components, such as plasma‐reduced platelet‐pheresis at high PLT concentration. We investigated whether this collection modality could induce more PLT activation compared to standard plateletpheresis. STUDY DESIGN AND METHODS:  Forty‐one plateletpheresis collections (20 Trima and 21 Spectra LRS Turbo v.7.0, COBE) were evaluated. Donor, procedure, and product data were recorded. ADP, collagen, and U46619 (a thromboxane‐A2 analog)‐induced PLT aggregation was investigated in basal (donor) and final (plateletpheresis unit) samples. The expression of PLT activation marker P‐selectin (CD62P) was studied using flow cytometry in basal and final samples. In all cases, P‐selectin was investigated in final samples after stimulation with ADP to assess for a possible further release of the antigen. Four additional plateletpheresis procedures were performed in donors from Group A, using the traditional, nonplasma‐reduced program. RESULTS:  Plateletpheresis obtained by means of the Trima device showed a lower response to in‐vitro induced PLT aggregation and a higher percentage of P‐selectin‐expressing PLT when compared to products obtained using the Spectra device. Moreover, P‐selectin release after ADP stimulation was reduced in plateletpheresis units obtained using the Trima device. These differences disappeared when a nonplasma‐reduced collection program was used. In‐vivo evaluation did not detect any difference between platelepheresis obtained by means of the two cell separators. CONCLUSIONS:  Plateletpheresis units obtained by means of multicomponent collection show a higher degree of PLT activation compared to traditional plateletpheresis procedures when high‐concentration plasma‐reduced products are collected. Randomized clinical studies are needed to assess the real impact of these findings in terms of in‐vivo efficacy of plasma‐reduced plateletpheresis units.

A phase I study was carried out to test the feasibility and toxicity of infusing large numbers of autologous, alloactivated helper lymphocytes into patients with metastatic melanoma. Patient peripheral blood lymphocytes (Pt-PBL) obtained by lymphopheresis and expressing the helper phenotype BT5/9 were separated and stimulated for 48 or 72 h with a pool of PBL from four to six healthy donors. Patients were then infused with such activated lymphocytes over a 2-3 h period. A total of 4 phereses and infusions (2/week for 2 weeks) were carried out for each cycle in each patient. Of the five patients treated, two received a second round of infusions. Infusion of autologous PBL stimulated in vitro for 48 h caused chills, fever, headache, and increased blood pressure. All symptoms disappeared in 2-3 h and were easily controlled by appropriate therapy. When lymphocytes were given after 72 h of allostimulation, no or very mild toxicity was observed. Serum chemistry, coagulation, autoimmunity, and urine analysis showed no gross abnormalities during therapy or follow-up of the patients. Immunological parameters (OKT4/OKT8 ratio, NK activity and cytotoxic T cell activity to autologous melanoma) were evaluated before starting the therapy, during its course and during the 3 to 6 months follow-up. The OKT4/OKT8 ratio increased significantly but transiently soon after the first course of infusions in one of the two patients tested. NK activity increased after 75-100 days in the three patients tested and in one of them it was high even after 180 days. No correlation between NK activity and prognosis was apparent. Cytotoxicity to autologous tumor was assessed in two patients, only of one of whom exhibited an increased activity from 75 to 180 days, which was associated with a prognosis better than that of the negative patient. Five patients were treated: two had progressive disease, two had stable disease for 5 and 6 months, respectively. In the first of these patients, a new cycle of lymphocyte infusions was carried out which caused a measurable reduction of lung tumor nodules whose growth, however, resumed 4 months later. This patient died 14 months after the onset of therapy. The fifth patient had a partial regression of pulmonary and intracranial metastases after therapy, but eventually died 3 months later. These results indicate that infusion of a high numbers of autologous, allostimulated helper PBL is a feasible and safe procedure, which could therefore be used in future studies of adoptive immunotherapy of cancer.

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