Sindbis Virus with Anti-OX40 Overcomes the Immunosuppressive Tumor Microenvironment of Low-Immunogenic Tumors

Abstract

Despite remarkable responses to cancer immunotherapy in a subset of patients, many patients remain resistant to therapies. It is now clear that elevated levels of tumor-infiltrating T cells as well as a systemic anti-tumor immune response are requirements for successful immunotherapies. However, the tumor microenvironment imposes an additional resistance mechanism to immunotherapy. We have developed a practical and improved strategy for cancer immunotherapy using an oncolytic virus and anti-OX40. This strategy takes advantage of a preexisting T cell immune repertoire in vivo, removing the need to know about present tumor antigens. We have shown in this study that the replication-deficient oncolytic Sindbis virus vector expressing interleukin-12 (IL-12) (SV.IL12) activates immune-mediated tumor killing by inducing OX40 expression on CD4 T cells, allowing the full potential of the agonistic anti-OX40 antibody. The combination of SV.IL12 with anti-OX40 markedly changes the transcriptome signature and metabolic program of T cells, driving the development of highly activated terminally differentiated effector T cells. These metabolically reprogrammed T cells demonstrate enhanced tumor infiltration capacity as well as anti-tumor activity capable of overcoming the repressive tumor microenvironment. Our findings identify SV.IL12 in combination with anti-OX40 to be a novel and potent therapeutic strategy that can cure multiple types of low-immunogenic solid tumors.

The Combination Immunotherapy of TLR9 Agonist and OX40 Agonist via Intratumoural Injection for Hepatocellular Carcinoma

“…The anti-tumour effect of anti-OX40 mAb is limited by insufficient OX40 expression on tumoural T cells. 21 , 34 , 35 Thus, we hypothesized that CpG treatment might contribute synergistically to the anti-tumour effect of anti-OX40 mAb by increasing OX40 expression on T cells. To verify our hypothesis, mice were subcutaneously inoculated with Hepa1-6 HCC cells on the left and right sides of the abdomen and received different immunotherapies (anti-OX40 mAb, CpG, or the combination of anti-OX40 mAb and CpG) via intratumoural injection only on the left side ( Figure 2A ).…”

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 ).…”

“…The strength of the use of alphavirus vaccine utilization is the generation of rapid, high-level, and transient nature of transgene expression ( 33 ). Importantly, we have shown in our earlier preclinical work ( 34 – 36 ) that alphavirus vaccine platforms have the advantage to directly deliver antigens and immune modulatory molecules to lymph nodes, where they are expressed transiently to elicit diversified CD4+ and CD8+ T-cell immunity effective at controlling tumors throughout the body. These vectors represent a highly effective self-amplifying mRNA vaccine that can be engineered to express multiple antigens and stimulatory molecules.…”