Low-Frequency PPM1D Gene Mutations Affect Treatment Response to CD19-Targeted CAR T-Cell Therapy in Large B-Cell Lymphoma.

Chimeric antigen receptor T (CAR T)-cell therapy has become a standard treatment option for patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). Mutations in the PPM1D gene, a frequent driver alteration in clonal hematopoiesis (CH), lead to a gain of function of PPM1D/Wip1 phosphatase, impairing p53-dependent G1 checkpoint and promoting cell proliferation. The presence of PPM1D mutations has been correlated with reduced response to standard chemotherapy in lymphoma patients. In this study, we analyzed the impact of low-frequency PPM1D mutations on the safety and efficacy of CD19-targeted CAR T-cell therapy in a cohort of 85 r/r DLBCL patients. In this cohort, the prevalence of PPM1D gene mutations was 20% with a mean variant allele frequency (VAF) of 0.052 and a median VAF of 0.036. CAR T-induced cytokine release syndrome (CRS) and immune effector cell-associated neuro-toxicities (ICANS) occurred at similar frequencies in patients with and without PPM1D mutations. Clinical outcomes were globally worse in the PPM1D mutated (PPM1Dmut) vs. PPM1D wild type (PPM1Dwt) subset. While the prevalent treatment outcome within the PPM1Dwt subgroup was complete remission (56%), the majority of patients within the PPM1Dmut subgroup had only partial remission (60%). Median progression-free survival (PFS) was 3 vs. 12 months (p = 0.07) and median overall survival (OS) was 5 vs. 37 months (p = 0.004) for the PPM1Dmut and PPM1Dwt cohort, respectively. Our data suggest that the occurrence of PPM1D mutations in the context of CH may predict worse outcomes after CD19-targeted CAR T-cell therapy in patients with r/r DLBCL.

Increases in the competitive fitness of West Nile virus isolates after introduction into California.

To investigate the phenotypic evolution of West Nile virus (WNV) in California, we competed sixteen isolates made during 2007-08 against COAV997-5nt, a genetically marked clone from the founding 2003 California isolate COAV997-2003. Using in vivo fitness competitions in House Finches (HOFI) and Culex tarsalis mosquitoes, we found that the majority of WNV WN02 and SW03 genotype isolates exhibited elevated replicative fitness in both hosts compared to COAV997-5nt. Increased replicative capacity in HOFIs was not associated with increased mortality, indicating that these isolates had not gained avian virulence. One WN02 isolate from Coachella Valley, a region geographically close to the isolation of COAV997, showed neutral fitness in HOFIs and reduced fitness in Cx. tarsalis. Two isolates from Kern County and Sacramento/Yolo County out-competed COAV997-nt in HOFIs, but were transmitted less efficiently by Cx. tarsalis. Competition demonstrated neutral or increased fitness that appeared independent of both WN02 and SW03 genotypes.