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Page 6 of 24 Tokuyasu et al. J Cancer Metastasis Treat 2018;4:2 I http://dx.doi.org/10.20517/2394-4722.2017.52

At the other end of the spectrum, CAR-T therapy does not rely on the host immune system for tumor
killing. These span so-called active to passive therapies. Passive therapies do not necessarily induce immune
memory, although T cell proliferation may allow extended response. The various immunotherapies can be
[59]
visualized in an informative hierarchy . The 2014 Society for Immunotherapy of Cancer (SITC) primer
[60]
provides an unhurried perspective on many of these developments .
[55]
While the current wave of immunotherapies was heralded by dendritic cell therapy (sipuleucel-T) , the
most notable breakthrough was probably the development of anti-CTLA4 checkpoint blockade, which
utilizes antibodies to block receptors that inhibit T cell activation. This treatment allowed some of the first
[61]
demonstrations in humans of the therapeutic efficacy of neoantigen-specific T cells . Checkpoint therapies
based on programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) blockade have
further demonstrated improved efficacy with reduced toxicity.

Impacts of immunotherapy on standard practice
The mainstream acceptance of cancer immunotherapy has stimulated efforts to modify clinical trial
[62]
reporting , with the introduction of “immune-related” adverse events (irAE) and response criteria (irRC).
Progression criteria must now allow for pseudo-progression, i.e. the appearance of growing or new lesions
that indicate T cell infiltration. A call for “assay harmonization” seeks to reduce variability in cellular immune
response reporting. Survival criteria must account for time-dependent hazard ratios, with agent-specific
delays in Kaplan-Meier survival curve separation ranging from four to eight months.

Clinical trial design itself is evolving, a process that began in response to targeted therapies (precision
[63]
oncology) and is now accelerating . This has seen the advent of expansion cohorts, and platform, bucket,
[64]
adaptive , and seamless trials. It will be increasingly important to understand the cohort and trial design to
interpret results.

[65]
We note in passing the recent reports of hyperprogression . Tumor size has been observed to dramatically
increase with anti-PD-1/PD-L1 treatment, although whether this is more than a statistical fluctuation has
[66]
been questioned . It is nevertheless safe to say immunotherapies behave differently than previous standard
therapies.
[67]
The effort to go beyond tumor cell-based staging has begun with the proposal of an Immunoscore ,
+
+
which quantifies the density of CD3 and CD8 T cells in solid tumors. Due to its prognostic value, it
[68]
has been proposed to augment traditional tumor size/nodal status/distant metastasis (TNM) staging .
Recent advances have triggered a reconsideration of the effect of conventional therapies (surgery,
chemotherapy, radiation) and of molecularly targeted therapies [69,70] . Oncogenes such as Myc have been found
to also regulate immune response. When such oncogenes are inactivated, immune response is restored and
[71]
plays a role in the subsequent “oncogene withdrawal” . Chemotherapy perhaps surprisingly also appears to
[72]
rely in part on the immune system for cytotoxic effect .

Cancer immunotherapies can in principle have much milder side effects compared to radiotherapy and
chemotherapy. In practice, they are associated with their own spectrum of adverse events [73,74] . In particular,
cytokine release syndrome (“cytokine storm”) can lead to organ failure and death. Both treatment efficacy
and adverse events are associated with proliferative and persistent cellular responses, which can vary
[75]
significantly between individuals, thus requiring careful monitoring . Adverse events associated with
neoantigen vaccines appear to be relatively mild, compared to adoptive cell transfer, checkpoint blockade,
[76]
and tumor-associated antigen (TAA) vaccine therapies .