Personalized neoantigen vaccines as early intervention in untreated patients with lymphoplasmacytic lymphoma: a non-randomized phase 1 trial.
Szymon J SzymuraLin WangTiantian ZhangSoung-Chul ChaJoo SongZhenyuan DongAaron AndersonElizabeth OhVincent LeeZhe WangSapna ParshottamSheetal RaoJasper B OlsemBrandon N CrumptonHans C LeeElisabet E ManasanchSattva S NeelapuLarry W KwakSheeba K ThomasPublished in: Nature communications (2024)
Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade lymphoma with no standard therapy. Nine asymptomatic patients treated with a first-in-human, neoantigen DNA vaccine experienced no dose limiting toxicities (primary endpoint, NCT01209871). All patients achieve stable disease or better, with one minor response, and median time to progression of 72+ months. Post-vaccine single-cell transcriptomics reveal dichotomous antitumor responses, with reduced tumor B-cells (tracked by unique B cell receptor) and their survival pathways, but no change in clonal plasma cells. Downregulation of human leukocyte antigen (HLA) class II molecules and paradoxical upregulation of insulin-like growth factor (IGF) by the latter suggest resistance mechanisms. Vaccine therapy activates and expands bone marrow T-cell clonotypes, and functional neoantigen-specific responses (secondary endpoint), but not co-inhibitory pathways or Treg, and reduces protumoral signaling by myeloid cells, suggesting favorable perturbation of the tumor immune microenvironment. Future strategies may require combinations of vaccines with agents targeting plasma cell subpopulations, or blockade of IGF-1 signaling or myeloid cell checkpoints.
Keyphrases
- single cell
- bone marrow
- low grade
- rna seq
- induced apoptosis
- endothelial cells
- diffuse large b cell lymphoma
- cell cycle arrest
- end stage renal disease
- high throughput
- signaling pathway
- high grade
- cell proliferation
- dendritic cells
- chronic kidney disease
- pi k akt
- stem cells
- randomized controlled trial
- induced pluripotent stem cells
- mesenchymal stem cells
- ejection fraction
- acute myeloid leukemia
- binding protein
- newly diagnosed
- open label
- oxidative stress
- immune response
- endoplasmic reticulum stress
- long non coding rna
- gene expression
- peripheral blood
- cancer therapy
- double blind
- poor prognosis
- dna methylation
- patient reported outcomes
- free survival
- smoking cessation
- patient reported