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

• Published in: Nature communications 2024-08, Vol.15 (1), p.6874-15, Article 6874
• Main Authors: Szymura, Szymon J., Wang, Lin, Zhang, Tiantian, Cha, Soung-chul, Song, Joo, Dong, Zhenyuan, Anderson, Aaron, Oh, Elizabeth, Lee, Vincent, Wang, Zhe, Parshottam, Sapna, Rao, Sheetal, Olsem, Jasper B., Crumpton, Brandon N., Lee, Hans C., Manasanch, Elisabet E., Neelapu, Sattva, Kwak, Larry W., Thomas, Sheeba K.
• Format: Article
• Language: English
• Subjects: 13/31; 13/51; 38/39; 49/91; 631/250/251/1567; 692/4028/67/1990/291/1621/1915; 692/4028/67/327; 96/21; Aged; Antigens, Neoplasm - immunology; Antitumor activity; Asymptomatic; B-Lymphocytes - immunology; Beta cells; Bone growth; Bone marrow; Cancer Vaccines - administration & dosage; Cancer Vaccines - immunology; Cancer Vaccines - therapeutic use; Customization; DNA vaccines; Down-regulation; Female; Growth factors; Histocompatibility antigen HLA; Humanities and Social Sciences; Humans; Insulin-like growth factor I; Insulin-like growth factors; Lymphocytes T; Lymphoma; Male; Microenvironments; Middle Aged; multidisciplinary; Myeloid cells; Neoantigens; Perturbation; Plasma cells; Precision Medicine - methods; Science; Science (multidisciplinary); Signal transduction; Subpopulations; Therapy; Transcriptomics; Tumor Microenvironment - immunology; Tumors; Vaccines; Vaccines, DNA - immunology; Vaccines, DNA - therapeutic use; Waldenstrom Macroglobulinemia - genetics; Waldenstrom Macroglobulinemia - immunology; Waldenstrom Macroglobulinemia - therapy
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50880-2

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. Lymphoplasmacytic lymphoma is a B-cell low-grade lymphoma with no approved standard therapy. Here the authors report a non-randomized phase 1 clinical trial performing early intervention with personalized neoantigen vaccines in asymptomatic patients and associating clinical efficacy with successful perturbation of the tumor immune microenvironment.