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Tokuyasu et al. J Cancer Metastasis Treat 2018;4:2 I http://dx.doi.org/10.20517/2394-4722.2017.52 Page 13 of 24

A B

Figure 3. Origin of metastases. (A) TNM staging, closedly related to Halsted-Meyer theory of breast cancer progression, suggests that
remote metastases arise late in the progression of the primary tumor, with disseminating cells first traveling to the lymph nodes; (B) the
cancer dormancy hypothesis suggests that tumor cells disseminate early to remote sites and are then forced into a dormant state by
immune surveillance. These two alternatives can be distinguished in part by examining cell genomes to trace cell lineages

between adjuvant and therapeutic agent blurring. New adjuvants and combinations thereof show promise
and are proposed as the focus of clinical trials [194] .

Improved outcomes are being reported for combined checkpoint therapies, though at the cost of more
adverse events [195,196] . Even those withdrawing from combination treatment due to severe adverse events may
still be receiving benefit [197] . Emens et al. [198] present a list of clinical development priorities to push forward
the state of the cancer immunotherapy art.

The literature on combination therapies is expanding rapidly. Dunn and Rao [199] have reviewed the
combination of epigenetics and immunotherapies. Increasing attention is being paid to traditional targets of
the innate immune system. Expression of endogenous viral peptides [200] and dsRNA have been shown to lead
to innate and adaptive responses. The role of microbes, both as commensal microbiota that are modulatory
targets [201] and as therapeutic agents [202] , are subjects of active research. The universe of immunomodulator
targets is rapidly growing [203] , expanding the scope of possible combinations.

We note that therapy modalities in combination are not necessarily additive, e.g. the combination of
chemotherapy (tyrosine kinase inhibitor) and a TAA vaccine required careful scheduling to avoid failure in
a mouse model [204] . A literature review of combination (mostly targeted) therapies in metastatic renal cancer
expresses both the promise and challenges of extracting benefit from such studies [205] . Careful reporting as
captured e.g. in the Consolidated Standards of Reporting Trials (CONSORT) guidelines [206] will be essential
for trial data to have maximum value.

MONITORING AND MODELING
Immunological research is increasingly driven by the ability to gather data, often in a high throughput
manner. This opens new vistas that will allow therapy to be properly targeted and monitored, and may
eventually alter the character of therapy itself.

The ease with which data can now be generated highlights the responsibility to employ best practices in
experimental and trial design, data acquisition (including patient metadata), and downstream analysis. The