Advances in Immuno-Oncology

Cancer and Immunotherapy

Cancer is one of the leading causes of deaths worldwide. Standard of care consisting of radiation, chemotherapies, and surgical resections provide limited relief for most cancer patients due to their non-specific approach and related toxicities. While targeted therapies have emerged, innovative cancer treatments are urgently needed for patients with late-stage and refractory disease. Recent advancements in cancer immunology have produced several new approaches that can stimulate the immune system against the tumor or inhibit immune-suppressive signals by cancer cells. While these novel immunotherapies may generate a more potent and durable response than standard treatments, their efficacy is however limited to a subset of patients.

Genetic Mutations

Cancer is a disease of the genome; it is the result of the gradual accumulation of genetic mutations that successively increase cell proliferation. In general, cancer cells have more genetic mutations than normal cells, but each person’s cancer has a unique combination of genetic alterations. Leveraging the advances of Next Generation Sequencing, we can now rapidly generate increasingly comprehensive genetic maps of tumor cells and by comparing to the genetic map of the normal cells of the patient, identify the entire maps of the tumor mutational burden (mutanomes). These mutanomes have brought to our attention the enormous diversity of unique mutations in each tumor. Such unique genetic variations in mutanomes infer that a one-size-fits-all modality is outdated. Our approach is to develop highly personalized or precision immunotherapies based on the unique genetic makeup of each patient tumors.

What are Neoantigens?

Neoantigens are newly formed antigens that have not been previously recognized by the immune system. Neoantigens can arise from altered tumor proteins formed as a result of genetic mutations or from viral proteins.

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References
1. Yuan J et al. J Immunother Cancer. 2016; 4:3.

Immune Response and the Importance of Identifying and Removing Inhibitory Neo-Epitopes

The immune system regularly surveys the body using major histocompatibility complexes (MHC) atop the immune cell surfaces. Cells regularly display native (“self”) and foreign (“non-self”) antigens onto their surface for immune system recognition, also known as immune-surveillance. Antigens are presented through two classes of MHC’s: Class I for intracellular protein display towards cytotoxic (effector) CD8+ T cells, and Class II for extracellular protein display towards helper CD4+ and regulatory T cells. While both MHC classes support the surveillance and eradication of cancer tissue, regulatory T cells (Tregs) are a highly immune-suppressive subset of CD4+ T cells. Tregs are potent suppressors of effector T cells, and, consequently, increased densities of tumor-infiltrating Treg cells have been associated with poor prognosis in a number of cancers. Treg cells protect healthy individuals from developing autoimmune diseases and allergies, whereas in cancer malignancies, they promote tumor progression by suppressing effective anti-tumor immunity.

 

Cancer cells acquire resistance from the immune system by selecting less immunogenic cells and exploiting the immunosuppressive nature of Tregs. However, cancer cells harboring inherent genetic instability, form new antigens (so-called neo-antigens) that present their “non-self” neo-epitopes, which have not been previously recognized by the immune system. Thus, allowing for a novel approach of precision immunotherapy by targeting neo-epitopes.

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