1. DiGiulio, Sarah

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Cancer immunotherapies have led to some of the best outcomes when it comes to anticancer drugs. Except, that is, when they don't work.

Ton Schumacher, PhD.... - Click to enlarge in new windowTon Schumacher, PhD. Ton Schumacher, PhD

But new findings suggest there may be another way to make cancer immunotherapy drugs a lot more effective more of the time. The new study suggests some T cells from healthy donors may be able to specifically recognize neoantigens present on human tumors and mount effective attacks against those tumors (Science 2016;352:1337-1341).


"[The study] showed that neoantigen-specific T cells from healthy donors could recognize and kill melanoma cells harboring the relevant mutation in vitro," Mahesh Yadav and Lelia Delamarre, both of the Department of Cancer Immunology at Genentech, wrote about the new research in an accompanying editorial (Science 2016;352:1275-1276). "The findings point to a new individualized approach for expanding immunotherapies."


The difference between this approach and previous T-cell therapies, they argue, is that this approach might be a way to systematically identify allogeneic T-cell receptors directed against neoantigens to build effective therapies.


"A systematic approach for identifying immunogenic neoantigens in a high-throughput manner is needed to advance neoantigen-based approaches in cancer immunotherapy. The findings of Stronen et al. now put us more firmly on that path," they write about the new research.


The approach has only been tested in the lab, so much more research is still needed to know if and/or how well the approach will work in developing new cancer drugs.


Study author Ton Schumacher, PhD, Senior Member at the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital and Professor of Immunotechnology at Leiden University, told Oncology Times more about the research and why it might be so promising.


1 For oncologists without expertise in translational research, what are neoantigens and what do they (or might they) play in cancer immunotherapies?

"Recent research by others and us has shown that the DNA damage that, on the one hand leads to oncogenic transformation, also leads to the formation of aberrant peptides (neoantigens) that can be recognized by T cells. T-cell recognition of such neoantigens appears to explain much of the clinical activity of the cancer immunotherapies, such as PD-1 blockade, that are now revolutionizing cancer treatment for a number of human malignancies.


"A surprising finding in the prior research on T-cell recognition of neoantigens has been that in most patients the number of neoantigens to which a T-cell response is mounted is very modest, even for tumors with large amounts of DNA alterations. Here we wanted to determine whether the T-cell based immune system might perhaps not respond to 'all that is foreign' on the tumor cells.


"To address this, we first determined which neoantigens would be predicted to be present on the tumors of three patients. We then showed that the vast majority of these predicted neoantigens were not seen by T cells from the patients. But, when we used T cells from healthy donors, we could induce T-cell recognition of a large set of these neoantigens in an in vitro system.


"The research can be seen as further evidence that even though tumors arise from our own tissues, the DNA damage that they often carry offers an opportunity for attack by the immune system, and that therapies that aim to exploit this 'foreignness of human cancers' are of high interest."


2 So how do these findings change the way researchers currently think about immunotherapies?

"The key finding of our research is that there are many tumor antigens on human melanoma that can be recognized by T cells, but to which the T-cell pool of the patient did not mount a measurable response. These data thereby indicate that it should be feasible to broaden the tumor-specific T-cell response in cancer patients.


"Most current cancer immunotherapies rely on the endogenous T-cell pool of the patient to recognize cancer cells. The current data suggest it may actually be feasible to exploit an 'outsourced immune response,' using T cells from healthy donors as a starting point, to boost tumor-specific immunity."


3 This study looked at melanoma cells. How broadly do you expect this approach to work outside of melanoma?

"We expect that this approach may also be effective for other tumor types with similar amounts of DNA damage, such as lung cancer or bladder cancer


"The next step [of our research] is to further optimize the technology we have developed to create neoantigen-specific T-cell responses in vitro and to develop efficient strategies to transfer the neoantigen specific T-cell responses from these T cells into patient T cells. Together, this would allow us to test the concept within the clinic."