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   <h class="highlight-title dark-blue"><center></br></br></br>SwordS</br></br>Antigen density heterogeneity and limited treatment, </br>two obstacles in improving therapeutic effect and applicability of immunotherapy</center></h>
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<h class="bold-text dark-blue"><center></br>Antigen density heterogeneity and limited treatment, </br>two obstacles in improving therapeutic effect and applicability of immunotherapy</center></h>
 
   <h class="highlight-title dark-blue"></br></br>Target antigen density heterogeneity</h>
 
   <h class="highlight-title dark-blue"></br></br>Target antigen density heterogeneity</h>
 
   <p></br>The expression of the antigen on individual cells within a given tumor is different or heterogeneous. A solid tumor mass consists of numerous tumor cells. In these tumor cells, some may express relatively less tumor antigens, others may express relatively more tumor antigens. Meanwhile, a given tumor antigen is not only expressed on malignant cells, but may also be expressed on normal cells at a low level <font color="#004a84">(Figure 1A)</font>. Thus, normal cells expressing low level of tumor antigens subsequently should not be targeted, otherwise would casuse complications. Carefully control the on-target/off-tumor effect is critical for the success of immunotherapy. <font color="#004a84">(Figure 1B)</font> </br></br>
 
   <p></br>The expression of the antigen on individual cells within a given tumor is different or heterogeneous. A solid tumor mass consists of numerous tumor cells. In these tumor cells, some may express relatively less tumor antigens, others may express relatively more tumor antigens. Meanwhile, a given tumor antigen is not only expressed on malignant cells, but may also be expressed on normal cells at a low level <font color="#004a84">(Figure 1A)</font>. Thus, normal cells expressing low level of tumor antigens subsequently should not be targeted, otherwise would casuse complications. Carefully control the on-target/off-tumor effect is critical for the success of immunotherapy. <font color="#004a84">(Figure 1B)</font> </br></br>
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Revision as of 14:52, 30 October 2017



SwordS

Antigen density heterogeneity and limited treatment,
two obstacles in improving therapeutic effect and applicability of immunotherapy

Target antigen density heterogeneity


The expression of the antigen on individual cells within a given tumor is different or heterogeneous. A solid tumor mass consists of numerous tumor cells. In these tumor cells, some may express relatively less tumor antigens, others may express relatively more tumor antigens. Meanwhile, a given tumor antigen is not only expressed on malignant cells, but may also be expressed on normal cells at a low level (Figure 1A). Thus, normal cells expressing low level of tumor antigens subsequently should not be targeted, otherwise would casuse complications. Carefully control the on-target/off-tumor effect is critical for the success of immunotherapy. (Figure 1B)



Limitedtreatment cannot suit all cases


Carcinogenesis is a gradual progress driven by the accumulation of mutations. Tumor cells are highly heterogeneous in their surface tumor antigen expression(1), thus immune resistance(2), sensitivity to the treatment and so on. Meanwhile, efficient recognition by immunotherapy, as one of the fundamental challenges for solid tumors, is still in the way comparing with exciting results shown in treating hematological cancers(3).Currently, most existing immunotherapies exhaust in trying multiple methods to improve recognition(4-6), without considerating tumor heterogeneity. They focus narrowly on finding an ideal tumor antigen as the target and hope to generate a effective therapeutic response – monotonic response.We believe these conventional one-size-fits-all immunotherapies cannot adapt itself to all complex disease occasions in various types of tumors.(Figure 1B)



Read more: Current methods to improve recognition and their imperfections


Current methods to improve recognition are not perfect
Emerging methods to improve recognizing precision, like dual recognition (6,7)and tunable sensitivity (5), have been proved capableof eliminating specific tumor cells. However,these methods cannot completely solve the problem.

Specific tumor antigens for dual recognition is hard to find
The first step for immunotherapy is to select a highly specific tumor antigen as the target. However, qualified candidates for tumor antigens are rare in most cases. Taking HCC (hepatocellular carcinoma) as an example, although HCC-associated antigens, like EpCAM(8), NY-ESO-1(9), and GPC3(10), are potential targets of cellular immunotherapies for advanced HCC. However, only GPC3, is wildly accepted as the tumor antigen of HCC owing to its high specificity.(6,11,12). Only one tumor antigen for HCC prevents the use of dual recognition.

Tunable sensitivity requires optimized scFv– it is very get
The affinity of single-chain variable fragment (scFv) is essentialfor recognition. Even though recently highthroughput methods have been developed to screen forscFvs with different affinity to the same antigen(13), specialized knowledge and high expense render it impossible to perform inall laboratories. Only one or two laboratories around the world have the capability to develop scFv with tunable sensitivity.