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Vaccination with neoantigenic peptides or RNA may extend the survival of melanoma patients: implications for COVID-19 therapy

The recent years have seen the development of multiple innovative treatments for cancer to complement standard therapies consisting of surgery, radiotherapy and chemotherapy.  These include targeted therapy, anti-hormone therapy, etc., which may prolong the lifespan of patients (though less as effective in reducing mortality for advanced stage cancers).  Nevertheless, for the year 2020, National Cancer Institute predicts ~1.8 million people will be expected to be diagnosed with cancer—with ~606,000 deaths—in the U. S. alone, a sobering figure given the steady decline in cancer mortality rate observed since 1991.

In clinical oncology, there has been a resurgent interest in immunotherapy.  For cytokine immunotherapy, the use of IL-2 (interleukin 2) was approved by FDA (Food and Drug Administration) for the treatment of metastatic melanoma and renal cell carcinoma in 1990s.  Since then, various antibodies (monoclonal or humanized type) recognizing antigenic molecules expressed on the surface of cancer cells have been FDA approved.  These include antibodies targeting CD20 (leukemia), PD-1 (melanoma), Her2 (breast cancer) and EGF receptor (non-small cell lung cancer)

For cellular immunotherapy, currently available methods include vaccination with dendritic cells that have been incubated with tumor associated proteins or T cells engineered to express T cell receptors recognizing tumor specific antigens, i.e. CAR-T (chimeric antigen receptor) therapy.   The recognition of cancer target by these modified cells is mediated through the interaction of T cell receptor with the MHC (major histocompatibility complex) molecule presenting a peptide derived from tumor specific antigen. 

Tumor specific antigens’ can be immunogenic domains of normal proteins aberrantly expressed in tumor cells (ex. via gene amplification, promoter mutation) or mutant proteins exclusively expressed by cancer cells.  ‘Neoantigens’ refer to the latter type and are derived from mutant genes, which may play a role in cancer development.  Targeting neoantigens is ideal as it avoids inducing autoimmunity against normal tissues.  It may allow greater target-binding affinity as neoantigen-activated T cells may escape clearance (removal of self-reactive T cells) through programmed cell death.
                    
 Identification of neoantigens can be challenging.  In addition to being mutated, other criteria must be met: (i) translation into protein, (ii) proteolytic degradation into peptides; (iii) high affinity to MHC; (iv) strong binding of mutant peptide-MHC complex to T cell receptor.  To identify, whole-exon sequencing is performed on cancer cell’s DNA using next generation sequencing, followed by comparison with the corresponding normal sequences to identify candidate neoantigens.  It takes into account of the binding pattern of individual MHC alleles—a considerable feat given that ~5000 class I MHC alleles exist and each patient may express 3 to 6 alleles.  To assist, various bioinformatics software have been developed to predict neoantigens (Peng et al., 2019), with some incorporating artificial intelligence for machine learning (Ott el al., 2017).  Yet, it has been a difficult endeavor as very few candidates were found to be expressed by tumors or capable of triggering immune response.  Nonetheless, in 2017, several reports described that vaccination with long synthetic neoantigenic peptides or RNA-based poly-neo-epitope could extend the survival of a limited number of melanoma patients (Ott el al., 2017; Sahin et al., 2017).

Similarly, an immunological solution to the current pandemic caused by COVID-19 coronavirus is being sought.  Recently, the investigators at Oregon Health & Science University (USA) performed an in silico (computer modeling-based) study to characterize potential peptides for vaccination (Ngyuen et al., 2020).  They identified three HLA alleles that may bind to highly conserved peptides, which suggested that prior exposure to other coronaviruses (OC43, HKU1, NL63, and 229E) may endow cross-protection (T cell-based immunity) against COVID-19. They also found correlation between a HLA allele with fewest binding peptides (of COVID-19) and the vulnerability of individuals expressing this specific allele to SARS coronavirus.  Hence, conducting HLA typing concomitantly with COVID-19 testing was suggested.

The key to preventing epidemic is the ability to diagnose the infected early to preempt further propagation.  For this, Bio-Synthesis, Inc. provides primers and probes (as well as synthetic RNA control) for COVID-19 diagnosis via RT-PCR assay.  For medicinal chemistry, it specializes in peptide synthesis, characterization, modification, purification to generate various peptide-based building blocks as well as pharmaceutical intermediates.  Antibody purification, characterization/quantification, modification and labeling are also offered.  It specializes in oligonucleotide modification and provides an extensive array of chemically modified nucleoside analogues (over ~200) including bridged nucleic acid (BNA).  A number of options are available to label oligonucleotides (DNA or RNA) with fluorophores either terminally or internally as well as conjugate to peptidesIt recently acquired a license from BNA Inc. of Osaka, Japan, for the manufacturing and distribution of BNANC, a third generation of BNA oligonucleotides.  To meet the demands of therapeutic application, its oligonucleotide products are approaching GMP grade.  Bio-Synthesis, Inc. has recently entered into collaborative agreement with Bind Therapeutics, Inc. to synthesize miR-21 blocker using BNA for triple negative breast cancer.  The BNA technology provides superior, unequalled advantages in base stacking, binding affinity, aqueous solubility and nuclease resistance.  It also improves the formation of duplexes and triplexes by reducing the repulsion between the negatively charged phosphates of the oligonucleotide backbone.  Its single-mismatch discriminating power is especially useful for diagnosis (ex. FISH using DNA probe).  For clinical application, BNA oligonucleotide exhibits lesser toxicity than other modified nucleotides.

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References

Nguyen A, David JK, Maden SK, Wood MA, Weeder BR, Nellore A, et al. Human Leukocyte Antigen Susceptibility Map for Severe Acute Respiratory Syndrome Coronavirus 2.  J Virol  94:e00510-20 (2020).  PMID: 32303592

Ott PA, Hu Z, Keskin DB, Shukla SA, Sun J, Bozym DJ, et al.  An immunogenic personal neoantigen vaccine for patients with melanoma.  Nature 547:217-221 (2017). PMID: 28678778

Peng M, Mo Y, Wang Y, Wu P, Zhang Y, Xiong F, Guo C, et al.  Neoantigen vaccine: an emerging tumor immunotherapy.  Mol Cancer 18:128 (2019).  PMID: 31443694  

Sahin U, Derhovanessian E, Miller M, Kloke BP, Simon P, Löwer M, et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer.  Nature 547:222-226 (2017).  PMID: 28678784