Molecular and metabolic pathways mediating curative treatment of a non-Hodgkin B cell lymphoma by Sindbis viral vectors and anti-4-1BB monoclonal antibody

Abstract

Background Limitations to current therapies for treating non-Hodgkin B cell lymphoma include relapse, toxicity and high cost. Thus, there remains a need for novel therapies. Oncolytic viral (OV) therapy has become a promising cancer immunotherapy because of its potential effectiveness, specificity and long-lasting immunity. We describe and characterize a novel cancer immunotherapy combining Sindbis virus (SV) vectors and the agonistic monoclonal antibody (mAb) to the T cell costimulatory receptor, 4-1BB (CD137). Methods A20 lymphoma was transfected with luciferase and tumor cells were inoculated to BALB/c mice. Tumor growth was monitored by IVIS imaging. Tumor bearing mice were treated with Sindbis virus, α4-1BB Ab or SV plus α4-1BB Ab. On day 7 after treatment, splenocytes were harvested and surface markers, cytokines, and transcription factors were measured by flow cytometry or Elispot. Splenic T cells were isolated and RNA transcriptome analysis was performed. Tumor cured mice were rechallenged with tumor for testing immunological memory. Results SV vectors in combination with α4-1BB monoclonal antibody (mAb) completely eradicated a B-cell lymphoma in a preclinical mouse model, a result that could not be achieved with either treatment alone. Tumor elimination involves a synergistic effect of the combination that significantly boosts T cell cytotoxicity, IFNγ production, T cell proliferation, migration, and glycolysis. In addition, all mice that survived after treatment developed long lasting antitumor immunity, as shown by the rejection of A20 tumor rechallenge. We identified the molecular pathways, including upregulated cytokines, chemokines and metabolic pathways in T cells that are triggered by the combined therapy and help to achieve a highly effective anti-tumor response. Conclusions Our study provides a novel, alternative method for B cell lymphoma treatment and describes a rationale to help translate SV vectors plus agonistic mAb into clinical applications. Electronic supplementary material The online version of this article (10.1186/s40425-019-0664-3) contains supplementary material, which is available to authorized users.

Combination of a Sindbis-SARS-CoV-2 spike vaccine and αOX40 antibody elicits protective immunity against SARS-CoV-2 induced disease and potentiates long-term SARS-CoV-2-specific humoral and T-cell immunity

“…The combination of SV vectors encoding a selected antigen with immunomodulatory antibodies makes them far more effective than they are alone[40; 41; 42]. In particular we have found that combining SV vectors expressing specific antigens with αOX40 generates very potent immune responses capable of eradicating tumors in multiple murine models and conferring long-term protection against tumor recurrences or rechallenges[40].…”

Combination of a Sindbis-SARS-CoV-2 Spike Vaccine and αOX40 Antibody Elicits Protective Immunity Against SARS-CoV-2 Induced Disease and Potentiates Long-Term SARS-CoV-2-Specific Humoral and T-Cell Immunity

“…The combination of SV vectors encoding a selected antigen with immunomodulatory antibodies makes them far more effective than they are alone ( 35 , 36 , 56 ). In particular we have found that combining SV vectors expressing specific antigens with αOX40 generates very potent immune responses capable of eradicating tumors in multiple murine models and conferring long-term protection against tumor recurrences or rechallenges ( 36 , 56 ).…”

Oncolytic Virotherapy: From Bench to Bedside

“…As a new potential cancer therapy, oncolytic viruses can prevent tumor recurrence by establishing immune memory in the body. Minjun Yu et al induced lymphoma regression in mice by administering Sindbis virus vectors in combination with α4-1BB monoclonal antibodies (Yu et al, 2019). In addition, all mice treated with Sindbis virus vectors and α4-1BB monoclonal antibodies were proven to have durable antitumor immune memory.…”