The treatment of cancer using immunotherapies has garnered substantial attention and excitement considering the clinical benefits observed in patient populations previously refractory to treatment. Tumor infiltrating T cells can significantly impact cancer progression and immunotherapy response; however, immunosuppressive tumor microenvironments can impede antitumor T cell induction, trafficking, and local activity. Thus, personalized immunotherapy approaches have shown limited efficacy against most solid tumors. In addition, manufacturing complexities remain, with high costs of development and implementation. Novel approaches are needed to effectively induce antitumor T cell responses despite heterogeneity in the tumor microenvironment and antigen landscape. Improved development costs and strategies for these approaches are also desired.
Researchers at the NCI developed a method to harness heterogenous antigens for the effective induction of antitumor T cell responses. This method is a tumor antigen-agnostic approach based on virus-derived peptide epitopes to mobilize dynamic antiviral T cell responses. In particular, it harnesses the potent pre-existing cellular immunity against a commonly acquired virus, human cytomegalovirus (HCMV) that causes well controlled chronic infection in immunocompetent people. This methodology does not require clonal T-cell expansion or other complex manufacturing strategies, instead using either tumor tropic human papillomavirus pseudovirions that contain plasmids expressing HCMV peptides or direct intratumoral injection of HCMV peptides, thus directing the pre-existing anti-HCMV immunity against those peptides to the tumors.
In mouse models, intratumoral injection of murine CMV (MCMV)-derived T cell epitopes triggered local and systemic expansion of MCMV-specific CD4+ or CD8+ T cells when challenged with lung, colon or melanoma tumor cells. CMV-derived CD8+ T cell epitopes alone or CD4+ T cell epitopes in the presence of an immune response modifier – such as polyinosinic acid:polycytidylic acid (pI:C), elicited T cell responses – enhanced tumor growth arrest and clearance, and conferred durable remission and protection against tumor rechallenge. Thus, persistent infection with MCMV-derived peptide epitopes has been validated in vivo to promote potent cytotoxic T cell responses in the tumor microenvironment and promote epitope spreading against tumor-associated antigens, as well as provide long-term antitumor immunity.
The NCI seeks licensing and/or co-development partners for a cancer immunotherapy based on harnessing the pre-existing immune response to a chronic viral pathogen, such as HCMV, to target solid tumors.
- No requirement to characterize tumor-associated antigens
- The tumor antigen–agnostic nature of this approach is applicable across a broad range of solid tumors, regardless of origin
- No requirement for the laborious process of clonal T-cell expansion versus CAR-T cell-based immunotherapies
- More patients potentially treated in shorter amount of time from diagnosis to treatment
- “Off the shelf” capabilities provide easier scale-up manufacturing and cost-of-goods
- Therapeutic for the treatment of cancer
- Immunotherapy in solid tumors leverage pre-existing immunity to chronic viral pathogen, such as HCMV
- Cell therapies for which clonal T-cell expansion is challenging from either a technically or manufacturing standpoint