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

OX40/CD30 lay off Foxp3

 Since it's discovery in 2001, a transcription factor called Foxp3 has been recognized as a master regulator of autoimmune disease. It's total deficiency in CD4 T cells has such a profound effect that mouse that lacks it usually die of inflammatory multi-organ failure within 3 weeks of birth.

We don't know how exactly Foxp3+ CD4 T cells prevent autoimmunity. Currently, there is no mechanistic model that could satisfactorily explain their function. Even at the theory level, Foxp3+ T cell role is either totally ignored/dismissed (for example, in SNS model) or characterized as an immune class-specific effector/memory T cells (for example, in danger model). In short, the viable concept of negative regulation of immune system by antigen-specific Foxp3+ CD4 T cells is yet to come.

If you are interested in Foxp3+ T cell biology, I recommend reading a new study recently published in Journal of Experimental Medicine (1). This study, by Fabrina M. Gaspal and et al, made an interesting observation that mice triple deficient in OX40/CD30/Foxp3 are healthy. It appears that OX40/CD30 pathways control autoimmune potential of self-specific T cells. The simple explanation I favor is that in the absence of OX40/CD30 signaling, effector/memory T cell differentiation is impaired in general and as a consequence, self-specific T cells loose the capability to damage the tissue. Of course, the one caveat of the paper is that we have no idea whether those triple deficient mice are capable of mounting a proper immune response to non-self antigenic challenge or infection. If they cannot, then the absence of autoimmunity is the direct consequence of immunodeficiency (similar to gamma-c receptor deficient mouse model). However, if they could respond to non-self antigenic challenge or infection, then this model has made an unique contribution to our understanding of Foxp3 biology.

David Usharauli

(1) http://jem.rupress.org/content/208/8/1579.abstract