Overcoming Immune System Evasion by Personalized Immunotherapy

Kevin C Soares; Lei Zheng; Nita Ahuja


Personalized Medicine. 2014;11(6):561-564. 

In This Article

Epigenetic Therapy & its Implication in Personalized Immunotherapy

Understanding the genetic and epigenetic components of tumor immune evasion is critical. Most of the discussion regarding tumor immune evasion has centered on mutations in the cancer genome. For example, structural alterations in the MHC class I antigen-processing pathway allow for the immune escape of melanoma and microsatellite unstable colorectal cancer.[8,9] Notably, however, very few cancer genome mutations have been associated with a direct effect or correlated with immune evasion.[10] More recently, intense investigation on the relationship of epigenetic modulation and immune escape has revealed a dynamic and critical interplay between epigenetic and immune modulation, laying the groundwork for highly promising combinatorial therapies.

Epigenetic regulation of immunity includes direct regulation of genes involved in B-cell maturation, cytokine gene expression (i.e., IFN-γ, IL-12, IL-10), MHC class I and II expression and costimulatory genes (CD40, CD80, CD86).[11–13] Certain tumors produce consistent immune inhibitory changes, such as in breast cancer where upregulation of immunosuppressive pathways including IL-10, TGF-β and ref-7-H4 and downregulation of the T-cell costimulatory molecules CD28 and CD83 is commonly seen.[4,14] By contrast, other neoplasms produce markedly different immune signatures from one tumor to the next.[14] Therefore, there is a role for the determination of tumor immune signatures to more accurately tailor immunotherapeutics.

The tumor's immune suppressive pathways are dynamically related to epigenetic regulation and epigenetic therapy can specifically target this pathway in human cancers. In recent reports by our group, we demonstrated that low doses of DNA methyltransferase inhibitor 5-azacitidine (5-AZA) administered in vitro to human breast, ovarian, lung and colon cancer cell lines resulted in upregulation of immunomodulatory pathways, including IFN-γ, antigen-processing pathways, and cytokine and chemokine expression.[15] Moreover, correlative in vivo studies demonstrated similar findings.[15] In addition, upregulation of cancer antigens was also observed, specifically cancer testis antigen. Epigenetic modifications to antigen expression and presentation will vary among individual patients. Characterization of the response to epigenetic therapy in individual patients will lead to personalized therapies against specific tumor subtypes. For example, robust induction of cancer testis antigens in a subset of patients as a result of epigenetic therapy can be used as targets in antigen-specific vaccines and antibody therapy.

Currently, clinical trials using epigenetic agents such as histone deacetylase inhibitors and demethylating agents (i.e., 5-AZA) focus directly on the therapeutic potential of these compounds. Although some studies have reported encouraging results in this regard,[16–18] most have failed to demonstrate clinical efficacy as single agents in early phase clinical trials and recent reports suggest that an intact immune system is critical to the anticancer activities of these agents.[19] Therefore, as we gain a better understanding of epigenetics' role in immune system regulation, a new and important therapeutic role for epigenetic agents as part of combinatorial therapy is readily apparent.

Combination epigenetic therapy of 5-AZA and entinostat in patients with refractory advanced non-small-cell lung cancer patients demonstrated objective durable responses in only two of 65 patients according to response evaluation criteria in solid tumors (RECIST). After demonstrating disease progression, the remainder of these patients underwent a variety of treatment modalities including chemotherapy and immunotherapy targeting the immune checkpoint programmed death-1 (PD-1). When anti-PD-1 blockade was used in patients who had previously been primed with epigenetic therapy, most patients responded to anti-PD-1 monotherapy.[17,20] Preclinical studies using an in vitro model characterized the 5-AZA-induced expression signature of immune genes and pathways, which are characteristically downregulated during immune surveillance, including the core interferon pathway transcription factor IRF7.[20] The interplay of PD-1/PD-L1 interaction and epigenetic therapy reflects the complex interactions and synergistic possibilities. Epigenetic therapy targeting the tumor results in an increased proinflammatory response and re-expression of hypermethylated antigens. Concurrently, epigenetic therapy acts directly on T cells to increase IFN-γ secretion as well as upregulate PD-1 expression.[21] In addition, the elevated IFN-γ levels upregulate tumor cell PD-L1 expression thereby abrogating this epigenetically induced immune activation.

Although some neoplasms are associated with optimal survival rates using current therapies, most tumors are poorly susceptible to current treatment modalities and new therapies are sorely needed. In addition to new therapies, a better understanding of the disease biology and its capability to render antineoplastic agents ineffective, even in the setting of initial clinical efficacy, argues for a different approach in addition to new treatment modalities. Cancer cells within individual primary tumors contain a variety of genetic, epigenetic and molecular variations. Therefore it is highly unlikely that a single antineoplastic agent will cure a given disease and history has thus far proven this to be true. Future oncologic clinical investigations call for an ever-expanding role of personalized combinatorial therapies including chemotherapy, radiation, surgery, epigenetic modulation, immunotherapy and genetic characterization. The cancer genome is constantly changing, therefore genetic and epigenetic biomarker-driven combinatorial therapy will have the highest likelihood of success.

A core component of effective combinatorial, personalized therapy will be epigenetic therapy given that it is intricately related to our other treatment modalities. For example, chemotherapeutic agents induce epigenetic modifications in the epigenome. Alternatively, epigenetic therapy can render certain tumors sensitive to a previously resistant chemotherapy regimen. Current ongoing trials at our institution are testing this premise (NCT01896856; NCT01935947). From an immunotherapeutic perspective, it is well established that epigenetic therapy upregulates previously suppressed immune effector genes as well as the expression of certain tumor antigens. Despite these promising results, future obstacles include identifying the appropriate strategy of combining therapies and identifying appropriate patient populations for those regimens.