T cell compatible cancer chemotherapy synergizes with cancer adjuvant vaccine

Nowadays it is well acknowledged that optimal cancer treatment would require multi-pronged approach, for example, combining cancer chemotherapy with cancer antigen-specific vaccine to boost tumor-specific T cell response. However, such combination is not always feasible since (a) both tumor and activated T cells are highly proliferative cell types and (b) vast majority of chemotherapy drugs target cellular replication machinery. Basically, it is matter of trial and error to find T cell compatible chemotherapy drugs.

Such combination was recently described in new paper published in Science Translational Medicine. Here, the authors showed that cervical cancer treatment with CarboTaxol (carboplatin + paclitaxel) synergizes with therapeutic T cell vaccine that consisted of HPV16 overlapping synthetic long peptides (HPV16-SLPs) admixed with adjuvant Montanide ISA-51.

Most cervical cancers in humans are induced by human papillomavirus type 16 (HPV16). Initially, the authors showed that CarboTaxol synergized with HPV16-SLP vaccination in HPV16-positive TC-1 tumor-bearing mouse model.

Next, the authors noticed that CarboTaxol [and vaccine too] reduced level of CD11b^highGr1^high myeloid [suppressor] population within tumor tissue.

Similar depletion of myeloid population was observed in blood samples of cervical cancer patients undergoing CarboTaxol therapy.

In fact, CarboTaxol treatment cycles significantly improved T cells proliferation in response to minor [bacterial recall antigen mixture, MRM)] and major HLA antigens [MLR].

Finally, combining CarboTaxol treatment with HPV16-SLP vaccination improved T cell stimulation in response to HPV16 antigens E6/E7.

In summary, this study indicates that CarboTaxol chemotherapy augments, rather than inhibits, tumor-specific T cell priming in response to HPV16-SLP vaccination.

David Usharauli

DC vaccines produced with tumor cells undergoing immunogenic cell death

Dendritic cells are the most potent activators of naïve T cells. A lot of effort has been spent to develop DC-based cellular vaccine. We even had some success in mouse models. But, so far no DC based vaccine worked in humans to significantly prolong patients survival. It is not surprising that only company that developed FDA-approved DC vaccine prostate cancer went bankrupt. There are many reasons as to why it is so hard. For one, there are several types of dendritic cells. Secondly, just pulsing [tumor] antigens on dendritic cells were found not to be sufficient.

Few weeks ago, Science Translational Medicine published study wherein the authors had tested next-generation tumor vaccine produced by pulsing DCs with tumor cells undergoing immunogenic cell death.

Basically, the authors had used a high-grade glioma (HGG) cell lines as a source of tumor. To generate immunogenic cell death, tumor cells were exposed to hypericin-based photodynamic therapy (Hyp-PDT). This treatment induces expression/release of several damage-associated molecular patterns (DAMPs) acting as potent danger signals for DCs. When mice were injected with DCs pulsed with Hyp-PDT treated glioma cells, they showed resistance to subsequent live glioma brain challenge.

Mechanistically, tumor protection provided by Hyp-PDT DCs depended on (1) DAMPs, (2) DC-specific MyD88, (3) CD8 T cells (T cells data are shown here).

Importantly, Hyp-PDT DC vaccines improved survival of brain tumor-bearing mice when applied therapeutically and in combination with standard-of-care therapy such as temozolomide (TMZ).

In summary, this study showed that hypericin-based photodynamic therapy could generate immunogenic tumor cells required for proper activation of DC for vaccination purpose. Conceptually, such mode of DCs preparation makes a lot of sense, but there are several technical challenges before this system could be translated into clinic, as discussed by the authors (such as, how to avoid presence of "surviving" live tumor cells within DC vaccine, route of DC vaccine injection [the authors have used intra-peritoneal injection, for some reason], what type of DC is the best for this purpose). 

David Usharauli

CD4 T cell-centric vaccine produces immunopathology and death

CD4 T cells are thought to orchestrate immune response to infections and vaccines. They provide help to CD8 T cells (to become cytotoxic cells and develop memory), B cells (to secrete antibodies) and macrophages (to eliminate intra-cellular microbes in type 1 response).

So, naturally, it is logical to assume that vaccine priming (activation) of CD4 T cells could provide huge benefits to host later. However, human logic and nature logic appears to be at odds in this situation.

The new study published in journal Science showed that CD4 T cell-centric vaccine strategy could backfire with deadly consequences. 

This research led by Prof. Dan Barouch (Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center) analyzed mice immune responses to live virus after vaccination with viral-specific CD4 T cell antigen.  

Surprisingly for the authors and regretfully for the experimental mice, they found that when mice were first vaccinated with intra-cellular microbial vector carrying inserted CD4 T cell specific viral epitope and then exposed to live virus, almost 90% of vaccinated mice died from what appeared to be a cytokine storm.

The authors found that rather than helping to fight virus, vaccine primed CD4 T cells inhibited viral-specific antibody production or maintenance of viral-specific CD8 T cells response.

Mechanistically, the authors found these deadly outcome were mediated by (1) activated viral-epitope specific CD4 T cells; (2) could be prevented by administration of anti-viral antibody or (3) with the simultaneous vaccination with CD8 T cell-specific viral epitope. 

In summary, these results showed that disproportional priming of CD4 T cells during initial vaccination could impair subsequent anti-viral protection. It appears that this outcome maybe specific for viruses producing chronic, long-term infection, since infection of vaccinated mice with viral clone producing acute, short-term infection did not show immunopathology.  

The data in this paper highlight our still so inadequate knowledge of such basic immune response properties as T cell response. If just having simply high frequency of antigen-specific CD4 T cells can produce such immunopathology, how immune system determines beneficial frequency of CD4 T helper (CD4 T_H) cells? It's just another of nature's mystery to be solved.     

David Usharauli