Personalized neoantigen vaccines as early intervention in untreated patients with lymphoplasmacytic lymphoma: a non-randomized phase 1 trial

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 () and Sheeba K. Thomas
Additional contact information
Szymon J. Szymura: Beckman Research Institute and Hematologic Malignancies Research Institute, City of Hope
Lin Wang: Beckman Research Institute and Hematologic Malignancies Research Institute, City of Hope
Tiantian Zhang: Beckman Research Institute and Hematologic Malignancies Research Institute, City of Hope
Soung-chul Cha: Beckman Research Institute and Hematologic Malignancies Research Institute, City of Hope
Joo Song: City of Hope
Zhenyuan Dong: Beckman Research Institute and Hematologic Malignancies Research Institute, City of Hope
Aaron Anderson: Beckman Research Institute and Hematologic Malignancies Research Institute, City of Hope
Elizabeth Oh: Beckman Research Institute and Hematologic Malignancies Research Institute, City of Hope
Vincent Lee: Beckman Research Institute and Hematologic Malignancies Research Institute, City of Hope
Zhe Wang: Beckman Research Institute and Hematologic Malignancies Research Institute, City of Hope
Sapna Parshottam: The University of Texas M.D. Anderson Cancer Center
Sheetal Rao: The University of Texas M.D. Anderson Cancer Center
Jasper B. Olsem: The University of Texas M.D. Anderson Cancer Center
Brandon N. Crumpton: The University of Texas M.D. Anderson Cancer Center
Hans C. Lee: The University of Texas M.D. Anderson Cancer Center
Elisabet E. Manasanch: The University of Texas M.D. Anderson Cancer Center
Sattva Neelapu: The University of Texas M.D. Anderson Cancer Center
Larry W. Kwak: Beckman Research Institute and Hematologic Malignancies Research Institute, City of Hope
Sheeba K. Thomas: The University of Texas M.D. Anderson Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50880-2

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