Saturday, November 28, 2015

Immunotoxins show anti-cancer synergy with immune checkpoint inhibitors

This week Science Translational Medicine published 2 papers directly or indirectly related to Foxp3T cells [this is in in addition of two Foxp3+ T cell papers in Nature]. Since I am very curious about the role of Foxp3+ T cells in immune regulation I decided to review them.

First paper I review here is not a typical Foxp3+ T cell paper. It is actually a study of tumor immunotherapy. The authors showed that when combined with checkpoint inhibitors CTLA-4/PD-1, direct tumor immunotoxins, such as T-DM1 [trastuzumab emtansine], significantly augment anti-cancer immune response and immune memory.

Trastuzumab [herceptin] is a humanized antibody that targets HER2 antigen over-expressed in breast cancer cells. Initially, the authors showed that anti-cancer effect of ado-trastuzumab conjugated to cancer toxin, T-DM1 (Kadcyla®), was depended on T cells [as revealed by T cell depletion]. This suggested potential synergy with checkpoint inhibitors.

Indeed, a combined application of T-DM1 and CTLA-4/PD-1 antibodies showed close to  100% protection against breast cancer in mice.

Surprisingly, the authors noticed that combo therapy, that fully protected mice against tumors, actually increased infiltration of tumor tissue by functioning Foxp3+ T cells [in addition to conventional T cells]. This was counter-intuitive.

However, T cell depletion confirmed that when CD4 T cells [that includes Foxp3+ T cells] were removed, more than 50% of mice on combo therapy [100% tumor-free] developed severe autoimmune inflammation [results with Treg-specific depletion would have been more valuable here, of course].

In summary, this study points to 2 distinct results: first, direct cancer cytotoxocity by immunotoxins could synergize with checkpoint inhibitors, probably via efficient antigen uptake and DC maturation [antigen processing stage]. Second, tumor infiltrating Foxp3+ T cell could play not yet understood tissue protective role during such combo immunotherapy [in effector stage].

David Usharauli


  1. Does the same effect occur when the naked anti-body Herceptin is used?

  2. Most likely not. The paper only mentioned that T-DM1 is used against Herceptin resistant cancers.

  3. This is an interesting result, I wonder how it compares to other tumorcidal agents like TKIs or traditional taxane based chemotherapy. Perhaps the former don't have any native immune effect like a mAb does and the latter is not specific enough to prime DC's to just tumor cells. Page 31 of the presentation "ImmunoGen_10-27-15_for_website.pdf" has another demonstration of the synergies between immune checkpoint inhibition and ADCs, and there are other mAb + maytansine ADCs to test this mechanism against such as Mirvetuxemab Soravtansine which has shown promise against ovarian cancer; the base mAb of this ADC doesn't seem to have any effect alone, whereas naked Trastuzumab itself seems to elicit an immunological response.

  4. Thanks for expressing your opinion.

    For me this study has 2 major significance [the reasons I reviewed it]:

    1. triple Ab application primed "memory" response, suggesting that one [or two] time application should provide life-long immunity to the tumor.

    2. Presence of Foxp3 Tregs within tumor tissue or other tissues were necessary to prevent excessive inflammation when triple Ab were applied.

  5. I was surprised at the immunological response to T-DM1. The other two mAbs (presumably Nivolumab and Ipilimumab) are well known in theory and practice to elicit an enhanced immune response, but Trastuzumab itself isn't primarily known as an immune acting agent although its effect on the immune system has been studied. It would be interested to see why T-DM1 in particular combined so well and compare this to TKIs, naked Abs, taxane chemotherapies, and other ADCs; maybe it's because of the immune response native to Trastuzumab and the specificity of released antigens to just tumor cells (instead of a mix of normal cells and tumor cells as with taxanes) once some tumors have been killed.

  6. It is my understanding [based on this study] that this particular toxin-conjugated HER2 antibody induces so called "immunogenic" cell death and allows priming against mutant antigens released from dying cancer cells [ and once it is taken up by professional antigen presenting cells]. CTLA4/PD1 will then simply amplify this anti-cancer response.