Allogeneic Anti-BCMA CAR T Cells Are Superior to Multiple Myeloma-derived CAR T Cells in Preclinical Studies and May Be Combined with Gamma Secretase Inhibitors.

Multiple myeloma remains an incurable plasma cell malignancy despite the rapidly evolving treatment landscape. Chimeric antigen receptor T cells targeted against BCMA have recently shown great promise in relapsed refractory multiple myeloma; however, all patients ultimately still progress from their disease. Lack of CAR T-cell persistence, impaired T-cell fitness in autologous CAR T-cell products and the presence of an immunosuppressive bone marrow (BM) microenvironment are contributory factors to treatment failure. We generated anti-BCMA CAR T cells from healthy donors (HD) and patients with multiple myeloma at different stages of disease to compare their T-cell profile, fitness, and cytotoxic activity in preclinical studies. We also used an ex vivo assay with multiple myeloma BM biopsies from distinct genomic subgroups to test the efficacy of HD-derived CAR T cells in a clinically relevant model. HD volunteers showed increased T-cell counts, higher CD4/CD8 ratio, and expanded naïve T-cell population compared with patients with multiple myeloma. After anti-BCMA CAR T-cell production, patients with relapsed multiple myeloma had lower frequencies of CAR+ T cells, decreased central memory phenotype, and increased checkpoint inhibitory markers compared with HD-derived products, which compromised their expansion and cytotoxicity against multiple myeloma cells in vitro. Importantly, HD-derived CAR T cells efficiently killed primary multiple myeloma cells within the BM microenvironment of different multiple myeloma genomic subgroups and their cytotoxic activity could be boosted with gamma secretase inhibitors. In conclusion, allogeneic anti-BCMA CAR T cells are a potential therapeutic strategy for patients with relapsed multiple myeloma and should be further developed in the clinic. Significance: Multiple myeloma is an incurable cancer of the plasma cells. A new therapy with anti-BCMA CAR T cells - the patient's own T cells genetically engineered to find and kill myeloma cancer cells - has shown encouraging results. Unfortunately, patients still relapse. In this study, we propose to use T cells from HD volunteers, which have a stronger T-cell fitness, higher cancer killing capacity, and are ready to be administered when needed.

Disseminated adenovirus infection after allogeneic stem cell transplant and the potential role of brincidofovir - Case series and 10 year experience of management in an adult transplant cohort.

BACKGROUND: Adenovirus infection is a recognized complication following haematopoietic stem cell transplantation. We present a review of our experience of these infections in our transplant cohort over 10 years including 3 patients treated with the novel antiviral brincidofovir. OBJECTIVES: We aimed to describe the presentation, response to treatment and outcomes of adult stem cell transplant patients with disseminated adenovirus infection. STUDY DESIGN: All adult cases of disseminated adenovirus infection following haematopoietic stem cell transplant in our unit between 2005 and 2015 were identified. Transplant details and data on timing of diagnosis, course of infection, viral co-infection and treatment were collected. RESULTS: Of 733 patients transplanted, 10 patients had disseminated infection, including 4 male and 6 female patients with median age of 36.5 (range 19-59) years. 6/10 received an allograft from an unrelated donor. Median post-transplant time to detection of viraemia was 67days (range 20-1140days). Median peak viral load was 3133 copies/ml (352-11,000,000) in survivors received cidofovir alone, one cidofovir then brincidofovir and two brincidofovir alone. 8/10 p and 1,580,000 copies/ml (41,999-3,000.000) in those who died. Five patientsatients had a decrease in viral load following antivirals and/or reduction in immunosuppression including all on brincidofovir. Three died on treatment. CONCLUSIONS: Disseminated adenovirus infection is uncommon in adult transplant patients and uncertainties remain surrounding effective treatment. In our cohort, brincidofovir has shown promise in treatment of adenoviral infection. However, randomized controlled studies are required to confirm this impression.