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Something about immunotherapy

August 28, 2017

 

Ghost wanna share a good video illustrating how immunotherapy works.

 

 

Immunoediting

Battle between tumor and immune system is a equilibrium phrase that can last years. This dynamic process consists of immunosurveillance and tumor progression.

 

During immunosurveillance, immune system recognizes tumor cells through neoantigens presented by MHC (HLA) on the surface of the cell. Those neoantigens include

  • tumor associated antigen: Proteins expressed in some normal tissues at low levels but over-expressed in malignant cells. 

  • Tumor specific antigen: Proteins only expressed in tumor cell.

Expression of these antigens in normal cells can trigger central and peripheral tolerance mechanisms that lead to the selection of T cells with low-affinity T cell receptors (TCR). Conversely, attempts to target tumor-associated antigens with high-affinity TCRs can lead to severe toxicities due to normal tissue destruction.

 

During tumor progression, tumors can escape immune surveillance through multiple mechanisms. For example:

  • Reduced immune recognition due to absent of neoantigen, loss of MHC complexity or compromised immune competency.

  • Increased resistance or survival.

  • Development of an immunosuppressive tumor environment.

     

 

How immunootherapy works?

  • Enhance (vaccination) and somehow modify the immune cell (Adoptive cell transfer) tries to re-recognize tumor cell or at least counteract immune exhaustion and stop, especially tumor with MSI-H, from further growth.

  • Immune checkpoint blocker (PD-1, CTL-4)

 

 

However, immunotherapy not always works. 

  • 20-30% response rate

  • 30% toxicity (autoimmune)

 

 

How to evaluate efficacy of immunotherapy?

IHC and FISH are frequently used in detecting specific antigens that can be targeted by immunotherapy:

  • IHC is used for initial screening, and FISH testing is restricted to IHC undetermined case results (tumor-specific criteria (negative, 0 or 1+; indeterminate, 2+; positive, 3+).

  • IHC is faster, less labor-intensive, and less expensive, while FISH is considered more accurate, less vulnerable to tissue artifacts and offers a more objective scoring system

Besides, some bioinformatics methods have been established to evaluate some factors that may affect immunotherapy's efficacy:

  • TMB and MSI: High TMB (TMB-H) tumors implies increased chance of being recognized by immune system. There are usually two ways to evaluate TMB. If we have large genomic region sequenced (WES), we can directly calculate the total number of mutations within certain genomic length, for example per 1MB. If we only have limited genomic region sequenced (targeted sequencing) and can't obtain an accurate result of n_mutation per 1MB, then we can check microsatellite instability (MSI): an indicator of high TMB. Some  bioinformatics methods query the length of well known microsatellite (NR-27, BR21, BR24, BAT25 and BAT26) to evaluate microsatellite stability. However, keep in mind that MSI-H tumor only accounts for a portion of TMB-H tumor

  • Immune competency: Abundance and diversity of immune repertoire at tumor site can be evaluated by NGS-based method (Rep-Seq).

  • HLA: Studies have shown that patients with certain HLA types are more likely to benefit from immunotherapy.

 

 

Immunotherapy vs targeted therapy

Let's compare immunotherapy with other methods using the old table

 

 

In terms of toxicity

Just like targeted therapy that targets alterations existing only in tumor cells, immunotherapy only targets cell expressing neoantigens and leaves normal cell undamaged.

 

In terms of relapse

Unlike targeted therapy that can only target one or at most several tumor specific alterations, immunotherapy restores / re-triggers patients' immune response against tumor cells that present any neo-antigens. This more "versatile" method makes patient less likely to get relapse. This is what immunotherapy really good at: to overcome tumor heterogeneity.

 

 

 

 

 

 

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