Personalized Neoantigen Vaccines As Early Intervention in Untreated Patients With Lymphoplasmacytic Lymphoma: A Non-Randomized Phase 1 Trial

Authors

Szymon J Szymura
Lin Wang
Tiantian Zhang
Soung-Chul Cha
Joo Song
Zhenyuan Dong
Aaron Anderson
Elizabeth Oh
Vincent Lee
Zhe Wang
Sapna Parshottam
Sheetal Rao
Jasper B Olsem
Brandon N Crumpton
Hans C Lee
Elisabet E Manasanch
Sattva Neelapu
Larry W Kwak
Sheeba K Thomas

Publication Date

8-11-2024

Journal

Nature Communications

Abstract

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.

Keywords

Humans, Male, Cancer Vaccines, Middle Aged, Female, Waldenstrom Macroglobulinemia, Aged, Tumor Microenvironment, Precision Medicine, Vaccines, DNA, Antigens, Neoplasm, B-Lymphocytes

Comments

Supplementary Materials

Data Availability Statement

PMID: 39128904