Complete and long-lasting clinical responses in immune checkpoint inhibitor-resistant, metastasized melanoma treated with adoptive T cell transfer combined with DC vaccination.

Development of T cell-directed immune checkpoint inhibitors (ICI) has revolutionized metastatic melanoma (MM) therapy, but <50% of treated patients experience durable responses. This phase I trial (NCT01946373) investigates the safety/feasibility of tumor-infiltrating lymphocyte (TIL) adoptive cell therapy (ACT) combined with dendritic cell (DC) vaccination in MM patients progressing on ICI. An initial cohort (5 patients) received TIL therapy alone to evaluate safety and allow for optimization of TIL expansion protocols. A second cohort (first-in-man, 5 patients) received TIL combined with autologous tumor lysate-loaded DC vaccination. All patients received cyclophosphamide/fludarabine preconditioning prior to, and intravenous (i.v.) IL-2 after, TIL transfer. The DC vaccine was given as five intradermal injections after TIL and IL-2 administration. [18F]-FDG PET/CT radiology was performed to evaluate clinical response, according to RECIST 1.1 (on the CT part). Immunological monitoring was performed by flow cytometry and T-cell receptor (TCR) sequencing. In the safety/optimization cohort, all patients had a mixed response or stable disease, but none durable. In the combination cohort, two patients experienced complete responses (CR) that are still ongoing (>36 and >18 months, respectively). In addition, two patients had partial responses (PR), one still ongoing (>42 months) with only a small bone-lesion remaining, and one of short duration (<4 months). One patient died early during treatment and did not receive DC. Long-lasting persistency of the injected TILs was demonstrated in blood. In summary, we report clinical responses by TIL therapy combined with DC vaccination in 4 out of 4 treated MM patients who previously failed ICI.

Case-control comparison of at-home and hospital care for allogeneic hematopoietic stem-cell transplantation: the role of oral nutrition.

BACKGROUND: Acute graft-versus-host disease (GVHD) was reduced using home care compared with hospital care after allogeneic hematopoietic stem-cell transplantation (ASCT). METHODS: Between March 1998 and December 2006, 601 patients underwent ASCT at our unit. Requirements for at-home ASCT were fulfilled by 76 patients. A control group of 76 patients treated in the hospital were matched for age, sex, diagnosis, stage of disease, conditioning, stem-cell source, type of donor, and immunosuppression. Oral nutrition was determined as median kcal/kg/day for the first 21 days after ASCT. RESULTS: The home-care patients received more oral nutrition per day than hospital controls (P<0.05). Number of days at home correlated with oral nutrition (P=0.004). In multivariate analysis, acute GVHD of grades II to IV was associated with poor oral nutrition (P=0.003) and hospital care (P=0.06). Transplant-related mortality was associated with acute GVHD grades II to IV (P<0.0001) and bacteremia (P=0.004). In addition to acute GVHD and bacteremia, death was associated with absence of chronic GVHD (P=0.012). Five-year survival was 65% in patients treated at home, when compared with 47% in the controls (P=0.04). CONCLUSION: Better oral nutrition may be one reason for the reduced probability of acute GVHD and better survival with at-home care than with hospital care.

The effect of N-acetyl-l-cysteine (NAC) on liver toxicity and clinical outcome after hematopoietic stem cell transplantation.

Busulphan (Bu) is a myeloablative drug used for conditioning prior to hematopoietic stem cell transplantation. Bu is predominantly metabolized through glutathione conjugation, a reaction that consumes the hepatic glutathione. N-acetyl-l-cysteine (NAC) is a glutathione precursor used in the treatment of acetaminophen hepatotoxicity. NAC does not interfere with the busulphan myeloablative effect. We investigated the effect of NAC concomitant treatment during busulphan conditioning on the liver enzymes as well as the clinical outcome. Prophylactic NAC treatment was given to 54 patients upon the start of busulphan conditioning. These patients were compared with 54 historical matched controls who did not receive NAC treatment. In patients treated with NAC, aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) were significantly (P < 0.05) decreased after conditioning compared to their start values. Within the NAC-group, liver enzymes were normalized in those patients (30%) who had significantly high start values. No significant decrease in enzyme levels was observed in the control group. Furthermore, NAC affected neither Bu kinetics nor clinical outcome (sinusoidal obstruction syndrome incidence, graft-versus-host disease and/or graft failure). IN CONCLUSION: NAC is a potential prophylactic treatment for hepatotoxicity during busulphan conditioning. NAC therapy did not alter busulphan kinetics or affect clinical outcome.