-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

212 Early Intervention and Favorable Biologic Effects of Personalized Neoantigen Vaccines on the Tumor Immune Microenvironment in Smoldering Waldenstrom Macroglobulinemia

Program: Oral and Poster Abstracts
Type: Oral
Session: 654. MGUS, Amyloidosis and Other Non-Myeloma Plasma Cell Dyscrasias: Clinical and Epidemiological: Screening to Vaccines–The Spectrum of Plasma Cell Disorders
Hematology Disease Topics & Pathways:
Research, Biological therapies, Translational Research, Therapies, Vaccines
Saturday, December 9, 2023: 2:15 PM

Szymon Szymura1*, Soungchul Cha2*, Lin Wang3*, Tiantian Zhang, PhD, MD1*, Zhenyuan Dong, PhD2*, Aaron Anderson1*, Elizabeth Oh1*, Zhe Wang1*, Vincent Lee4*, Sapna Parshottham5*, Sheetal Rao6*, Jasper B Olsem5*, Brandon N Crumpton5*, Hans Lee, MD7, Elisabet E. Manasanch, MD8*, Sattva S. Neelapu, MD9, Sheeba K. Thomas, MD8 and Larry W. Kwak10

1City of Hope, Duarte, CA
2City of Hope, Duarte
3city of hope, Duate
4city of hope, Duarte, CA
5MD Anderson Cancer Center, Houston
6UT- MD Anderson Cancer Center, Houston, TX
7Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX
8Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
9Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
10Stephenson Lymphoma Center, Beckman Institute of the City of Hope, Duarte, CA

Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade B-cell lymphoma, characterized by the presence of clonal tumor cells infiltrating the bone marrow. Despite a cumulative risk of progression, there is no approved therapy for patients in the asymptomatic phase. We conducted a first-in-human clinical trial of a novel individualized therapeutic DNA idiotype neoantigen vaccine as an early intervention in nine patients with untreated asymptomatic LPL. The vaccine platform encoded the autologous LPL-derived Ig single chain variable fragment fused to human chemokine CCL20 (macrophage inflammatory protein-3, MIP-3a), which was designed to trigger T-cell immunity by targeting delivery of the expressed fusion protein to antigen presenting cells. The vaccine was well tolerated with no dose limiting toxicities. One patient achieved a minor response, and all remaining patients experienced stable disease, with median time to disease progression of 61+ months, which compares favorably to median time to progression of 3.9 years in published series.

Direct interrogation of the tumor microenvironment by single-cell transcriptome analysis revealed explanations for lack of more robust objective clinical responses. Comparing paired pre- and post- vaccine bone marrow samples, we observed a striking dichotomous pattern of significantly reduced numbers of clonal tumor cells, identified by their unique BCR sequences, and downregulation of genes involved in signaling pathways critical for B-cell survival among the mature B cells subpopulation post-vaccine in the majority of patients, but no change in clonally related plasma cell-like clusters of any patient (Figure 1). Downregulation of HLA molecule expression suggested intrinsic resistance by tumor plasma cell subpopulations and cell-cell interaction analyses predicted paradoxical upregulation of IGF signaling post vaccine by plasma cell, but not mature B-cell subpopulations, suggesting a potential mechanism of acquired resistance.

Vaccine therapy induced dynamic changes in bone marrow T-cells, including upregulation of signaling pathways involved in T-cell activation, expansion of T-cell clonotypes (Figure 2), increased T-cell clonal diversity, and functional tumor idiotype-specific cytokine production, with little change in co-inhibitory pathways or Treg.

Vaccine therapy also globally altered cell-cell communication networks across various bone marrow cell types. CellChat analysis inferred significant downregulation of signaling pathways post-vaccine that likely directly promote growth of LPL cells, such as APRIL and IL-6 which are known to promote B- or plasma cell survival. Other pathways were reduced post-vaccine, such as RESISTIN, which has a known role in supporting proliferation of solid cancers. A role for RESISTIN in supporting LPL has not been previously inferred, but it has been reported to induce multidrug resistance in multiple myeloma. Bioinformatic analysis also identified a predominant role for myeloid cells in the tumor microenvironment as a source of vaccine-induced, downregulated pro-tumoral signaling to LPL cells. The pathways affected were primarily associated with monocytic, rather than granulocytic or dendritic cell subpopulations, particularly non-classical CD14-CD16+ monocytes, and to a lesser extent classical CD14+CD16- monocytes . Recent reports indicate that an increased pro-inflammatory myeloid signature is an early step in the development of LPL and in monoclonal gammopathy of undetermined significance.

Taken together, these results suggest that this prototype neoantigen vaccine favorably perturbed the tumor immune microenvironment, resulting in reduction of clonal tumor mature B-cell, but not plasma cell subpopulations. Future functional studies of the pathways affected are needed to confirm mechanisms of resistance elucidated and to design combination strategies to circumvent them. Such strategies could include adding IFN gamma or epigenetic drugs, designed to increase HLA molecule expression on plasma cell-like LPL subpopulations and combining neoantigen vaccines with agents that specifically target plasma cells or pathways known to promote their growth, such as IGF-1 receptor inhibitors. Finally, our data suggest that combinations of these vaccines with myeloid cell checkpoint blockade may be worthwhile.

Disclosures: Cha: Pepromene bio. inc.: Consultancy. Lee: Celgene: Consultancy; AbbVie: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding; Allogene Thereapeutics: Consultancy; Regeneron: Consultancy, Research Funding; Amgen: Research Funding; Janssen: Consultancy, Research Funding; Monte Rosa Therapeutics: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding. Neelapu: Orna Therapeutics: Consultancy, Other: Advisory board member; Fosun Kite: Consultancy, Other: Advisory board member; Precision Biosciences: Research Funding; Athenex: Consultancy, Other: Advisory board member; Takeda: Consultancy, Other: Advisory board member; Immunoadoptive Cell Therapy Private Limited: Consultancy, Other: Scientific Advisory Board; Carsgen: Consultancy; N/A: Patents & Royalties: Related to cell therapy and the safety switch described (intellectual property); Morphosys: Consultancy, Other: Advisory board member; Kite, A Gilead Company: Consultancy, Other: Advisory Board Member, Research Funding; Merck: Consultancy, Other: Advisory Board Member; Sellas Life Sciences: Consultancy, Other: Advisory board member; Sana Biotechnology: Consultancy, Other: Advisory board member, Research Funding; Caribou: Consultancy, Other: Advisory board member; Janssen: Consultancy, Other: Advisory board member; Bluebird Bio: Consultancy, Other: Advisory board member; Astellas Pharma: Consultancy, Other: Advisory board member; Incyte: Consultancy, Other: Advisory board member; Longbow Immunotherapy: Current holder of stock options in a privately-held company; Synthekine: Consultancy, Other: Advisory board member; Chimagen: Consultancy, Other: Advisory board member; Adicet Bio: Consultancy, Other: Advisory board member, Research Funding; Allogene: Consultancy, Other: Advisory board member, Research Funding; Bristol Myers Squibb: Consultancy, Other: Advisory Board Member, Research Funding. Thomas: Bristol Myers Squibb, Janssen Pharma Genentech, X4 pharma, Cellectar Biosciences, Ascentage Pharma: Research Funding; Genentech: Research Funding; X4 pharma: Research Funding; Cellectar Biosciences: Research Funding; Janssen Pharma: Research Funding; Ascentage Pharma: Research Funding; Cellectar Biosciences: Consultancy; Abbvie, Cellectar Biosciences: Consultancy. Kwak: PeproMene Bio. Inc: Consultancy, Current equity holder in private company.

*signifies non-member of ASH