Cyclosporin A (CsA) ~ is a potent reversible immunosuppressive agent which is able to suppress allograft rejection and acute allogeneic graft-versus-host disease (GVHD) (1-7). Although CsA dramatically improves survival after allogeneic marrow transplantation, rats treated with a short course of CsA develop delayed onset GVHD after CsA withdrawal. This paper presents new evidence which indicates that GVHD may develop upon CsA withdrawal following not only allogeneic but also syngeneic and even autologous bone marrow reconstitution. Materials and MethodsRats. Lewis female RT1 ~ rats, 6-8 wk old, were purchased from Harlan Sprague Dawley, Inc., Indianapolis, IN.Radiation. Lewis rats were irradiated on day -1 (1,020 rad) at 120 rad/min from a dual source Cs ~3~ small animal irradiator (Atomic Energy of Canada Ltd., Ottawa, Ontario). Leg-shielded rats were then anesthetized with chloral hydrate, their right tibias shielded with a lead doughnut 1.5 cm thick and 2.5 cm long, and irradiated with 1,020 rad.Marrow Transplantation. Donor marrow from tibias, femurs, and humeri was sus-7 pended at 6 × 10 nucleated cells/ml in Hanks' solution supplemented with 50 U/ml penicillin and 50 ng/ml streptomycin. On day 0 rats received 1 ml via the tail vein.Antibiotics. Rats received medicated drinking water supplemented with bactrim, neomycin, and polymyxin B and were given 2.5 mg/kg gentamycin per day subcutaneously for 20 d. Rats that developed overt clinical infections were routinely sacrificed and excluded from the study.Cyclosporin A. CsA was the generous gift of Sandoz, Inc., Hanover, NJ. Emulphor EL-620 was obtained from GAF Corp., New York. Powdered CsA was dissolved in absolute ethanol, added to emulphor, and mixed with water to yield a final emulphor concentration of 5%. Rats were weighed daily and received 1 ml/100 g body weight per day subcutaneously from day 0 to 40 or as indicated.Assessment of GVHD. Rats were examined daily for signs of clinical GVHD such as red ears, dermatitis, or diarrhea. Skin biopsies were taken at frequent intervals. When rats developed severe clinical GVHD characterized by weight loss, hunched appearance, and extensive dermatitis they were sacrificed and autopsied. Previously described criteria were
TPS774 Background: SHARON is a phase 1, single-arm trial to assess the safety and preliminary efficacy of 2 cycles of melphalan, BCNU, hydroxocobalamin (vitamin B12b), dose-escalated vitamin C, and autologous stem cells in patients with stage IV pancreatic cancer and an inherited, deleterious BRCA1/2 mutation. Cancers that evolve in patients with a germline BRCA1/ 2 mutation generally have loss or inactivation of the wild type allele, which results in hypersensitivity to melphalan. The melphalan dose-response is log-linear: doubling the melphalan area under the curve (AUC) doubles the log reduction in clonogenic survival. The melphalan AUC that can safely be achieved with melphalan followed by stem cell rescue has the potential to provide major log reductions in cancer cell survival in BRCA-deficient cancers. However, reversion mutations in BRCA can cause resistance to DNA-crosslinking agents such as melphalan. Studies have shown that oxidizing cellular glutathione (GSH) to glutathione disulfide (GSSG) can inhibit DNA repair and hypersensitize wild-type cancer cells to melphalan. In this trial, BCNU, vitamin B12b, and vitamin C are used to increase cancer cell GSSG levels. Methods: Eligibility criteria include stage IV pancreatic cancer, an inherited deleterious BRCA1/2 mutation, life expectancy of at least 6 months, measurable or non-measurable disease, and suitability for apheresis, chemotherapy, and stem cell infusion. Prior treatment with PARP inhibitors is allowed. Stem cells are collected by apheresis. Participants receive 2 cycles of melphalan 100 mg/m2, BCNU 150 mg/m2, vitamin B12b 1.45 g/m2, and vitamin C 3, 6, or 8 g/m2 on Day −2. Stem cell infusion administered on day 0. A 2 + 4 dose-escalation schedule is employed for vitamin C. Adverse reactions summarized by CTCAE 5.0. The primary endpoint is safety, and secondary endpoints are objective response rate (overall and for metastatic lesions) and overall and progression-free survival. Amendment pending to include stage IV, BRCA-related, HER2-negative breast cancer and PALB2 mutations. The trial is enrolling at Memorial Sloan Kettering Cancer Center and Massachusetts General Hospital. Clinical trial information: NCT04150042 .
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