(1) Szymura SJ (2) Wang L (3) Zhang T (4) Cha SC (5) Song J (6) Dong Z (7) Anderson A (8) Oh E (9) Lee V (10) Wang Z (11) Parshottam S (12) Rao S (13) Olsem JB (14) Crumpton BN (15) Lee HC (16) Manasanch EE (17) Neelapu S (18) Kwak LW (19) Thomas SK

Nature communications

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.

Author Info: (1) Stephenson Lymphoma Center, Beckman Research Institute and Hematologic Malignancies Research Institute, City of Hope, Duarte, CA, USA. (2) Department of Computational and Quant

Author Info: (1) Stephenson Lymphoma Center, Beckman Research Institute and Hematologic Malignancies Research Institute, City of Hope, Duarte, CA, USA. (2) Department of Computational and Quantitative Medicine, Beckman Research Institute and Hematologic Malignancies Research Institute, City of Hope, Duarte, CA, USA. (3) Stephenson Lymphoma Center, Beckman Research Institute and Hematologic Malignancies Research Institute, City of Hope, Duarte, CA, USA. (4) Stephenson Lymphoma Center, Beckman Research Institute and Hematologic Malignancies Research Institute, City of Hope, Duarte, CA, USA. (5) Division of Hematopathology, Department of Pathology, City of Hope, Duarte, CA, USA. (6) Stephenson Lymphoma Center, Beckman Research Institute and Hematologic Malignancies Research Institute, City of Hope, Duarte, CA, USA. (7) Stephenson Lymphoma Center, Beckman Research Institute and Hematologic Malignancies Research Institute, City of Hope, Duarte, CA, USA. (8) Stephenson Lymphoma Center, Beckman Research Institute and Hematologic Malignancies Research Institute, City of Hope, Duarte, CA, USA. (9) Stephenson Lymphoma Center, Beckman Research Institute and Hematologic Malignancies Research Institute, City of Hope, Duarte, CA, USA. (10) Stephenson Lymphoma Center, Beckman Research Institute and Hematologic Malignancies Research Institute, City of Hope, Duarte, CA, USA. (11) Department of Lymphoma and Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. (12) Department of Lymphoma and Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. (13) Department of Lymphoma and Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. (14) Department of Lymphoma and Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. (15) Department of Lymphoma and Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. (16) Department of Lymphoma and Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. (17) Department of Lymphoma and Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. (18) Stephenson Lymphoma Center, Beckman Research Institute and Hematologic Malignancies Research Institute, City of Hope, Duarte, CA, USA. lkwak@coh.org. (19) Department of Lymphoma and Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

Citation: Nat Commun 2024 Aug 11 15:6874 Epub08/11/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39128904

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