Cancer and the immune system

The ability of the immune system to eliminate tumor cells has been proven and well documented over the last two decades. Tumor cells can be eliminated by cytotoxic T cells that recognize tumor antigens, most of which represent mutations that have occurred over time during metaplastic transformation of a normal cell to a malignant cell.

In the early phase of tumor formation, the immune system is able to recognize and eliminate most of the transformed cells. However, some tumor cell phenotypes avoid elimination that results in an equilibrium between the immune attack and tumor formation. Eventually, the malignant cells develop the potential to evade the immune system through different escape mechanisms.

 

Cancer immunotherapy

Currently there are several types of immunotherapies in development and in clinical use that either target cancer-mediated immune escape mechanism or boost the immune system. These include interleukins, Toll like receptor agonist for dendritic cell activation, cancer vaccines, T cell therapy and immune checkpoint inhibitors.

New immunotherapies, such as immune checkpoint inhibitors, tend to be most effective on tumors that are T cell inflamed (hot), whereas those that are not T cell inflamed (cold) are much less responsive to immunotherapy. The lack of ability to penetrate the parenchyma and microenvironment of tumors may result in limited T cell presence.

New immunotherapeutic strategies are therefore needed to enhance the presence of T cells in cold tumor and thereby making them more sensitive to immunotherapy.

 

New treatment strategies and challenges

An effective T cell mediated immune response can only occur if antigens are released from tumor cells and taken up by dendritic cells. The dendritic cells present the antigens to T cells, which then become activated and migrate into circulation to attack cancer cells.

 

Patients with low mutational burden

One reason why such priming of T cells does not occur is due to low mutational load. Tumor mutational load is a measure of the number of mutations in the coding regions of DNA and display a great variability within tumor types ranging from very few (i.e. low-grade tumors and pediatric malignancies) to several thousands (melanoma). These mutations can give rise to numerous aberrant structural proteins that can serve as neoantigens, and higher mutational load has been shown to correlate with higher levels of neoantigen. 

Several studies have shown that tumors with higher mutational loads respond better to immunotherapy. Hence, agents that can effectively release tumor antigens to trigger an effective T cell mediated immune response in patients with low mutational load is highly needed.  

 

Tumor heterogeneity

Tumor heterogeneity describes the observation that different tumor cells can display distinct genetical and phenotypical profiles, including gene expression, mutational burden, metabolism, proliferation and metastatic potential. The degree of heterogeneity can vary within a tumor, between tumor lesions in the same patient, or tumors of same type but in separate patients. The heterogeneity of the tumor cells introduces significant challenges when it comes to choice of treatment strategies.

Heterogenic tumor cells may exhibit different sensitivity to conventional therapy (i.e. chemotherapy and radiation) and resistance to therapy may evolve during treatment resulting in a relapse of an aggressive tumor.

Agents that can effectively release tumor antigens from all tumor cell phenotypes are critical to generate an effective T cell response that will target all phenotypes present in a treated tumor.

 

Local Immunotherapy

Many single agent immune therapies induce immune-related toxicity, therefore the potential for increased toxicity is even higher with combination treatment which will hamper development of multiple combinations.

In preclinical models, combinations administered intratumorally have shown equal or even better systemic effects compared to systemic administration of the same combinations.  It would be appropriate to assume that lower doses and less systemic exposure of such immune-activating agents will result in less toxicity when given locally, opening up the option for multiple immunomodulatory drug combinations  that are too toxic when used systemically.

Lytix Biopharma has developed an oncolytic peptide, LTX-315, that, when given intra-tumorally generates an immune response against a broad antigen repertoire without the need for identification of the antigens. Therefore, local use of LTX-315 has the potential to make cold tumors with low mutational burden hot and T cell inflamed. LTX-315 can induce complete regression both in experimental models and in cancer patients through an oncolytic mode of action, resulting in the release of tumor antigens from all tumor cell phenotypes invoking a polyclonal T cell response. LTX-315`s ability to activate and prime a broad repertoire of T cell clones makes it ideal for combining with other local and systemic immunotherapies.