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RESISTANCE AND ESCAPE
The fact that immunotherapies fail to produce durable responses in a majority of patients has spurred
intensive investigations of resistance. Both primary resistance, where no beneficial response is observed, and
secondary resistance, where initial benefit is followed by relapse, are observed.

Before proceeding, we first ask why neoantigen vaccines work at all, as they would appear catastrophically
prone to failure due to antigen loss. Such loss has been seen in checkpoint blockade therapy, where both
chromosomal deletion of clonal neoantigens and negative selection of tumor subclones were observed [148] .

Accumulating evidence suggests part of the answer lies in the phenomenon of antigen spreading, aka
cascade [149] . T cells are initially “instructed” by the vaccine epitopes, but effector activity need not be limited
to these. This hypothesis suggests that the role of the vaccine is to nucleate immunity to an iteratively
growing cascade of antigens, the epitopes of which are then committed to T cell memory. This could be key
to a durable response that can also target new tumor mutations. The time required to generate such a cascade
could also explain the lag often seen between vaccine administration and objective response. A related
idea suggests that the initial vaccine-induced attack reverses immuno-suppressive mechanisms, allowing
[79]
preexisting CTLs that already recognize other tumor neoantigens to be unleashed in a cascade .

Cancers can resist therapy by circumvention of each of the immune system roles mentioned previously:
• Disrupt presentation:
 Inhibit MHC-I expression [150-152] ;
 Disrupt dendritic cell trafficking to lymph nodes (i.e. T cell priming);
 Disrupt peptide processing;
 Disrupt recognition (prevent T-cell trafficking from lymph nodes back to tumor [153] , exploit holes in TCR
repertoire);
• Exploit immune suppressive mechanisms.

In addition, tumor cells employ explicit defense mechanisms, e.g. downregulation of pro-apoptotic pathways,
and counterattack by secreting FasL death ligands, resulting in CTL death [153] .

The tumor microenvironment (TME), i.e. the nearby cellular, vascular, and extracellular matrix environment
remodeled by the tumor, is the focus of much research into resistance [154] . Here tumors are seen to induce
[155]
host self-protective mechanisms, through recruitment of suppressive cells such as MDSCs , regulatory T
cells [156] , and tumor associated macrophages [157] . The tumor creates an immune privileged site, akin to the eye
and brain, that excludes T cells [158] . Recent work provides a detailed picture of effector T cell exclusion based
on a b-catenin signaling mechanism [159] .

The TME is a metabolically demanding place, with competition for oxygen and nutrients [160-162] . Tumor cells
can outlast T cells through the induction of T cell anergy or exhaustion, part of a class of phenomena termed
T cell dysfunction [10,162,163] . There also remains the possibility that the tumor simply grows faster than an often
aged and weakened immune system can eliminate it. A careful 2011 discussion of the TME in which CTLA4
operates is given by Quezada et al. [164] .

As antigen-specific vaccines seek to activate the adaptive system, harnessing the innate immune system,
and in particular natural killer (NK) cells [165-167] , would appear to be an attractive complementary approach.
+
Unlike naive CD8 T cells that require time to acquire cytotoxic activity, NK cells are “ready to kill” [168] . NK
and dendritic cells engage in mutual activation, and the former can “edit” the latter population [169] . Inhibitory
receptors that bind MHC-I allow NK cells to recognize and eliminate cells that do not present MHC-I, thus
closing one avenue of tumor cell escape. The activating receptor NKG2D has attracted particular interest, as