Intratumoral (IT) delivery of immune-activating viruses can serve as an important strategy to turn “cold” tumors into “hot” tumors leading to overcoming resistance to immune checkpoint blockade (ICB). Modified vaccinia virus Ankara (MVA) is a highly attenuated, non-replicative vaccinia virus that has a long history of human use. In this presentation, I will discuss strategies to engineer recombinant MVA to enhance both innate and adaptive immunity in several preclinical murine tumor models, which synergies with ICB.

Oncolytic viruses (OVs) elicit immunogenic cell death and promote anti-tumor immunity. Given the induction of in situ vaccination against cancer cells and the safety profile of OVs, there has been increased interest in integrating OVs’ more rational combination strategies. We have recently shown potent synergy between MEK inhibition and T-VEC in preclinical tumor models. In this presentation, emerging data on how to optimize anti-tumor immunity with OVs will be reviewed.

In solid tumors, CAR T cells must overcome the challenges of the immunosuppressive tumor microenvironment. We hypothesized that pretreating tumors with our oncolytic adeno-immunotherapy that produces local oncolysis and expresses immunostimulatory molecules would enhance the antitumor activity of adoptively transferred CAR T cells. Our results indicate that local treatment of our “all-in-one” vector can systemically enhance both adoptive CAR T cell and endogenous adaptive T cell responses to cancer cells.

Oncolytic herpes simplex virus (oHSV) is both directly cytotoxic and immunotherapeutic. To enhance efficacy, combination therapies are often used, especially those that alter the tumor microenvironment and immune milieu. Combinations include ‘arming’ oHSV with therapeutic transgenes or systemic administration of pharmacological agents, such as immune checkpoint antibodies and molecularly targeted drugs. We will discuss preclinical combination studies with oHSV and approved drugs that impacted immunological outcomes beneficially and adversely.

Targovax is developing ONCOS-102, an armed oncolytic adenovirus, which is being tested in three Phase I/II combination trials in mesothelioma, melanoma, and peritoneal cancers. The mesothelioma and melanoma trials have reported encouraging efficacy data over the past months, and a summary of the findings to date will be presented.

Several picornaviruses, including CVA21, have proven safe and demonstrated preliminary efficacy based on oncolytic and immunotherapeutic mechanisms. Formulating oncolytic picornaviruses as synthetic infectious RNA provides a mechanism for enhancing cytolytic activity during repeat dosing that can in turn augment the antitumor immune response. Both full-length picornaviral genomes and self-amplifying replicons encoding immune-modulating cargo can be formulated as infectious RNA. Preclinical development of both platforms will be discussed in this presentation.

Replimune has developed enhanced potency versions of oncolytic HSV designed to maximize direct tumor destruction and immunogenic cell death, and also maximize the systemic anti-tumor immune response then generated through arming with genes encoding multiple immune-stimulating proteins. Progress with
the development of this plaform, the lead product from which is now in registration-directed clinical development, will be discussed.

Oncolytic HSV therapy is a biotherapy that can change both tumor and tumor microenvironment. NOTCH signaling is a signaling pathway that communicates between cells and plays an important role in tumor biology. The impact of oncolytic HSV therapy on NOTCH signaling has not been described to our knowledge. Impact of HSV virotherapy on NOTCH signaling will be discussed in this presentation.

CG Oncology is currently investigating the company’s first product, CG0070, for the treatment of non-muscle invasive bladder cancer in the BCG-unresponsive patient population. In addition, CG Oncology is exploring the use of CG0070 in combination with immune checkpoint inhibitors in various solid tumors.

ONCR-177 is a highly engineered recombinant oncolytic Herpes Simplex Virus (oHSV) designed to be a well-tolerated and efficacious therapy for the treatment of solid tumors. ONCR-177 is armed with five transgenes selected for activation of antitumor immunity. Significant efficacy, survival benefit, and the elicitation of protective immunity were demonstrated in multiple syngeneic tumor models and warrant the clinical investigation of ONCR-177 in patients with metastatic cancer.