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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & , 2024. "Personalized neoantigen vaccines as early intervention in untreated patients with lymphoplasmacytic lymphoma: a non-randomized phase 1 trial," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50880-2
    DOI: 10.1038/s41467-024-50880-2
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