Immuno-Oncology and Aptamers

The immune system is a sophisticated network of cells and signaling molecules designed to detect and eliminate threats. In most cancers, the body’s innate and adaptive immunity are able to generate an anti-tumor response. In some cases, however, tumor cells develop ways to manipulate the host’s own immune system to suppress immune activity or disguise themselves to avoid detection. Immunotherapy involves understanding and countering the mechanisms exploited by tumor cells to evade and inhibit immune response and boosting the body’s natural ability to fight cancer (1). 

Treatments in Immuno-Oncology

A few of the many treatments in immuno-oncology include:

Immune Checkpoint Blockade (ICB): Use of monoclonal antibodies to bind immune checkpoint proteins and prevent the receptor-ligand binding that causes down-regulation of immune response (9). Researchers in France used HSP70-specific aptamers to block the interaction of HSP70-expressing, tumor-derived exosomes with toll-like receptors (TLR2) on myeloid-derived suppressive cells (MDSC), blocking the activation of MDSCs and decreasing imunosuppression. (3)

Immune Proteins: Cytokines, interferons, and other immune proteins can be administered to non-specifically boost immune response (12). Researchers in Korea developed RIG-1 aptamers that increase RIG1-mediated IFN beta production. Activation of this immune pathway was shown to inhibit viral replication when tested with Newcastle disease virus (NDV) and Vesicular stomatitis virus (VSV). (4)

CAR T-cells: A patient’s own T-cells are modified with a receptor (chimeric antigen receptor) that identifies a specific cancer cell antigen (11).

Epigenetic Therapy: Treatment includes inhibition of histone deacetylases or DNA methyltransferases to increase anti-tumor response (9).

Despite advancements in recent years, there are ongoing challenges in immuno-oncology. Several of these challenges may be addressed with aptamers.

Discovering New Biomarkers

One key challenge in immuno-oncology is identifying tumor-specific antigens and increasing the number of predictive and prognostic biomarkers available (9,10). Cell-SELEX, or the discovery of aptamers that selectively bind tumor cells, can be used to identify novel biomarkers. The aptamer library is screened against the tumor cell of interest along with negative targets, including normal cells and possibly other types of tumor cells. (Read more about biomarker discovery using Cell-SELEX). Aptamers that selectively bind a tumor of interest can be used in diagnostic tests, targeted drug delivery, and biosensors for treatment monitoring.

Cell Targeting in Immunotherapy

Aptamers selective for specific cancer cells can facilitate targeted delivery of a wide range of therapeutic agents, including antibodies, toxins, siRNAs, and aptamers. Researchers in Jiangsu, China utilized aptamers for targeted delivery of the chemotherapeutic drug doxorubicin in mice. Using whole cell SELEX, the researchers identified an aptamer with high affinity and selectivity for the 4T1 mouse mammary breast cancer cell line. By conjugating 4T1 cell-specific aptamers to doxorubicin-loaded liposomes, they increased internalization of doxorubicin by 4T1 cancer cells, increased tumor suppression, and reduced toxicity to normal cells. (7) An aptamer conjugate consisting of a VEGF-specific targeting aptamer and an agonistic 4-1BB aptamer showed an improved therapeutic index and reduced toxicity compared to a 4-1BB antibody therapeutic. (6,2) 

Nonsense-mediated mRNA decay (NMD) is a cellular quality control mechanism designed to degrade incomplete mRNAs. (1) Researchers in Spain combined an anti-CD40 aptamer with a shRNA that inhibits SMG1, an important kinase in MSD. The result is the production and expression of nonsense proteins on the cell surface of CD40+ cells and enhanced immunogenicity. (8) Some tumor cells have been shown to assume control of T regulatory cells (Treg), immunosuppressive cells, to evade an immune response. Another team in Spain combined a CD28-targeting aptamer with a P60 Foxp3 inhibitor peptide for targeted reduction of Treg immunosuppressive activity. (5) In several studies, aptamer-based, targeted drug delivery has been shown to increase drug efficacy, lower required dose, and decrease side effects.

Many antibody-based immunotherapies are associated with toxicity that limits dosage and effectiveness. While aptamers themselves can be powerful cancer-fighting agents offering reduced immunogenicity and enhanced cellular access, the use of aptamers as combinational therapies designed to block immune suppression, boost the natural immune response, and deliver targeted treatment appear to be winning strategies in the war on cancer.

References

Image of cytotoxic T cells attacking an oral squamous cancer cell courtesy of Rita Elena Sarda, National Cancer Institute \ Duncan Comprehensive Cancer Center at Baylor College of Medicine

  1. Cheng, Y. et al. (2007). The nonsense-mediated decay RNA surveillance pathway. Annu. Rev. Biochem. 76 :51-74.
  2. Gilboa, E. et al. (2015). Reducing toxicity of immune therapy using aptamer-targeted drug delivery. Cancer Immunol Res; 3(11).
  3. Gobbo, J. et al. (2016). Restoring anti-cancer immune response by targeting tumor-derived exosomes with a HSP70 peptide aptamer. JNCI Natl. Cancer Inst. 108(3). Doi: 10.1093/jnci/djv330.
  4. Hwang, S. et al. (2012). 5′-Triphosphate-RNA-independent activation of RIG-I via RNA aptamer with enhanced antiviral activity. Nucleic Acids Research. 40(6) :2724-2733.
  5. Lozano, T. et al. (2016). Targeting inhibition of Foxp3 by a CD28 20-Fluro oligonucleotide aptamer conjugated to P60-peptide enhances active cancer Immunotherapy. Biomaterials. 91:73-80. Dx.doi.org/10.1016/j.biomaterials.2016.03.007
  6. Schrand B, et al. (2014). Targeting 4–1BB costimulation to the tumor stroma with bispecific aptamer conjugates enhances the therapeutic index of tumor immunotherapy. Cancer Immunol Res. 2:867–77.
  7. Song, X. et al. (2015). Targeted delivery of doxorubicin to breast cancer cells by aptamer functionalized DOTAP/DOPE liposomes. Oncology Reports. Pages 1953-60. Doi.org/10.3892/or.2015.4136.
  8. Soldevilla, M. M. et al. (2015).  2-fluoro-RNA oligonucleotide CD40 targeted aptamers for the control of B lymphoma and bone-marrow aplasia. Biomaterials. 67:274-285.
  9. Allard, B., et al. Immuno-oncology-101: overview of major concepts and translational perspectives. Seminars in Cancer Biology. 2018. 52:1-11. 
  10. Oncology Central. 2018, Jan 26. Seven challenges in immuno-oncology. Accessed March 20, 2018. [https://www.oncology-central.com/subject-area/immuno-oncology/seven-challenges-immuno-oncology/] 
  11. American Cancer Society. CAR T-Cell Therapy to Treat Cancer. Accessed July 12, 2019. [https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/car-t-cell1.html]
  12. NIH. Immunotherapy to treat cancer. Accessed July 12, 2019. [https://www.cancer.gov/about-cancer/treatment/types/immunotherapy]