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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 .
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