Friday, October 30, 2015

Almost every cancer patient harbors tumor-specific T cells

We know now that adaptive immune system (T and B cells) can detect single amino acid changes in mutated proteins. However, such efficiency of immune system was (and still) in odds with cancer development since tumors invariably express mutated proteins. So what's the deal?

Until recently in vitro detection of tumor-specific immune response was technically challenging. First, detection of mutated proteins or RNA was not easy task. Second, culture conditions for expansion and identification of viable tumor-infiltrated lymphocytes (TIL) specific for tumor antigens were not easy either. Today we have different situation. We can both detect and identify both tumor antigens and tumor antigen-specific TILs.

This study is kind of follow up from earlier study published in 2014. Here, for each cancer patient, the authors [led by Steven Rosenberg/NIH] first identified cancer mutations by rapid RNA sequencing and designed dozen of tandem minigene constructs containing mutated RNA sequences. These TMGs were then transfected into patient's autologous DCs and co-cultured with multiple TIL cultures harvested from metastatic tumors. This technique revealed presence of tumor-specific T cells (example below, TMG7, 14).

These tumor-specific TCRs were cancer antigen specific [showed no reactivity towards wild-type epitopes].

In 1 patient, the authors found TIL culture reactive to cancer driver gene KRAS (KRASG12D). The authors could identify HLA allele presenting mutated peptide (the authors even filed a patent for TCR directed to mutant KRAS. But the TCR itself is a product of nature and not patent eligible and TCR transduction into other T cells is by now considered "prior art". So I am not sure if they have a valid patent claim here. Another point is that it is safe to assume the authors already have earlier patents for transduction techniques and other TCRs. If so, then why they would need a new patent for just another TCR?).

however, the most relevant results are not shown in the paper but just discussed. The authors mentioned that 4 patients were treated with adoptively transferred T cells. However, only 1 patient receiving tumor-specific CD4 T cells showed persistent response and ongoing tumor regression, while other 3 patients who received tumor-specific CD8 T cells either do not show any response or showed only transient response. This suggest that unlike CD4 T cells, tumor-specific CD8 T cells may be not very efficient against solid tumors [lack of persistence in transferred hosts].

In summary, this article supports a notion that cancers do not go unnoticed by immune system. It appears that almost every cancer patient harbor tumor specific T cells that can be harvested, expanded and re-introduced back to patients to target tumors [alone or in combination of checkpoint inhibitors]. However, understanding biological difference between effectiveness of tumor-specific CD8 and CD4 T cells surely requires further research.  

David Usharauli

1 comment:

  1. I've also read the related papers, and you explained it clearly.
    cells research