A Novel Approach in Engineering T Cells to Attack Cancer

A broad range of methods are under development to engineer T cells that can selectively attack cancer cells. If aggressive enough and selective enough, the immune system should in theory be able to tame and destroy most cancers, but the devil is in the details as is always the case in these matters. The use of chimeric antigen receptors in altered T cells is one noteworthy approach, and here researchers report on their efforts to mine the biochemistry of another species for similarly useful additions to human T cells:

T cells are the linchpin in the attack of the immune system. On their surface they have anchor molecules (receptors) with which they recognize foreign structures, the antigens of bacteria or viruses, and thus can target and destroy invaders. Cancer researchers and immunologists are attempting to mobilize this property of the T cells in the fight against cancer. The objective is to develop T cells that specifically recognize and attack only cancer cells but spare other body cells.

Researchers have now developed human T cell receptors (TCRs) that have no tolerance toward human cancer antigens and specifically recognize the antigen MAGE-A1, which is present on various human tumor cells. First, the researchers transferred the genetic information for human TCRs into mice, thus creating an entire arsenal of human TCRs. When the humanized mouse T cells come into contact with human cancer cells, they perceive the tumor antigens as foreign - like viral or bacterial antigens. Thus, the T cells can specifically target, attack and destroy the tumor cells. The researchers subsequently isolated the human T-cell receptors of these mice, which are specifically targeted toward the tumor antigen MAGE-A1. Then they transferred the T-cell receptors into human T cells, thereby training them to recognize the cancer cells as foreign.

Some people possess T cells which naturally recognize MAGE-A1 on tumor cells, but only in the Petri dish. In studies using an animal model, only the human TCRs derived from mice were shown to be effective against the tumor. The TCRs from human T cells ignored the tumor completely. "The fact that our TCRs from the mouse are better is a strong indication that the T cells of a human are tolerant toward MAGE-A1." Using the T-cell receptors they developed, the researchers are planning an initial clinical trial with patients with MAGE-A1 positive multiple myeloma, a malignant disease of the bone marrow.

Link: https://mdc-berlin.de/44321220/en/news/2015/20150319-mdc_and_charit__researchers_tweak_the_immu


Hmmm... this isn't exactly novel as researchers have been trying to engineer T Cell Receptors (TCRs) specific to MHC presented cancer peptides for a long time now. This just may be one of the first successful attempts. Is the TCR specific to a surface antigen on the cancer cells? I can't see from that Wikipedia link if MAGE-A1 is a cell surface protein, or an intra-cellular protein?

It is really interesting to find out that some people possess T cells which recognize MAGE-A1 but then these T Cells don't do anything in vivo:

"The comparison with the tweaked human TCRs from the mouse model shows that the TCRs of patients cannot recognize the tumor antigens sufficiently; they are too weak."

You'd think that the usual somatic hyper-mutation would take place in the human T cells that can already recognize MAGE-A1 leading to a very specific TCR? There must be some countervailing mechanisms that prevent this (or that I just don't know about with my layman's knowledge of immunology)?

I look forward to seeing how these genetically engineered T Cells do against multiple myeloma in a clinical trial.

Posted by: Jim at March 20th, 2015 3:03 PM

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