Type: Oral
Session: 622. Lymphomas: Translational – Non-Genetic: Elucidating Biomarkers and Mechanisms of Therapy in Lymphoma
Hematology Disease Topics & Pathways:
Research, Biological therapies, Antibody Therapy, Translational Research, Lymphomas, non-Hodgkin lymphoma, Non-Biological therapies, B Cell lymphoma, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Combination therapy, genomics, Diseases, indolent lymphoma, immune mechanism, aggressive lymphoma, Therapies, immunology, Lymphoid Malignancies, Infusion, computational biology, Biological Processes, Technology and Procedures, profiling, pathogenesis, Pathology
When MYD88L265P was activated in mature germinal-center B cells together with either Prdm1 or Trp53 deletion, mice developed extranodal ABC-DLBCL (MCD/C5 genomic class). IHC, flow cytometry and single-cell RNAseq revealed that DLBCL with Prdm1 loss showed morphologically heterogeneous B cells with abundant immune and T cells with activated/exhausted phenotypes, which recapitulated the inflammatory/immunosuppressive TME category in DLBCL patients (IN-LME, Kotlov- Cancer-Discovery-2021). In contrast, DLBCL with Tp53 deletion exhibited monotonous B-cell infiltrates with high proliferation index and a TME with depletion of T cells with effector/memory phenotypes and CD4+CD25+Foxp3+ Tregs, consistent with the immune depleted TME category (DP-LME). Analysis of 1,039 DLBCL patients demonstrated that majority of MCD cases with MYD88L265P showed either an IN-LME (43%) or DP-LME (44%). Consistent with the models, ABC-DLBCL patients with MYD88L265P and TP53 loss/mutation exhibited highly proliferative disease with a DP-LME, while ABC-DLBCLs with MYD88L265P but without TP53 abnormalities showed an IN-LME. Notably, the number of infiltrating CD4+ T cells correlated with TP53 activity score (PROGeNY) across MCD-DLBCLs. Overall, the presence or absence of TP53 alterations in MYD88L265P ABC-DLBCL induces TME characterized as DP-LME or IN-LME, respectively. Since DP-LME carries poor response to immune-chemotherapy (Kotlov-Cancer-Discovery-2021), we tested anti-CD19 CAR T-cells in the models. While CAR T-cells were initially effective in the two DLBCL models, progression occurred earlier in DLBCL with DP-LME than in IN-LME, which remained in remission 100 days after cell infusion. Responses correlated with persistence of circulating CD4+ CAR T cells. These data highlight that a TP53-driven DP-LME may limit immunotherapy activity in DLBCL, providing a scientific explanation to the poor outcome of DLBCL patients with TP53 alterations to CD19-directed CAR T cells (Shouval-JCO-2021). Collectively, our study defines the cellular origins and the stepwise genetic alterations of indolent and aggressive lymphomas with MYD88L265P, dissects distinct immunological paths underlying progression driven by oncogenic MYD88, and builds proof-of-concept for advancing precision immunotherapy in B-cell lymphomas.
Disclosures: Lossos: LRF: Membership on an entity's Board of Directors or advisory committees; NCI: Research Funding; Adaptive: Honoraria; University of Miami: Current Employment; NCI: Research Funding; BeiGene: Consultancy. Roa: Roche-Genentech: Research Funding. Roccaro: Italian Foundation for Cancer Research; Transcan2-ERANET; AstraZeneca: Research Funding; Amgen, Celgene, Janssen. Takeda: Consultancy. Canales: Beigene: Consultancy; BMS: Consultancy; Incyte: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Kite: Consultancy; Kyowa: Consultancy; Lilly: Consultancy; Roche: Consultancy; Takeda: Consultancy; Incyte: Speakers Bureau; Janssen: Speakers Bureau; Kite: Speakers Bureau; Kyowa: Speakers Bureau; Roche: Speakers Bureau; Takeda: Speakers Bureau. Paiva: Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; EngMab: Research Funding; Roche Glycart AG: Honoraria, Research Funding; Adaptive: Honoraria; Amgen: Honoraria; Gilead: Honoraria; Oncopeptides: Honoraria. Martinez-Climent: Roche/Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Janssen: Research Funding; Astra Zeneca: Research Funding; Palleon Pharnaceuticals: Research Funding; Regeneron: Research Funding; Priothera: Research Funding.