Thursday, January 7, 2016

DC vaccine synergizes with αCTLA4/αOX40 against solid tumors

The Objective of any tumor immunotherapy is to achieve tumor-specific T cell response while avoiding any bystander T cell activation. The reason why checkpoint inhibitors, such as αPD-1 and αCTLA4 antibodies work only in a fraction of patients have to do with the fact that only those "responders" have enough pre-existing tumor-specific T cells "responsive" to αPD-1 and αCTLA4 inhibitions. 

Other patients are refractory because their immune system is "blind" or "ignorant" of tumor antigens, i.e. first stage of T cell priming has failed due to lack of antigenic load in DCs (for example, if tumor express few mutated antigens). This situation, however, is potentially reversible with DC vaccines, wherein tumor-specific antigens/epitopes are loaded into DCs. Such "loaded" DCs would then prime T cells which in turn become responsive to checkpoint inhibitors.

So, solid tumor immunotherapy would require multi pronged approach to improve its efficacy. In this regard, I found this new paper in PNAS worth reviewing. Here, the authors showed that combination of "loaded" DC vaccine with αCTLA4/αOX40 treatment were able to overcome dormant state of T cells and allowed efficient control of solid tumors.

Initially, the authors showed that dual αCTLA4/αOX40 antibody treatment allowed substantial expansion of antigen-specific CD8 T cells (in a CD4 T cell-dependent manner).

However, these expanded CD8 T cells were not able to control solid tumor in mice challenged with HER2-expressing TUBO mammary cancinoma cells. However, when αCTLA4/αOX40 antibody treatment were combined with DC vaccine (DEC-205/HER2/PolyI:C), half of tumor challenged mice achieved long-term tumor-free status. 

Now, this is just an example of what potentially could be accomplished with the right concept. In general, OX40 is a complex molecule that has additional role in TH2 immunity, so it is not clear whether this particular combination would be useful in humans. PolyI:C, TLR3 agonist, is not approved for human use either, so it is also not very relevant right now.

In summary, combination of DCs vaccine with checkpoint inhibitors could add missing piece necessary to arm T cells against solid tumors.

David Usharauli

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